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Crohn’s disease from past to present: Research trends and global outcomes with scientometric analysis during 1980 to 2022

Karabulut, Alpaslan MD a,* ; Kaya, Muhammed MD b

a Faculty of Medicine, Department of Internal Medicine, Hitit University, Çorum, Turkey

b Faculty of Medicine, Department of Gastroenterology, Hitit University, Çorum, Turkey.

Received: 12 June 2023 / Received in final form: 11 July 2023 / Accepted: 27 July 2023

This article does not contain any studies with human participants or animals performed by any of the authors.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Karabulut A, Kaya M. Crohn’s disease from past to present: Research trends and global outcomes with scientometric analysis during 1980 to 2022. Medicine 2023;102:35(e34817).

* Correspondence: Alpaslan Karabulut, Faculty of Medicine, Department of Internal Medicine, Hitit University, Çorum 19000, Turkey (e-mail: [email protected] ).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Currently, there is no comprehensive bibliometric study in the literature on Crohn’s disease (CD). The aim of this study was to analyze articles published on CD using bibliometric and statistical methods. The aim was to identify current research trends, show global productivity, and determine important players such as countries, journals, institutions, and authors. A total of 16,216 articles published on CD between 1980 and 2022 were analyzed using various statistical and bibliometric methods. Bibliometric network visualization maps were used to perform trend topic analysis, citation analysis, and international collaboration analysis. Spearman’s correlation coefficient was used for correlation analysis. The top 3 contributing countries to the literature were the United States of America (USA) (n = 4344, 26.7%), the United Kingdom (UK) (n = 2036, 12.5%) and Germany (n = 1334, 8.2%). The most active institutions were Udice French Research Universities (n = 696), Assistance Publique Hopitaux Paris (n = 570), and Institut National de la Sante et de la Recherche Medicale Inserm (n = 479). The most productive journals were Inflammatory Bowel Diseases (n = 1100), Journal of Crohn’s & Colitis (n = 579), and Gut (n = 510). The most prolific author was Colombel JF. (n = 290). The most frequently researched topics from past to present included infliximab, ulcerative colitis, surgery, pediatrics, adalimumab, magnetic resonance imaging, inflammation, perianal CD/perianal fistula, azathioprine, magnetic resonance enterography, small bowel, stricture/strictureplasty, recurrence, therapy/treatment, ustekinumab, mucosal healing, biomarkers, fistula, quality of life, ultrasonography, epidemiology, capsule endoscopy, laparoscopic surgery/laparoscopy, endoscopy, disease activity, postoperative recurrence, and the Nucleotide Binding Oligomerization Domain Containing 2 gene. We have seen an exponential increase in worldwide publications on CD. In recent years, the major research topics related to CD have been ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. We determined that countries with large economies, particularly the United States, United Kingdom, Germany, France, Canada, Italy, Japan and China, have taken the lead in research contributions to the development of CD literature.

1. Introduction

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology that is thought to result from the interplay of environmental factors in genetically predisposed individuals. [ 1 , 2 ] CD is a disease characterized by progressive intestinal damage and disability. It can affect individuals of all ages, from children to the elderly, leading to significant morbidity and diminished quality of life. [ 3 ] Patients are often hospitalized with clinical symptoms such as abdominal pain, fever, signs of intestinal obstruction, and bloody or mucopurulent diarrhea, or a combination thereof. [ 4 ] Chronic diarrhea is the most commonly observed symptom. [ 5 , 6 ]

The underlying pathology of CD is thought to be due to a dysfunctional interaction between the human immune system and the symbiotic intestinal commensal microbiota. [ 4 ] Genetic studies and in silico meta-analyses have identified and confirmed 71 susceptibility loci for CD on 17 chromosomes thus far. [ 7 ] The identification of susceptibility loci has provided important insights into the dysfunctional pathways of the intestinal immune system, contributing to our understanding of the etiopathogenesis of the disease. [ 4 ] Studies conducted in individuals with CD have demonstrated clustering and decreased biodiversity of Firmicutes and Bacteroidetes species, which are beneficial for intestinal health. A reduction in Faecalibacterium prausnitzii (a Firmicute) has been associated with an increased risk of postoperative recurrence in ileal CD. [ 4 , 8 ]

There is no single gold standard method for diagnosing CD. The diagnosis is usually made by a combination of clinical assessment, endoscopy, computed tomography and magnetic resonance imaging (MRI) enterography or enteroclysis, ultrasound, and biomarkers such as C-reactive protein and the stool granulocyte proteins lactoferrin and calprotectin, or their combinations. [ 4 , 6 ] In clinical studies, the Crohn’s Disease Activity Index (CDAI) is commonly used to select CD patients in clinical remission. CDAI index values of 150 and below are associated with disease remission, while values above indicate active disease. CDAI values above 450 are indicative of extremely severe disease. However, due to the limitations of the CDAI, objective data such as C-reactive protein < 10 mg/L, endoscopy, imaging, and even histology are increasingly needed to define disease remission. [ 6 , 9 ]

In a recent systematic review that included 147 incidence and prevalence studies, the highest reported CD prevalence was found to be 322 per 100,000 in Germany in Europe and 319 per 100,000 in Canada. Overall, 16 out of 22 CD-related studies in North America and Europe reported a stable or declining incidence of IBD, although since 1990, the incidence has been increasing in newly industrialized countries in Africa, Asia, and South America, including Brazil and Taiwan. [ 10 ] In a recent study in Sydney, the age-standardized rate for CD was reported as 166 cases per 100,000 populations (95% confidence interval [CI]: 141–192 cases). [ 11 ]

Since the exact etiology of CD is unknown, there is currently no curative treatment. [ 3 , 6 ] Existing treatments do not address the genetic basis of this chronic disease, leaving patients in need of long-term management. [ 4 , 12 ] Classifying patients based on prognostic risk factors and personalizing treatment are important steps to optimize patient care. Several factors, such as disease location, disease activity and severity, response to previous treatments, and presence of complications, influence the choice of medical treatment. [ 3 ] CD is classified based on disease phenotype (Montreal classification), disease activity (often based on CDAI), and response to treatment (steroid-resistant or steroid-dependent). [ 6 ]

Various agents are used for the medical treatment of CD, including mesalazine, locally acting steroids (such as budesonide), systemic steroids, thiopurines (such as azathioprine and mercaptopurine), methotrexate, and biologic therapies (anti-tumor necrosis factor [anti-TNF] and anti-interleukin agents). [ 3 ] Effective drugs for maintaining remission in CD are known, including azathioprine, infliximab, adalimumab, and vedolizumab. There is also sufficient evidence to support the use of ustekinumab, methotrexate, certolizumab, and natalizumab. [ 6 ]

The specific indications for surgical intervention at CD include abscesses, complex perianal or internal fistulas that are unresponsive or poorly responsive to medical treatment, fibrostenotic strictures with symptoms of partial or complete intestinal obstruction, high-grade dysplasia, and cancer. [ 4 , 12 ]

In recent years, the scientific literature has grown rapidly with the development of online publishing and advances in technology. Also, the increasing number of articles, bibliometric studies have been conducted in various medical fields and have become a widely used quantitative research method for evaluating the literature. [ 13 , 14 ] Bibliometrics provides comprehensive analysis and structured information about a specific topic, research area, institution, or country, assisting in the identification of important insights for future research. [ 15 , 16 ] Currently, there is no comprehensive bibliometric study available in the literature focusing on CD. This study aims to analyze articles published between 1980 and 2022 using bibliometric and statistical methods in the field of CD. The aim is to uncover current research trends, determine global productivity, and identify key players such as countries, journals, institutions, and authors.

2.1. Search strategy

Web of Science (WoS) (Clarivate Analytics, Philadelphia, PA, USA) was used to search for publications indexed in CD between 1980 and 2022,. The search strategy used in this study was as follows: [(Title = (crohn disease*) OR Title = (crohns disease*) OR Title = (crohn’s disease*)] AND [Document Type = (Article) AND Publication period: 1980–2022)]. This search strategy was used to access all studies that contained any of the phrases “Crohn disease,” “Crohns disease,” or “Crohn’s disease” in their title (Articles were accesses on March 1, 2023). Only original articles were included in the bibliometric analysis, whereas other publication types were excluded.

2.2. Statistical analysis

Statistical analyses were performed with the SPSS package programme (Version: 22.0; SPSS Inc., Chicago, IL). Bibliometric analyses were performed using the VOSviewer package programme (Version 1.6.19; Leiden University). [ 17 ] VOSviewer is a software package used for visualizing and constructing bibliometric networks. These bibliometric networks can include researchers, journals, or specific publications, and they can be constructed based on citation, co-citation, or co-authorship relationships. VOSviewer also provides text mining capabilities to create and visualize co-occurrence networks of important terms from the scientific literature. Analysis of the co-occurrence of keywords is a bibliometric method used to map the research landscape. In bibliometrics, co-occurrence analysis is used to examine the potential relationship between 2 terms that appear in the same publication. It examines the presence of item pairs (keywords) that appears together in a document to determine the relationships between the terms presented in the text. There is a relationship between co-word analysis and co-citation analysis. While co-word analysis focuses on the keywords in the documents, co-citation analysis focuses on the citations. Co-citation analysis provides a method for mapping the structure of a research field through jointly cited pairs of documents. [ 13–17 ]

To predict article trends in CD for the next 5 years, the Smoothing Forecast function in Microsoft Office Excel was used. Seasonal adjustment was applied in the prediction model. The world map of countries’ contributions to the literature in the field of CD, presented as a color intensity graph, was obtained from the website https://app.datawrapper.de . The normality of the data was tested using the Kolmogorov–Smirnov test. The Spearman correlation coefficient was used to analyze the correlation between the number of articles from WoS and economic indicators obtained from the World Bank. [ 18 ] A significance level of P < .05 was considered statistically significant.

As a result of the literature search, we obtained 39,022 publications on CD. Out of these publications, 16,216 (41.6%) were articles, 15,478 (39.7%) were meeting abstracts, 2605 (6.7%) were letters, 1890 (4.8%) were review articles, 895 (2.3%) were proceeding papers, and the remaining were categorized as other publication types such as editorial material, notes, biographical articles, book chapters, etc. Only the 16,216 articles were included in the bibliometric analyses. Almost all articles, 92% (n = 14,925), were indexed in SCI-expanded, and 7.1% (n = 1152) were indexed in ESCI. The articles were predominantly published in English, 93% (n = 15,087), while the remaining articles appeared in other languages, including German (494), French (329), Spanish (157), Russian (55), Polish (28), Korean (22), Italian (13), Hungarian (8), Portuguese (7), Turkish (5), Japanese (4), Czech (3), Dutch (1), Estonian (1), Flemish (1), and Norwegian (1).

3.1. Prominent research areas on CD

The research areas with the highest number of published articles on CD (areas where at least 60 articles were flagged) are presented in Table 1 . The top research areas on CD are as follows, based on the number of articles and corresponding research fields where CD-related articles were extensively tagged: Gastroenterology Hepatology (number of articles = 9110), Surgery (1926), Medicine General Internal (1394), Pharmacology Pharmacy (795), Paediatrics (793), Radiology Nuclear Medicine Medical Imaging (726), Nutrition Dietetics (617), Immunology (563), Medicine Research Experimental (417), Multidisciplinary Sciences (320), Pathology (281), Genetics Heredity (235), Microbiology (229), Cell Biology (211), and Biochemistry Molecular Biology (210).

These research areas highlight the multidisciplinary nature of CD research, encompassing various medical specialties and scientific fields, including gastroenterology, surgery, internal medicine, pharmacology, pediatrics, radiology, nutrition, immunology, pathology, genetics, microbiology, cell biology, and biochemistry.

3.2. Publication trend of Crohn’s disease from past to future

Figure 1 shows a line graph depicting the historical and predicted publication trends of articles related to CD taking into account seasonal adjustments using the smoothing estimator. The model-generated results show that an estimated 972 articles (95% CI: 895–1050) related to CD will be published in 2023. Furthermore, it is predicted that the number of publications will increase to 1191 articles (95% CI: 871–1511) in 2027 ( Fig. 1 ).

3.3. Active countries in Crohn’s disease

Figure 2 shows a bar graph of the top 20 countries that have made the highest contributions to the literature on CD, as well as a world map is showing the countries’ contributions to the literature by color intensity. Among the 101 countries that have published articles on CD, the top 25 countries with more than 200 contributions are as follows: USA: 4344 articles (26.7%), UK: 2036 articles (12.5%), Germany: 1334 articles (8.2%), France: 1303 articles (8%), Canada: 1225 articles (7.5%), Italy: 1225 articles (7.5%), Japan: 970 articles (5.9%), China: 924 articles (5.6%), Spain: 761 articles (4.6%), Netherlands: 742 articles (4.5%), Belgium: 680 articles (4.1%), Israel: 493 articles (3%), Sweden: 454 articles (2.8%), Australia: 420 articles (2.5%), Denmark: 405 articles (2.4%), South Korea: 372 articles (2.2%), Switzerland: 299 articles (1.8%), Austria: 270 articles (1.6%), Poland: 252 articles (1.5%), and Greece: 209 articles (1.2%).

Among the 101 countries that published articles on CD, analysis of international collaboration was conducted and cooperation scores were calculated to determine the collaboration strength. The 10 countries with the highest collaboration scores are as follows: USA (Total collaboration score = 2810), England in UK (1911), Canada (1741), Germany (1674), Belgium (1602), France (1549), Netherlands (14,759), Italy (1411), Spain (1111), and Israel (953). Significant correlations were found between the number of articles published by countries on CD and their economic indicators, especially Gross Domestic Product (GDP) and GDP per capita ( R = 0.705, P < .001; R = 0.691, P < .001) respectively.

3.4. Prominent journals in CD research

All articles on CD were published by 1918 different scientific journals. The top 43 journals (publishing 50 or more articles), their total number of citations (NC) and the average NC per article are shown in Table 2 .

3.5. Prominent institutions in CD research

The following institutions have made significant contributions to the literature on CD with 300 or more articles: Udice French Research Universities: 696 articles, Assistance Publique Hopitaux Paris: 570 articles, Institut National De La Sante Et De La Recherche Medicale Inserm: 479 articles, Harvard University: 468 articles, Universite Paris Cite: 460 articles, University of California System: 418 articles, Katholieke Universiteit Leuven: 402 articles, University of London: 401 articles, Icahn School of Medicine at Mount Sinai: 385 articles, Mayo Clinic: 370 articles, University of Toronto: 357 articles, Cleveland Clinic Foundation: 350 articles, Universite De Lille: 336 articles, University of Amsterdam: 317 articles.

3.6. Active authors on CD

The active authors who have made significant contributions to research of CD by publishing 100 or more articles are listed below: Colombel JF. (290 articles), Sandborn WJ. (246 articles), Rutgeerts P. (233 articles), Vermeire S. (187 articles), Peyrin-biroulet L. (141 articles), Feagan BG. (136 articles), Schreiber S. (125 articles), Reinisch W. (111 articles), D’haens G. (108 articles), Li Y. (108 articles), Loftus EV. (106 articles), Louis E. (106 articles), Panaccione R. (102 articles).

3.7. Co-word analysis: past and current research trends on CD

To perform the co-word (or co-occurrence) analysis, a threshold of 40 (minimum number of occurrences of a keyword) was chosen in the VOSviewer package. This means that 77 different keywords were identified that were used together in at least 40 different articles. In a total 13,305 different keywords were used in all 16,216 articles published on CD. Table 3 shows 77 different keywords that were used in 40 or more articles. The results of the clustering analysis showing the association clustering of the keywords are shown in Figure 3 . The results of the clustering analysis show that the research on CD has 7 main foci. These foci, in order of cluster size, were as follows: the red cluster focused on diagnostic imaging techniques such as endoscopy, computed tomography, MRI enterography, ultrasound; the green cluster focused on mucosal healing, nutrition, and biomarkers; the blue cluster on therapeutic drug treatments; the yellow cluster on surgical treatments and complications; the purple cluster on genetic studies; the turquoise cluster on cellular aspects (apoptosis, autophagy, cytokines); and the orange cluster on perianal fistula. Additionally, through the analysis of co-occurrence of keywords, the development of research hotspots was identified. The visualization map of the trend network depicting the presence of keywords in past and current research is shown in Figure 4 . Using to the network map, we were able to identify 7 clusters of keywords representing important areas of interest at CD. The citation network visualization map showing the keywords in the most frequently cited articles is also presented in Figure 5 .

3.8. Citation analysis in CD

To perform the citation analysis, the “Documents” option was selected in the VOSviewer software package and a threshold of 1000 (minimum NC of a document) was chosen. Table 4 presents the publication information, total NC, and average NC per year for 28 influential articles with over 1000 citations selected from the 16,216 articles published on CD. The citation networks of the articles presented in Table 4 were shown in Figure 6A . Articles that did not have citation links with other studies were not shown in the map. Normalized citation values were used for weighting when determining the size of the circles in the network map. The normalized citation count of a document is obtained by dividing its citation count by the average citation count of all documents published in the same year. Normalization corrects for the fact that older documents have more time to receive citations compared to newer ones. [ 17 ]

3.9. Co-citation analysis in CD

For the analysis of co-citations, the “cited-references” option in the VOSviewer package was used, with a threshold of at least 200 citations for a cited reference. In this way, 86 studies were identified that were cited together in at least 200 different articles. The co-citation networks of the articles in CD research were presented in Figure 6B . Additionally, the 7 most influential studies, which were cited together in at least 700 different articles, were identified. In the reference section of all 16,216 articles published on CD, a total of 163,675 publications were cited. Among these publications, the 7 most influential studies with 700 or more co-citations were, in order: Best et al [ 9 ] (number of co-citations: 1463), Hanauer et al [ 19 ] (NC: 965), Harvey and Bradshaw [ 20 ] (NC: 778), Silverberg et al [ 21 ] (NC: 777), Satsangi et al [ 22 ] (NC: 718), Present et al [ 23 ] (NC: 708), and Targan et al (NC: 705). [ 24 ]

4. Discussion

When examining the article distribution in the field of CD between the years 1980 to 2022, 4 different publication trends were found: 1980–1995, 1996–2006, 2007–2019, and 2020–2022. During the period of 1980 to 1995, an average of 176 articles (minimum-maximum: 146–199) were published. Starting in 1996, the number of articles increased, and during the period of 1996 to 2006, an average of 308 articles (min–max: 244–407) were published. With the year 2007, a second increase in the number of articles began, and during the period of 2007 to 2019, an average of 570 articles (min–max: 417–709) were published. The increasing trend continued with the year 2020, and during the period of 2020 to 2022, an average of 867 articles (min–max: 830–900) were published. The results of the forecasts for the next 5 years, it is assumed that research on CD will continue to follow an exponential growth trend.

The top 25 countries in terms of global productivity from CD are mostly developed countries or countries with large economies such as India, China and Turkey. There is a high significant correlation between the number of articles related to CD, GDP, and GDP per capita of the countries, indicating that the economic indicators of the countries are also an influencing factor for the productivity of CD research. This effect has also been observed in the findings of correlation analyses conducted in various other research areas. [ 13–16 ] However, it is known that there are various factors beyond the economic development of countries that can influence the article productivity, such as prevalence rate, national medical burden, research infrastructure, investment and funding, scientific collaboration and networks, education and talent, scientific publishing and communication, and incentive and reward systems. One of the most important factors affecting the productivity of scientific articles in a country is having a strong research infrastructure. This infrastructure includes universities, research centers, laboratories, and other scientific institutions. Well-equipped laboratories, technological facilities, and financial resources that support researchers are important for article productivity. [ 25 ] Countries should provide adequate funding for research and development activities, support researchers, and invest in scientific projects. Well-funded projects can contribute to higher article productivity. [ 26 ] International scientific collaboration can increase article productivity. Collaboration and knowledge sharing among researchers across countries should be encouraged. Scientific networks promote collaborative research projects, conferences, and workshops, fostering scientific cooperation. [ 27 ] Well-educated and talented researchers are critical for scientific article productivity. Countries should focus on cultivating qualified human resources for scientific research and promoting scientific education. [ 28 ] It is important for a country to have accessible scientific journals for researchers to publish and share their work. The ease of access to scientific publications and the speed of publication processes can influence article productivity. Countries should develop a suitable system to promote scientific research and article productivity. Awards can provide incentives for researchers and recognize their scientific achievements. [ 29 ]

In terms of international collaboration, it was determined that the USA, Canada, and European countries (England, Germany, Belgium, France, Netherlands, Italy, Spain, Sweden, Denmark, Switzerland, Austria) are pioneers, along with Israel and Australia. Epidemiological studies related to IBD in the early 21st century indicate an increasing incidence in newly industrialized countries with westernization. [ 10 ] Although the disease incidence has stabilized in western countries, the prevalence has exceeded 0.3%, indicating the continued importance of CD. New research is needed to manage this complex and costly disease. [ 10 ] Epidemiological studies on IBD in many developing countries indicate an increase in both the incidence and prevalence of CD in different regions of the world. [ 30 ] When evaluating the findings of our study on the global productivity of CD, we believe that it is necessary to support research on CD in underdeveloped or developing countries as well.

In terms of contributing to the literature in the field of CD, the prominent journals were ranked as follows: Inflammatory Bowel Diseases, Journal of Crohn’s & Colitis, Gut, American Journal of Gastroenterology, Digestive Diseases and Sciences, Gastroenterology, Alimentary Pharmacology & Therapeutics, Scandinavian Journal of Gastroenterology, Journal of Paediatric Gastroenterology and Nutrition, Diseases of the Colon & Rectum, European Journal of Gastroenterology & Hepatology, World Journal of Gastroenterology, and Journal of Clinical Gastroenterology. These journals can be recommended as a priority for authors who want to publish their research in this field. When comparing the average NC per article published by these journals, the most influential journals were found to be Nature (1827), Nature Genetics (741), New England Journal of Medicine (688), Nature Medicine (494), Nucleic Acids Research (438), Cell Host & Microbe (426), Science (356), Proceedings of the National Academy of Sciences of the United States of America (343), Clinical Microbiology Reviews (324), Cell (315), Lancet (314), and Current Biology (305). We can suggest researchers who want their articles to have a greater impact to consider these journals.

Among all the articles, the most influential article in terms of total citations was determined to be the study titled “Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease” by Hugot et al, [ 2 ] published in Nature. The second most impactful study was “A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease” by Ogura et al, [ 1 ] also published in Nature. The third most effective study was the article “Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial” by Hanauer et al [ 19 ] published in The Lancet. The fourth and fifth most influential studies were the articles published by Sokol et al [ 8 ] in the Proceedings of the National Academy of Sciences of the United States of America and by Targan et al [ 24 ] in the New England Journal of Medicine.

The main findings of the articles by Hugot et al and Ogura et al are that the NOD2 gene predisposes to CD and there is a link between innate immune response to bacterial components and disease development. [ 1 , 2 ] These articles have contributed to our understanding of one of the pathophysiological mechanisms of CD. The main finding of the study by Hanauer et al is that Crohn’s patients who respond to an initial dose of infliximab have a higher likelihood of being in remission and discontinuing corticosteroids. [ 19 ] This article has contributed to our understanding that maintenance infliximab is a safe and well-tolerated treatment option in CD. The main finding of the study by Sokol et al is that Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified through intestinal microbiota analysis in CD patients. [ 8 ] This article has contributed to our understanding that the commensal bacterium Faecalibacterium prausnitzii can be used as a probiotic agent in CD treatment and holds promise for future CD therapies. The main finding of the study by Targan et al is that a single chimeric monoclonal antibody infusion, cA2, is an effective treatment for patients with treatment-resistant moderate to severe CD. [ 24 ] This study has provided information that chimeric monoclonal antibody therapy, which remains one of the most effective treatment methods today, was used as early as 1997.

The study that had the highest impact in terms of the average NC per year among all the articles was “The Treatment-Naive Microbiome in New-Onset Crohn’s Disease” by Gevers et al. [ 31 ] The second most efficient one was the one by Hugot et al. [ 2 ] The third most influential study was the one by Sokol et al. [ 8 ] The fourth most influential study was the consensus on the “Diagnosis and Management of Crohn’s Disease” published by Gomollon et al. [ 6 ] The fifth most influential study was the one by Ogura et al. [ 1 ] Noteworthy studies in recent years, based on the average NC per year, were “Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease” by Feagan et al [ 32 ] published in the New England Journal of Medicine and “ECCO Guidelines on Therapeutics in Crohn’s Disease” by Torres et al [ 3 ] published in the Journal of Crohn’s & Colitis.

According to the co-citation analysis conducted on all the analyzed articles, the notable high-impact studies based on the shared co-citation counts were Best et al, [ 9 ] Hanauer et al, [ 19 ] Harvey and Bradshaw, [ 20 ] Silverberg et al, [ 21 ] Satsangi et al, [ 22 ] Present et al, [ 23 ] and Targan et al. [ 24 ] We can recommend researchers interested in this subject to read these studies as a priority.

When evaluating the findings of the citation analysis network visualization map, it can be observed that articles with the highest NC form 5 distinct clusters based on total citation count ( Figure 6A ). These clusters are related to microbiota (blue cluster), biological drug treatments for CD (red cluster), CD and its treatment (yellow cluster), pathophysiological mechanisms (purple cluster), and genetics (green cluster).

In the co-citation analysis of the CD topic, it is seen that it forms 4 distinct clusters ( Figure 6B ). These clusters are related to the effects of biological drugs on treatment (yellow cluster), general IBD (blue cluster), CD diagnosis, monitoring, and classification (red cluster), and CD surgery (green cluster).

When considering the citation and co-citation analyses, it is evident that research on CD has focused on surgical and drug treatments, activity indices, diagnosis, monitoring and classification, microbiota, pathophysiological mechanisms, and the genetic dimension from the past to the present.

According to the keyword analysis, the most extensively studied topics in the field of CD from the past to the present (with at least 100 different articles) were infliximab, ulcerative colitis, surgery, pediatrics/children, adalimumab, MRI, inflammation, perianal CD/perianal fistula, azathioprine, magnetic resonance enterography, small bowel/small intestine, stricture/strictureplasty, recurrence, therapy/treatment, ustekinumab, mucosal healing, biomarkers, fistula, quality of life, ultrasonography/ultrasound, epidemiology, capsule endoscopy, laparoscopic surgery/laparoscopy, endoscopy, disease activity, postoperative recurrence, and NOD2.

According to the cluster analysis findings, it was determined that CD research has 7 main focal points. The main focal points, where the literature studies clustered, were imaging techniques, surgery and complications, genetic studies, perianal fistula, treatments with a particular emphasis on therapeutic drugs, mucosal healing/nutrition/biomarkers and cells.

The most cited keywords from the past to the present were abscess, genetics, caspase recruitment domain-containing protein 15, treatment, cytokines, perianal CD, budesonide, microbiota, ulcerative colitis, inflammation, and strictureplasty.

According to the findings of the keyword analysis, 12 keywords were identified as the emerging trends. The trending topics studied in recent years were ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. This indicates the latest developments in CD treatments. The trend keyword analysis shows us the focus areas of CD treatment in the past and present. Before 2014, the main areas of focus were CD complications, surgery, and postoperative complications. However, after 2016, topics related to CD diagnostic methods and medical treatment regimens became the primary research points. We anticipate that in future research, medical treatments will replace surgery and complication studies as the main focus in CD treatment.

There is no specific bibliometrics study published so far for the overall topic of CD in the literature. Only the studies by Kostoff [ 33 ] and Schöffel et al [ 34 ] related to CD were found. Kostoff attempted to identify text-based common factors for Parkinson’s disease and CD. [ 33 ] Schöffel et al [ 34 ] did not include recent publications after 2013. One of the strengths of this research is that it is the first comprehensive and up-to-date bibliometrics study conducted on the subject of CD. In our study, we preferred to search only the WoS database because citation analyses cannot be performed in the PubMed database. The Scopus database also indexes articles published in lower impact journals that are not included in the SCI-expanded or ESCI indexes. [ 13–16 , 35 ] A second limitation of our study is that descriptive statistics were provided only for the number of articles published by journals, institutions, and authors, without qualitative evaluation. However, since the primary aim of this study was trend keyword, co-word, and co-citation analysis, qualitative evaluation of journals, institutions, and authors was not conducted. Therefore, a higher number of articles does not necessarily imply better quality for authors and institutions in this study, as the focus was primarily on quantitative analysis.

5. Conclusions

This study demonstrates the general trends in scientific research on CD. We identified an exponential increase in global publications. In recent years, the trending research topics related to CD are ustekinumab, vedolizumab, fecal calprotectin, therapeutic drug monitoring, biologics, biomarkers, exclusive enteral nutrition, microbiome/microbiota, magnetic resonance enterography, anti-TNF, postoperative complications, and mucosal healing. We determined that countries with significant economies, especially the USA, UK, Germany, France, Canada, Italy, Japan, and China, have research leadership in the development of CD literature. This study can provide researchers with new ideas for future studies on CD.

Author contributions

Conceptualization: Alpaslan Karabulut.

Data curation: Alpaslan Karabulut, Muhammed Kaya.

Formal analysis: Alpaslan Karabulut, Muhammed Kaya.

Investigation: Alpaslan Karabulut, Muhammed Kaya.

Methodology: Alpaslan Karabulut, Muhammed Kaya.

Resources: Alpaslan Karabulut, Muhammed Kaya.

Software: Alpaslan Karabulut, Muhammed Kaya.

Supervision: Alpaslan Karabulut, Muhammed Kaya.

Visualization: Alpaslan Karabulut.

Writing – original draft: Alpaslan Karabulut, Muhammed Kaya.

Writing – review & editing: Alpaslan Karabulut, Muhammed Kaya.

Abbreviations:

• Cited Here |
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• Google Scholar
• PubMed | CrossRef |
• View Full Text | PubMed |
• View Full Text | CrossRef |

bibliometric analysis; citation analysis; Crohn’s disease; research trends; scientometric analysis

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Small bowel cancer in crohn’s disease.

Simple Summary

1. introduction, 2. materials and methods, 3.1. epidemiology, 3.2. etiopathogenesis, risk factors, and molecular characterization, 3.3. clinical presentation and diagnosis, 3.4. prognosis, 3.5. the role of immunosuppressants and advanced therapies in crohn’s disease-associated small bowel cancer, 4. discussion, 5. conclusions, author contributions, conflicts of interest.

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Faggiani, I.; D’Amico, F.; Furfaro, F.; Zilli, A.; Parigi, T.L.; Cicerone, C.; Fiorino, G.; Peyrin-Biroulet, L.; Danese, S.; Allocca, M. Small Bowel Cancer in Crohn’s Disease. Cancers 2024 , 16 , 2901. https://doi.org/10.3390/cancers16162901

Faggiani I, D’Amico F, Furfaro F, Zilli A, Parigi TL, Cicerone C, Fiorino G, Peyrin-Biroulet L, Danese S, Allocca M. Small Bowel Cancer in Crohn’s Disease. Cancers . 2024; 16(16):2901. https://doi.org/10.3390/cancers16162901

Faggiani, Ilaria, Ferdinando D’Amico, Federica Furfaro, Alessandra Zilli, Tommaso Lorenzo Parigi, Clelia Cicerone, Gionata Fiorino, Laurent Peyrin-Biroulet, Silvio Danese, and Mariangela Allocca. 2024. "Small Bowel Cancer in Crohn’s Disease" Cancers 16, no. 16: 2901. https://doi.org/10.3390/cancers16162901

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Latest Crohn's Research

Crohn's disease can be a frustrating cycle of diarrhea, belly cramps, and constipation. There's still a lot we don't know about this long-lasting inflammatory disease. But for the 3 million Americans living with Crohn's, the latest research sends a message of hope. Scientists are getting a better understanding of what triggers Crohn's disease and how diet can make it worse (or better). They're also studying new ways to find, track, and treat it.

Predicting and Preventing Crohn's Disease

In their search for ways to prevent Crohn's, researchers have looked at everything from diet to things in the environment.

A typical "Western" diet, high in calories, saturated fat , and sugar, increases inflammation in your gut. And inflammation could trigger bowel diseases. This type of diet also throws off the gut microbiome. That's is a careful balance of bacteria and other tiny organisms found in your intestines.

A Harvard University study found that people who ate lots of foods linked to inflammation were at higher risk of getting Crohn's. These foods include processed meat, sweets, and refined grains like white bread.

Early research hints that fructose, a type of sugar often found in sweetened drinks and processed foods, might be a problem. A study in mice found that a high-fructose diet could make symptoms of inflammatory bowel diseases ( IBD ) like Crohn's worse.

But a Mediterranean diet, high in fruits, vegetables, beans, and nuts, could have the opposite effect. It may reduce inflammation and improve Crohn's symptoms . One small study offered a possible environmental clue why Crohn's and other types of IBD are on the rise. Researchers analyzed the baby teeth of 30 adults in Portugal, where there's a tradition of saving these teeth. Those whose teeth showed they'd been exposed to lead, copper, zinc, and chromium soon before and after birth were more likely to have Crohn's.

Another study indicated that blood tests could someday show who's likely to get Crohn's, years before symptoms show up.

Researchers found 51 characteristics (called biomarkers) in blood that were 76% accurate at predicting whether someone would get Crohn's, 5 years before their diagnosis. Understanding the body processes that lead to Crohn's could help scientists find ways to prevent or delay it.  

Expanding Treatment Options

There's still no cure for Crohn's. But researchers are looking at lots of new drugs, especially anti-inflammatory biologics. These are complicated mixtures grown in a lab. They stop proteins in your body from creating inflammation.

Some drugs they're studying focus on your T-cells, white blood cells that are an important part of your immune system . Others stimulate your natural immunity or use prebiotics to change your gut bacteria. Prebiotics are plant fibers that help healthy bacteria grow.

Other researchers have focused on ways to treat Crohn's. In an approach called "tight control," doctors treat both Crohn's symptoms and the inflammation that causes them. One study showed that doing this early on helped heal the intestinal linings of people with Crohn's.

Some people in this study achieved what doctors call "deep remission ." That means they felt well and had no signs of disease activity.

Researchers looked at the same people again 3 years later. In those who'd reached deep remission, Crohn's disease was much less likely to have gotten worse. This was true even if they didn't use the tight control method.

Other Findings

Scientists recently learned more about why abdominal fat sometimes gets into the intestines of people with Crohn's. This process is called "creeping fat." It can lead to intestinal scars that require surgery.

Researchers found that creeping fat happens when bacteria called Clostridium innocuum leak from the small intestine, which has been damaged by Crohn's. They think the fat wraps around your intestine to keep the bacteria from getting into your bloodstream, where it could do harm. But the creeping fat itself ends up causing problems.

This finding could someday lead to new therapies that target C. innocuum. They might prevent creeping fat or reduce its damage.  

Researchers are also looking at a possible way to predict and track Crohn's flare-ups . They're testing a wearable device that monitors biomarkers in your sweat. You wear it around your wrist like a watch. Scientists hope the device could help people gain more control over this unpredictable condition.

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Crohn's disease: a review of treatment options and current research

Affiliations.

• 1 Georgia Regents University, Medical College of Georgia, Augusta, GA, United States. Electronic address: [email protected].
• 2 Emory University School of Medicine, Atlanta, GA, United States.
• 3 Georgia Institute of Technology, Coulter Department of Biomedical Engineering, Atlanta, GA, United States.
• PMID: 24321565
• DOI: 10.1016/j.cellimm.2013.11.003

Crohn's disease is an autoimmune disorder that affects nearly 1.4 million Americans. The etiology of Crohn's disease is not completely understood, however, research has suggested a genetic link. There is currently no known cure for Crohn's disease and, as a result, most government-funded research is being conducted to increase the quality of life of afflicted patients (i.e. reducing chronic inflammation and alleviating growth impairment in pediatric patients). A number of treatment options are available including an alpha-4 integrin inhibitor and several TNF-alpha inhibitors. Furthermore, research is being conducted on several alternative treatment options to help understand exactly which cellular mechanisms (i.e. inducing apoptosis in leukocytes) are required for clinical efficacy. This review seeks to chronicle the current available treatment options for patients affected by Crohn's disease to aid in understanding potential cellular mechanistic requirements for an efficacious drug, and shed light on potential options for future treatment.

Keywords: Crohn’s disease; DC; IL; TNF; TNF-alpha blocker; dendritic cell; interleukin; tumor necrosis factor.

Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

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Single-cell analysis of Crohn’s disease reveals a detailed picture of inflammation in the gut

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Researchers at the Broad Institute of MIT and Harvard and Massachusetts General Hospital have constructed a high-resolution cellular map of Crohn’s disease, a chronic condition in which a hyperactive immune system causes inflammation throughout the gut, leading to symptoms including abdominal pain, diarrhea, and weight loss. The disease is difficult to treat and often requires hospitalization.

The atlas is the largest study of single cells from Crohn’s patients to date, and contains the gene expression profiles of more than 700,000 cells from 71 healthy individuals and patients in varying states of inflammation.

Published today in Immunity , the findings offer a detailed cellular portrait into the biological processes underlying Crohn’s that are unique to the small and large intestines. The data also reveal genes and pathways involved in complications of the disease, which could one day be targeted by new drugs. Moreover, the results could help researchers predict and ultimately prevent flares of symptoms, or understand why some patients respond to treatments and others don’t.

“We’re beginning to see that Crohn’s disease is not one disease, and that it has many subtypes,” said Ramnik Xavier , senior author of the study, core institute member and director of the Klarman Cell Observatory at the Broad. Xavier is also the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital, and co-director of the Center for Microbiome Informatics and Therapeutics at MIT. Lingjia Kong, a research scientist in Xavier’s lab, was the study’s first author.

“We really wanted to build a resource for the field,” said Jacques Deguine, an author on the study and the associate director of the Immunology Program at the Broad. “There have been atlases across a range of diseases, but now our field has grown enough that we can start tackling these questions in complex diseases, involving different organs. This is moving the needle towards an individualized understanding of biology.”

Inflammation insights

Previous genetic studies have identified more than 200 places in the genome linked to Crohn’s. But Xavier’s team knew that to fully understand the disease, they’d need a cellular map that captured its full complexity. They studied inflamed and non-inflamed cells from both segments of the gastrointestinal tract: the large intestine and the ileum, the last segment of the small intestine that is often affected in Crohn's disease.

The scientists used single-cell RNA sequencing to analyze gene activity in the individual gut cells. They found that immune cells and the stroma — the cells inside the gut that shape and support underlying connective tissue — changed in composition during disease. The lining of the intestines showed more changes in gene expression, with some changes unique to the large or small intestine. They also found that expression of genes previously linked to disease risk was distinct in each organ.

“I think this really lays the foundation for understanding why Crohn’s disease inflammation manifests in one organ versus another, and how some treatments might influence different disease subtypes differently,” Deguine said.

Towards personalized medicine

About 50 to 60 percent of Crohn’s patients respond to drugs and some experience a relapse of symptoms. Xavier said this suggests that Crohn’s is caused by a variety of biological mechanisms requiring treatments that are tailored to individual patients. He and Deguine added that many of their team’s findings point towards possible targets for personalized treatments. For instance, they identified three genes involved in collagen production that likely contribute to scar tissue in the gut, making the intestines stiffer and less able to pass along food — a common complication of Crohn’s.

To their surprise, the researchers discovered that Crohn’s patients had certain gene expression signatures even when their tissues didn’t look inflamed. This could indicate that there are detectable signs of disease even when the tissue appears to be healed on an endoscopy. Understanding the pathways that contribute to low-grade inflammation could help predict when symptoms will flare.

In the future, Xavier’s team plans to extend their atlas by collecting samples from patients of a range of ancestries. Deguine also hopes to study patients before and after different treatments to track how their disease progresses. 

“These projects are collaborative studies that include patients, clinicians, clinical coordinators, data generators, and computational biologists,” said Xavier. “It’s becoming clear that this is how biology needs to be done to have a real impact on human disease.”

This work was supported in part by The Helmsley Charitable Trust and the National Institutes of Health.

Paper(s) cited:

Kong L et al. The landscape of immune dysregulation in Crohn’s Disease revealed through single-cell transcriptomic profiling in the ileum and colon . Immunity . Online January 30, 2023. DOI:10.1016/j.immuni.2023.01.002.

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Rates of Crohn’s and Colitis have been vastly underestimated for decades, says new study

New research, led by experts at the University of Nottingham, shows that the number of people in the UK living with Inflammatory Bowel Disease (IBD) - the two main forms of which are Crohn's Disease and Ulcerative Colitis - has been vastly underestimated for years, and the rates are growing. [1]

Crohn's Disease and Ulcerative Colitis are both serious, life-long conditions that involve inflammation of the gut. They can cause debilitating pain and can have a huge impact on people's mental wellbeing due to the impact of their symptoms. Patients can also be at higher risk of bowel cancer and up to 80% of people with Crohn’s Disease and 15% of those with Ulcerative Colitis will need to have surgery at some point in their lives. There is no known cure for either condition. [2] [3]

The research, which was carried out by scientists at the University of Nottingham and funded by Crohn’s & Colitis UK and Coeliac UK, shows that the prevalence of Crohn’s and Colitis in the UK population is far higher than previously thought. The study shows there are over half a million people (1 in every 123) in the country living with inflammatory bowel disease, nearly double that of the 300,000 previously estimated, raising concerns about the capacity of the health service to provide the required care for thousands of people.

The research is the largest of its kind worldwide and measured the incidence (the diagnosis of new cases) and prevalence (the number of cases in the population in 2020) of Crohn’s and Colitis over the last 20 years. It gives the best picture so far of the scale of the problem across the country. [4]

Researchers analysed the health care records of 38.3 million people registered with GPs as part of a UK-wide study. It found that 0.81% of the population or one in every 123 people are living with Crohn’s or Colitis, increasing to one in every 67 for people in their 70s. Globally, this research puts the UK as second only to the US in terms of percentage of the population living with the condition and the problem is set to grow. [5]

Symptoms of Crohn's and Colitis include urgent and frequent diarrhoea (often with blood), abdominal pain, fatigue, and associated anxiety and depression. [6]

The causes of the conditions are unknown and some patients wait years to receive a diagnosis, meaning their symptoms could worsen and they potentially miss out on important treatment and care.[7]

People receiving treatment for Crohn’s or Colitis need specialist care and support from nurse specialists, dietitians and psychologists to help them manage the impact of their condition. Currently, and in part due to the underestimated prevalence, the health service is not equipped to manage this care adequately in any of the four nations.

IBD is unlikely to have reached its peak in the UK. This research estimates that the number of people living with the condition has grown to approximately half a million. It is a lifelong condition so it’s highly likely that the prevalence will continue to increase as the population ages. The associated complications, burden on individuals, capabilities of the healthcare system and other societal impacts of this all require serious consideration.” Dr Laila Tata, Associate Professor of Epidemiology in the School of Medicine at the University of Nottingham and lead researcher

Sarah Sleet, CEO at Crohn’s & Colitis UK and Chair of IBD UK said: “This study shows that there are nearly twice as many people living with Crohn's Disease and Ulcerative Colitis in the UK than previously thought, yet outdated figures mean the scale of the issue has been overlooked for too long. Lifetime costs for the NHS for treating these conditions are comparable to heart disease and cancer. They can have a profound impact on a person's life and patients need expert care from doctors, specialist nurses, dietitians, pharmacists and psychologists.

“It's crucial that the NHS recognises the scale of the growing numbers with Crohn’s and Colitis and does more to prevent lives being blighted for decades by these debilitating illnesses.”

Evelyn, 66 from Dorset said: “I had symptoms for over 3 years before I received my diagnosis. I was suffering pain, weight loss, sickness, and had been admitted to hospital several times. Yet doctors told me that it was psychosomatic and I wasn’t believed. I’ve now been living with Crohn’s for over 40 years, having tried years of different medications and had two bowel resections. It’s something you learn to live with, but even on good days I have near constant fatigue, frequent pain, and always have to think about where the nearest toilet is. The impact it has on your life is huge”.

The research found that the prevalence of Crohn's Disease and Ulcerative Colitis was lower in London compared to the rest of the UK and highest in Scotland. This could be due to a younger, urban population in London. The prevalence was also lower in more socioeconomically deprived areas and higher in people who declared their ethnicity as white compared with all other ethnicity groups. Researchers say this may have been due to lifestyle factors, although barriers to diagnosis likely account for most differences between groups, such as differences in awareness of the condition, suggesting a need for increased understanding of these barriers and public awareness of the conditions.[8]

Dr Tata added: “We need continued research to understand why we’re seeing inequalities in diagnosis.”

Dr Christian Selinger, Chair of the IBD Committee at the British Society of Gastroenterology, said:

“We have seen our workload in IBD increase over the years. The service is under strain as we have more patients and not enough staff. In terms of going forwards, we need to make a clear plea for investment in IBD services and the NHS, in order to deliver a high quality of care to patients and provide a better service.”

Story credits

[1] This research estimates that the number of people living with the condition has grown to over 540,000.

[2] https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/surgery-for-crohns-disease

[3] https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/surgery-for-ulcerative-colitis

[4] The study was based on health care records from 38.3 million people registered with GPs in the UK - a larger source of patient information than any previous research in this area.

[5] Globally, this puts the UK as second only to the US in percentage of the population living with the conditions, although lack of similar research elsewhere in the world may be hiding high numbers in other countries.

[6] https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/crohns-disease https://www.crohnsandcolitis.org.uk/about-crohns-and-colitis/publications/ulcerative-colitis

[7] https://academic.oup.com/ecco-jcc/article-abstract/15/2/203/5871943?redirectedFrom=fulltext

[8] Prevalence for London was 0.64% while it was highest in Scotland at 0.97%

IBD UK is a partnership of 17 professional bodies, royal colleges and patient organisations working together to improve care and treatment for everyone affected by Inflammatory Bowel Disease. Their main aim is to ensure that everyone with IBD has consistent, safe, high-quality personalised care, whatever their age and wherever they live in the UK.

Crohn’s & Colitis UK is the UK’s leading charity for Crohn’s and Colitis. Right now, new research is revealing over 500,000 people in the UK are living with a lifelong disease that many people have never heard of. Because of the stigma and misunderstanding surrounding these diseases, thousands of people are suffering in silence. But they are not alone. We’re here for everyone affected by Crohn’s and Colitis.

We’re working to improve diagnosis and treatment, and to fund research into a cure; to raise awareness and to give people hope, comfort and confidence to live freer, fuller lives.

• To drive world-class research that improves lives today and brings us closer to a world free from Crohn’s and Colitis tomorrow
• Everyone to understand Crohn’s and Colitis
• To support and empower everyone to manage their conditions
• To drive high-quality and sustainable clinical care
• Early and accurate diagnosis for all

Notes to editors:

About the University of Nottingham

Ranked 32 in Europe and 16th in the UK by the QS World University Rankings: Europe 2024 , the University of Nottingham is a founding member of the Russell Group of research-intensive universities. Studying at the University of Nottingham is a life-changing experience, and we pride ourselves on unlocking the potential of our students. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement.

Nottingham was crowned Sports University of the Year by The Times and Sunday Times Good University Guide 2024 – the third time it has been given the honour since 2018 – and by the Daily Mail University Guide 2024 .

The university is among the best universities in the UK for the strength of our research, positioned seventh for research power in the UK according to REF 2021 . The birthplace of discoveries such as MRI and ibuprofen, our innovations transform lives and tackle global problems such as sustainable food supplies, ending modern slavery, developing greener transport, and reducing reliance on fossil fuels.

The university is a major employer and industry partner - locally and globally - and our graduates are the second most targeted by the UK's top employers, according to The Graduate Market in 2022 report by High Fliers Research.

We lead the Universities for Nottingham initiative, in partnership with Nottingham Trent University, a pioneering collaboration between the city’s two world-class institutions to improve levels of prosperity, opportunity, sustainability, health and wellbeing for residents in the city and region we are proud to call home.

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Advances in endoscopic treatment for inflammatory bowel disease complications

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Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions affecting the gastrointestinal tract. These diseases can lead to various complications, including strictures, fistulas, and abscesses, significantly impacting patients' quality of life. Endoscopy plays a crucial role in diagnosing IBD, assessing disease activity, and monitoring treatment response. In recent years, advances in operative endoscopy have introduced novel strategies for managing IBD-related complications, particularly strictures and dysplastic lesions. This review summarizes the current endoscopic treatment approaches for IBD, highlighting their advantages and disadvantages.

Inflammatory bowel diseases and their complications

CD and UC are characterized by inflammation of the gastrointestinal tract, which can lead to irreversible structural damage. CD often presents with strictures, while UC affects gut integrity and increases the risk of colorectal cancer (CRC). Fibrotic strictures in CD and UC pose significant challenges for clinicians and often require surgical intervention. However, modern medical therapies have improved the natural history of IBD, particularly when initiated early.

Endoscopic treatment approaches

1. Strictures in IBD

Strictures in IBD are complex and can result from a combination of fibrosis and inflammation. The management of these strictures requires a tailored approach considering factors such as etiology, number, degree, shape, length, location, and associated conditions. Cross-sectional imaging modalities like ultrasound, CT, and MRI are valuable tools for diagnosing strictures and differentiating between fibrotic and inflammatory strictures. Anti-inflammatory medical therapy can reduce wall edema and intestinal wall thickness, while mechanical therapies, including endoscopic balloon dilation (EBD) and surgery, are primarily required for fibrotic strictures.

a. Endoscopic Balloon Dilation (EBD)

EBD is an effective technique for treating CD-related strictures, particularly those localized in the small bowel, ileocolonic, or colonic regions. EBD is best suited for accessible, short, and anastomotic strictures, with through-the-scope balloon catheters preferred due to their safety and ease of use. The dilation process involves inserting a balloon catheter through the stricture and inflating it under X-ray guidance, with the endoscopist determining the appropriate dilation diameter. Retrograde dilation is used for passable strictures, while anterograde dilation with wire-guided balloons is employed for non-passable strictures.

EBD offers short-term symptomatic improvement in the majority of patients, with a significant proportion avoiding surgery for extended periods. However, symptomatic recurrence is common, and the optimal technical details of EBD, such as balloon size and duration of insufflation, remain undefined.

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2. Management of dysplastic lesions

Dysplastic lesions in IBD patients, which may precede CRC, can be managed endoscopically. Techniques like endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) offer minimally invasive options for resecting dysplastic tissue. These techniques require expertise and careful patient selection, as they can be technically challenging and associated with complications. Nevertheless, they represent important tools in the management of dysplastic lesions in IBD.

Advantages and disadvantages of endoscopic approaches

Advantages :

• Minimally invasive, reducing surgery-related morbidity and mortality.
• Preserves bowel anatomy and function.
• Repeatable and can be performed as needed.
• Can be used to assess disease activity and progression.

Disadvantages :

• Technical challenges, particularly with complex strictures and dysplastic lesions.
• Risk of complications, including bleeding, perforation, and recurrence.
• Limited long-term data on efficacy and durability of endoscopic treatments.

Conclusions

Endoscopic treatment approaches have emerged as important tools in the management of IBD-related strictures and dysplastic lesions. While these techniques offer minimally invasive options, they also require expertise and careful patient selection. Future research is needed to refine technical details, optimize treatment strategies, and improve long-term outcomes. Endoscopic management of IBD should be approached by a multidisciplinary team involving gastroenterologists, radiologists, and colorectal surgeons, ensuring a patient-tailored approach that balances risks and benefits.

Xia & He Publishing Inc.

Barchi, A., et al . (2024). Endoscopic Treatment Approaches for Inflammatory Bowel Diseases: Old Friends and New Weapons.  Journal of Translational Gastroenterology . doi.org/10.14218/jtg.2023.00096 .

Posted in: Medical Procedure News | Medical Condition News

Tags: Adrenaline , Anatomy , Anti-Inflammatory , Bleeding , Cancer , Catheter , Catheters , Chronic , Colorectal , Colorectal Cancer , Crohn's Disease , CT , Edema , Efficacy , Endoscopy , Fibrosis , Gastroenterology , Gastrointestinal Tract , Imaging , Inflammation , Methylene Blue , Mortality , Research , Surgery , Translation , Ulcerative Colitis , Ultrasound , X-Ray

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Nutritional Treatment in Crohn’s Disease

Giacomo caio.

1 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; ti.efinu@islgnl (L.L.); [email protected] (F.C.); moc.oohay@aronoeleiloZ (E.Z.); [email protected] (F.G.); ti.efinu@trrrgd (R.D.G.)

2 Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy

3 Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy

4 Mucosal Immunology and Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA 02114, USA

Lisa Lungaro

5 Department of Internal Medicine, Santissima Annunziata Hospital, Cento (Ferrara), University of Ferrara, 44042 Ferrara, Italy

Fabio Caputo

Eleonora zoli, fiorella giancola, giuseppe chiarioni.

6 Division of Gastroenterology of the University of Verona, A.O.U.I. Verona, 37126 Verona, Italy; [email protected]

7 Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7080, USA

Roberto De Giorgio

Giorgio zoli.

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) which can affect any part of the whole gastrointestinal tract (from mouth to anus). Malnutrition affects 65–75% of CD patients, and it is now well acknowledged that diet is of paramount importance in the management of the disease. In this review, we would like to highlight the most recent findings in the field of nutrition for the treatment of CD. Our analysis will cover a wide range of topics, from the well-established diets to the new nutritional theories, along with the recent progress in emerging research fields, such as nutrigenomics.

1. Introduction

Nutrition has always had a marginal role in the management of Crohn’s disease (CD). A lack of dietary guidelines should be ascribed to the restricted time of clinical visits, to the scarcity of scientific data concerning the effect of alimentation on CD, and to the limited knowledge of nutrition [ 1 ]. However, in the past few years there has been a growing interest in nutrition as a critical factor for CD treatment. Awareness of the effects that the environment could exert on the disease pathogenesis, together with a better understanding of the microbiome and its functional role, have fueled scientific research on the impact that diet could have on gut health. This narrative review addresses the most recent dietary recommendations about the nutritional treatment of CD, considering also the latest contributions of emerging fields such as nutrigenomics, with the aim of informing gastroenterologists and improving the patients’ overall health condition.

2. Materials and Methods

The purpose of this narrative review is to describe the most recent findings in the nutritional treatment of CD. Three authors, L.L., G.C., and F.C., performed a comprehensive literature search on the electronic databases PubMed, EMBASE, MEDLINE, and Science Direct. Studies were assessed independently, following the narrative review checklist by the Academy of Nutrition and Dietetics. We considered the following terms for the literature search: “Crohn’s Disease”, “Nutritional treatment”, “Nutrition”, “Diet therapy”, “Nutritional strategies”, “Nutraceutical”, “Nutrigenomics”. The logical operators “AND” and “OR” were applied to combine different sets of results. The reference list of the collected papers was also considered to find any relevant articles. Included articles fulfilled the following criteria: (1) described nutritional approaches for the treatment of Crohn’s disease; (2) published in the last ten years (January 2010–December 2020); (3) written in English; (4) full text available. Articles not addressing the inclusion criteria or not pertinent were excluded.

3. Crohn’s Disease: Cause and Pathophysiology

CD is a chronic idiopathic inflammatory bowel disease that causes skip lesions and transmural inflammation from mouth to anus [ 2 ]. CD prevalence is increasing worldwide in adults and children, and its onset is often characterized by common presenting symptoms such as diarrhea, abdominal pain, rectal bleeding, fever, weight loss, and fatigue [ 3 ]. Endoscopy and cross-sectional imaging are the gold standard approaches used to establish a diagnosis and the extent of CD [ 3 ]. In addition, laboratory findings, such as thrombocytosis, C-reactive protein (CRP), and some stool markers, i.e., fecal calprotectin, are useful screening tests to assess the disease [ 4 ].

CD treatment is focused on the control of the inflammation and the induction of clinical remission; depending on the disease severity, it includes pharmacologic therapy based on 5-5-aminosalicylic acid/mesalazine up to corticosteroids to relieve symptoms. Patients at higher risk are treated with biologics, with or without concomitant immunomodulators, to induce and maintain remission [ 3 ]. In some patients, surgery is mandatory; however, in most cases, surgery is not completely effective, and medical therapy is needed to manage CD recurrence.

Although the exact etiology is still unknown, it is believed that the interplay between different factors such as genetic predisposition, environmental factors, microbiota dysbiosis, and defects affecting the innate immune system and the gut barrier functions can trigger the onset of CD [ 4 ]. Genetic heritability can be identified in up to 12% of CD patients, with a risk of disease onset that is higher in some populations, such as Ashkenazi Jews vs. others, and Afro-Americans and Asians [ 4 ]. Of the 200 alleles associated with IBD, 37 were found to be CD-specific. The NOD2, ATG16L1, LRRK2, IRGM, Il23R, HLA, STAT3, JAK2 genes, and Th17 pathways have been associated with host–microbe interactions, Th17-cell function, and MUC2-related altered mucus layer [ 5 , 6 ]. These findings highlight the importance of bacteria in disease development. However, genetic variations were shown to be causative only in a minority of cases, thus implying that other players, e.g., epigenetic factors, can contribute to CD.

Other relevant mechanisms involve a number of environmental factors. Indeed, a Western life style (with a diet rich in saturated fat and poor in fibers), antibiotic exposure during the childhood, and smoking addiction have all been implicated in the onset of the disease. Dysbiosis has been thought to play a crucial role in CD pathogenesis. Bacteroides, Firmicutes , and Faecalibacterium prausnitzii species were all demonstrated to be reduced in CD patients, whereas Gammaproteobacteria and Actinobacteria were increased [ 7 , 8 , 9 ]. Moreover, one-third of CD patients show an increase of mucosa-associated Escherichia coli . This adherent-invasive strain is able to cross the mucosal barrier and replicate within macrophages, causing the production of tumor necrosis factor-α (TNF-α). Although microbiota manipulation is a growing research field, thus far the evidence is still too limited to propose probiotics and prebiotics as a treatment option for CD. Moreover, defects of the gut barrier may exert a contributory role in CD pathogenesis. Emulsifiers that are present in the Western diet, together with intestinal tight junction leakage, MUC2 mutations, and autophagy-related ATG16L1 and IRGM genes, can promote intestinal barrier injury and inflammation, thereby eliciting the onset of CD [ 4 , 5 ].

Immune system dysregulation is also involved in CD. Innate lymphoid cells (ILCs) contribute to the maintenance of intestinal barrier integrity. When an offending chemical agent/germ is introduced with the diet, it evokes the synthesis and release of cytokines, such as TNF-α, interleukin 17, interleukin 22, and interferon-γ, by a number of immune/inflammatory cells. Among ILCs, ILC1 and ILC3 are directly involved with CD pathogenesis. Intra-epithelial and lamina propria ILC1 were found to be abundant in the ileum of CD patients [ 10 ]. Increased gene expression of key ILC3 cytokines (IL17A and IL22), transcription factors (RORC and AHR), and cytokine receptors (IL23R) has been shown in the inflamed areas of patients with Crohn’s colitis [ 11 ].

CD manifestations occur according to three phenotypes: inflammatory, stenosing, and penetrating forms. Regardless of the phenotype considered, in a third of patients there is a perianal involvement, while extra-intestinal symptoms involving the eyes, hematologic system, joints, and skin may also occur [ 3 ]. In the majority of CD patients, the most affected GI segments are the terminal ileum and colon, whereas the least involved is the mouth (5% of cases) [ 12 ]. At this level, “cobblestone” (fissuring and serpiginous) ulcerations, along with gum swelling and infiltration, are signs detectable in patients with active disease [ 12 ]. The oral involvement, together with other symptoms, prevent patients from following a correct diet, resulting in inadequate nutritional support.

4. Crohn’s Disease and Nutritional Deficiencies

Malnutrition is often the natural consequence of IBD, detectable in about 65–75% of patients with CD and 18–62% of patients with ulcerative colitis (UC) [ 13 ]. IBD-related malnutrition can be ascribed to various mechanisms: (1) reduced intestinal absorption; (2) gut microbiota changes, i.e., intestinal dysbiosis (a typical example of these abnormalities is given by small intestine bacterial overgrowth); and (3) symptoms such as the loss of appetite, nausea, and vomiting. Nutritional deficiencies including folate, vitamin A and D are common among CD patients [ 3 , 14 ]. Moreover, subjects who undergo extensive bowel resection have an increased risk of vitamin B12 malabsorption [ 15 ]. Some key nutritional elements, including magnesium, zinc, and iron, can be deficient [ 15 , 16 ]. Compared to UC, patients with CD show lower levels of hemoglobin [ 14 ]. Notably, nutritional concerns are particularly important in adolescents with inactive CD, who show an increased energy consumption that is not addressed by an adequate caloric intake [ 17 ]. In children, although not associated with increased resting energy expenditure, CD flare-ups compromise the nutritional status by diverting energy from growth to disease activity [ 17 ]. For this reason, in CD adolescents it is recommended to address nutritional therapy towards an increased caloric intake to improve both growth and development potential.

In this narrative review, we will describe the most commonly used dietary strategies for the treatment of CD and the latest findings in nutrigenomics, in order to inform and provide practical guidance to physicians and gastroenterologists.

5. Diets for the Treatment of Crohn’s Disease

5.1. liquid diets: enteral nutrition and parenteral nutrition as artificial diets for the preoperative nutritional optimization in cd.

Despite significant advances in medical care, stricturing or penetrating complications are very common in about 70% of CD patients, requiring elective surgery within the first 20 years of diagnosis [ 18 , 19 , 20 ]. Post-operative complications are common in patients undergoing intestinal resection, with a risk rate of 30% in the pre-biologic era [ 21 , 22 ], and lowered to 21% in recent times [ 23 ]. Poor nutritional status and a reduction of more than 10% in the body weight during the 6 months preceding surgery were generally associated with the worst post-operative outcomes [ 21 , 24 , 25 , 26 , 27 ]. Nutritional support could attenuate the inflammatory process of the gut, leading to bowel rest and improving postoperative prognosis. In CD patients, enteral nutrition (EN) and parenteral nutrition (PN) are recommended by the European Crohn’s and Colitis Organisation (ECCO) and by the guidelines of the European Society of Clinical Nutrition and Metabolism (ESPEN) for malnourished patients undergoing major gastrointestinal surgery and/or as a minor supportive therapy in addition to an oral diet [ 28 , 29 , 30 ].

The two artificial nutrition methods will be discussed and compared in the next paragraphs.

5.2. Enteral Nutrition

Enteral nutrition (EN) is a liquid dietary regimen, which excludes solid food, providing the full amount of necessary calories. The use of this type of diet is particularly recommended during relapse of the disease, when it is applied for 6–8 weeks to induce remission. EN is administered orally, as a drink, powder, dessert-like snack, or via a feeding tube, with similar efficacy [ 31 ]. To date, EN can be delivered in three formulations, depending the on protein and fat content: elemental, semi-elemental, and polymeric. Elemental formulas contain low-fat nutrients such as amino acids, mono- or oligo-saccharides, and medium-chain triglycerides that are easily absorbable. Semi-elemental formulas consist of peptides of different chain length, simple sugars, glucose polymers or starch, and medium-chain triglycerides. Finally, polymeric formulas contain whole proteins, complex carbohydrates, and long-chain triglycerides [ 32 ].

EN has also been recommended as a maintenance diet during the remission phases of CD, combined with the usual diet [ 33 ]. A maintenance enteral diet (MEN) has been shown to increase the positive effects of biological therapies (e.g., Infliximab), thus preventing the relapse of the disease after surgical-induced remission [ 34 , 35 , 36 , 37 , 38 ]. EN can also be administered as the only nutrition treatment, i.e., exclusive enteral nutrition (EEN). Besides the primary function, EEN provides other beneficial effects, such as improving the nutritional status and bone metabolism/turnover in children [ 34 , 39 , 40 ]. Indeed, EEN is the main therapy for mild-to-moderate CD in children and adolescents, as this regimen promotes, beside the remission of the illness in 80–85% of the cases [ 41 , 42 , 43 ], a reduced use of steroids, which are known to impair growth. However, despite the promising results of EEN over steroids in the treatment of pediatric CD [ 41 , 42 , 44 ], similar results have not been obtained in adult patients, since corticosteroids still show better remission rates when compared to EEN [ 37 , 45 , 46 ]. EEN is also suggested for the remission of complicated CD, improving the inflammatory strictures or entero-cutaneous fistulas [ 1 , 47 , 48 ].

EEN can affect the gut microbiota, i.e., the myriad of bacteria, archaea, eukarya, fungi, and viruses resident in the gut lumen [ 49 ]. It is currently accepted that intestinal dysbiosis (that is the altered richness and diversity of the microbiota) is one of the main trigger factors contributing to CD. Bacterial species that are altered in dysbiosis include Bacteroidetes and Firmicutes , together with deficiency of Faecalibacterium prausnitzii , a strain expressing a 15k Da protein with anti-inflammatory properties [ 8 , 9 , 50 ]. Furthermore, the prevalence of Enterobacteriaceae ( Salmonella , E. Coli , and Campylobacter spp.) has been associated to IBD, although it is still unclear whether the overgrowth of these species is the cause or a consequence of the disease [ 41 , 51 ].

Studies have shown that EEN reduces bacterial richness in children via the reduction of Bacteroidetes species [ 50 , 52 , 53 ] and the increase in Firmicutes phylum and T-regulatory cells of the intestinal lamina propria . EEN also promotes a reduction in the fecal calprotectin levels, a marker of gut inflammation [ 50 , 54 , 55 ]; however, this effect is rapidly lost after food re-introduction [ 50 , 53 , 55 ]. Moreover, EEN reduces the operational taxonomic units (OTU) [ 50 , 56 ], which is an index of bacterial diversity in adults.

Together with the reduction of possibly detrimental bacterial species, EEN evokes the reduction of F. prausnitzii spp. and of fecal butyrate production [ 52 ] 30 days after treatment, thus providing a rationale for supplementing butyrate to EEN [ 50 ]. Limitations of EEN are the poor palatability and the difficulty experienced by patients in following a liquid diet for a long period of time. All these factors hamper the patients’ compliance to the treatment [ 32 ]. In the attempt to make the EEN more palatable, a partial EEN has been proposed, where EEN has been combined with ad libitum solid food; however, this approach did not guarantee a similar rate of remission as total EEN [ 1 , 57 ]. Zoli et al. compared an elemental diet administered orally with a high-dose steroid therapy. The randomized study investigated 22 adult patients affected by moderately active CD. After two weeks of treatment, patients treated with the oral elemental diet achieved the same clinical and laboratory remission as patients treated with corticosteroids, thus proving that an oral elemental diet could be as effective as steroids in inducing CD remission in adults [ 58 ].

5.3. Parenteral Nutrition

Parenteral nutrition (PN), along with its exclusive form total parenteral nutrition (TPN), provides nutrients (macronutrients, micronutrients, and electrolytes) through a central venous catheter [ 59 , 60 ]. In agreement with the ECCO current practice position 2.3: “PN in patients with CD can optimize nutritional status prior to surgery as a supplement to EN, or as an alternative if the use of EN is not possible or is contraindicated” [ 61 ]. PN is commonly recommended for malnourished patients who are experiencing an acute inflammatory phase, with the aim of achieving bowel rest. Additionally, PN is recommended when postoperative complications affect gastrointestinal function, and it is difficult to feed patients with oral/EN for at least 7 days [ 62 ]. Other features making PN feasible include bowel obstruction or sub-occlusion, high-output fistulae, bowel ischemia, severe hemorrhage, anastomotic leak, or active disease causing gut dysfunction [ 30 , 61 ]. A systematic review by Comeche et al. [ 60 ] showed that PN ameliorates erythrocyte sedimentation rate [ 63 , 64 ], cholesterol [ 60 , 65 ], total phospholipids [ 65 ], and serum albumin [ 65 , 66 , 67 ], without producing the clinical symptoms of hypoglycemia [ 68 ]. Moreover, some studies found a significant reduction in the CD activity index (CDAI) after PN administration [ 64 , 69 , 70 ], although these results were not confirmed by Ockenga et al. [ 71 ]. However, despite these improvements and the concomitant use of immunosuppressive drugs, antibiotics, and fecal microbial transplantation, relapses of malabsorption remain frequent in CD patients [ 72 ].

5.4. Enteral Nutrition and Parenteral Nutrition for Safer Elective Surgery and Reduced Post-Operative Complications in Adults with CD

Heerasing et al. [ 18 ] conducted a retrospective case-control study to determine whether EEN, administered for at least 2 weeks prior to surgery, could improve post-operative complications in adult CD patients requiring surgery for stricturing or penetrating complications. Their findings showed that EEN reduced the need for surgery in 25% (13/51) of patients, shortening the length of stay in a surgical unit and dampening systemic inflammation (overall, serum CRP values dropped from 36 mg/L to 8 mg/L in the EEN treated patients). Moreover, patients who were referred to surgery displayed a nine-fold increase in the incidence of post-operative abscesses and/or anastomotic leak compared to those who were pre-treated with EEN. Similar results were obtained by Yamamoto et al. [ 73 ] in 24 CD patients receiving EN for 2–4 weeks before surgery compared to 24 untreated (control) patients. In the EN treated arm, the median serum albumin levels increased, while CRP significantly decreased. Furthermore, the incidence of septic complications (anastomotic leak, intra-abdominal abscesses, entero-cutaneous fistulas, or wound infection) was significantly reduced in patients who received EN pre-operatively (4% vs. 25%, p = 0.04). A retrospective study on 123 CD patients by Li et al. found similar results [ 74 ]. Fifty-five patients (44.7% of the total) were fed with EEN for 3 months prior to surgery, showing significantly higher serum albumin levels and lower CRP at operation, and showing a lower risk of intra-abdominal septic complications (IASCs) (3.6% vs. 17.6%, p < 0.05). Three months after surgery, IASCs occurred in 14 patients (11.4% of the total), nine with anastomotic leakage (of these only one received pre-operative EEN) and five with intra-abdominal abscesses (only one had pre-operative EEN). However, despite the lower number of post-operative complications observed in patients fed with EEN, two years after surgery the cumulative risk of IASCs was similar in the two groups ( p = 0.109).

A retrospective study analyzed the effect of TPN over 30-day infectious complications in 144 malnourished CD patients who underwent major abdominal surgery; 55 patients had pre-operative TPN vs. 89 untreated (control) patients [ 21 ]. The study concluded that receiving TPN for ≥60 days before surgery had a significantly lower risk of post-operative non-infectious complications compared to the controls ( p = 0.03).

Jacobson [ 65 ] compared the effect of pre-operative TPN administered for 18–90 days to 15 patients undergoing bowel resection and primary anastomosis with 105 matched controls. All the patients of the TPN group displayed clinical remission of CD (general well-being and improvement of abdominal pain, fever, and diarrhea). Moreover, postoperative complications occurred only in the control group (29 patients out of 105, a statistically significant result). Thus, TPN is recommended for patients with moderate to severe CD for at least a period of 18 days before major intestinal surgery.

5.5. Enteral vs. Parenteral Nutrition

An ESPEN panel of experts [ 30 ] conducted a systematic review exploring the prognosis of surgical patients treated with EN vs. PN. The authors reviewed twenty randomized studies recruiting patients with abdominal surgery, including patients after liver transplantation and trauma [ 30 ]. Six of the fifteen studies comparing PN directly with EN indicated the latter as the preferred artificial nutrition, due to the lower incidence of infectious complications, shorter length of stay, and best cost–benefit. Eight studies found no significant difference between EN and PN, and for this reason, they suggested using EN because of limited costs. A meta-analysis on 27 studies of TPN conducted by Heyland et al. [ 75 ] found a lower complication rate in surgical patients receiving TPN, compared to no TPN or standard care (usual oral diet with intravenous dextrose), especially in those with malnutrition. The high heterogeneity of the analyzed studies hampered the decision as to whether EN was better than TPN or vice versa. Another meta-analysis by Braunschweig et al. [ 76 ], comparing EN to PN in 27 studies with a total of 1828 patients, showed that the risk of infection is lower with oral/enteral nutrition, whereas in a subcategory of malnourished patients, infection and mortality rates were significantly reduced for those treated with PN. Peter et al. [ 77 ] found lower infection rates and a shortened length of hospitalization for EN fed patients. ESPEN 2017 guidelines state: “if oral feeding is not sufficient then tube feeding should be considered as supportive therapy. Enteral feeding using formulae or liquids should always take preference over parenteral feeding, unless it is completely contraindicated” [ 29 ]. However, although EN should always be preferred to PN, combined EN and PN may be considered in patients needing nutritional support and those in whom >60% of energy cannot be provided solely by EN (because the integrity of the gastrointestinal tract is compromised or due to intestinal dysfunction). Thus, EN often represents the main treatment option, alone or in association with PN [ 78 ].

5.6. Specific Carbohydrate Diet (SCD)

The SCD was developed in the 1920s for the treatment of celiac disease and then adopted by the gastroenterologist Dr. Sidney Haas in 1951 for the treatment of IBD [ 79 ]. SCD allows the consumption of monosaccharides, excluding disaccharides and most of the polysaccharides. In SCD, permitted foods include meat, eggs, oil, vegetables rich in amylose, dairies with low lactose content, e.g., dry-curd cottage cheese or home-made 24-h fermented yoghurt, nuts and fruits (all types). “Forbidden” SCD foods are sucrose, maltose, isomaltose, lactose, potatoes, okra, corn, fluid milk, soy, cheeses with a high amount of lactose (e.g., fresh cheese), food additives, and preservatives. Moreover, Gottshall suggested SCD for at least one year after symptom cessation; for this reason, it could be difficult to strictly adhere to this diet for various (e.g., working or social) reasons. Another study showed that SCD improves symptoms and patient quality of life, and in some cases maintained the remission without the need for medications [ 80 ]. In children, SCD also promotes the mucosa healing assessed with Lewis score [ 1 , 81 ] and induces the normalization of inflammatory markers, such as CRP, fecal calprotectin, and serum albumin [ 82 , 83 , 84 ]. A research project, promoted by the Patient-Centered Outcomes Research Institute (PCORI) and not yet concluded, aims to compare the SCD to the Mediterranean diet in terms of symptom remission in CD. The results will help to determine whether the Mediterranean diet, recommended for the treatment of many different conditions, should be considered in the management of CD patients [ 85 ].

5.7. Low FODMAP Diet

The acronym FODMAP stands for fermentable, oligosaccharides, disaccharides, monosaccharides, and polyols. The low FODMAP diet was initially created for IBS patients and then was also proposed for the treatment of IBD conditions. This diet is based on the exclusion of short-chain carbohydrates, which are poorly absorbed and highly fermented by intestinal bacteria, thereby promoting diarrhea, bloating, distention, and abdominal pain [ 80 ]. Patients on a low FODMAP diet should limit honey and some fruits, such as apples, dates, watermelon (source of fructose), onions and garlic (source of fructans), beans, lentils, and legumes (source of galactans), while there are no restrictions concerning the use of sucrose. Although this type of diet is associated with an improvement of gastrointestinal symptoms [ 1 , 86 ], there is no evidence for an improvement of calprotectin levels or of the reduction of the luminal inflammation [ 87 ]. The low FODMAP diet is advisable in patients with quiescent IBD [ 88 ] exhibiting IBS symptoms detectable in up to 57% of CD patients [ 89 , 90 ]. The downside of this diet is the reduced intake of inulin, fructo-oligosaccharides, and fructose, which are known prebiotics [ 79 ]; moreover, the FODMAP diet reduces the Bifidobacterium population [ 91 ], thus enhancing dysbiosis [ 92 ].

5.8. Semi-Vegetarian Diet (SVD)

The SVD, also referred to as “flexitarian”, describes a primarily vegetarian dietary regimen, which is “flexible” meaning that it strongly limits meat and fish, without eliminating them. The SVD is based on vegetable, fruits, cereals, eggs, yoghurt, and milk, while excluding all processed and refined foods [ 79 ]. Chiba et al. [ 93 ] carried out a 2-year clinical study administering SVD to CD patients in medically or surgically induced clinical remission. This was maintained in 15 of 16 patients on SVD (94%) vs. two of six (33%) patients who followed a free diet. Maintenance of remission rates with SVD was 100% at one year and 92% at two years, suggesting that SVD is effective in preventing CD relapses. In a case report by Sandefur et al. [ 94 ], a patient affected by CD for three years and who had been on infliximab for two years experienced a complete resolution of symptoms after 40 days of vegetarian diet and processed food avoidance for religious purposes. Thus, the patient decided to continue on a vegetarian diet, with rare periods of poor compliance (notably all accompanied by symptom relapse). Six months after switching to a full plant-based diet, complete mucosal healing with no visible evidence of CD was reported at follow-up ileo-colonoscopy. The same group [ 95 ] investigated the remission maintenance rate in CD patients treated with a lacto-ovo-vegetarian diet in which additional servings of fish once a week and meat once every two weeks were included. The proposed diet was particularly rich in fibers (soluble 6.8 ± 0.7 g vs. 23.3 ± 1.6 g insoluble dietary fiber), exceeding the recommended daily dose for the Japanese population (17 g/day for women and 20 g/day for men). Maintenance of remission in patients on the lacto-ovo-vegetarian diet was 92% at two years, and without therapy with biologic drugs, suggesting that a high-fiber content diet can be indicated in the management of a subset of patients with CD.

5.9. Other Diets

In recent years, some new dietary approaches have emerged. However, the lack of clinical trials and scientific data suggests a cautious approach to their uncontrolled use. Here we report the most popular ones. The low fat/fiber limited exclusion (LOFFLEX) diet, which follows the elemental (liquid) formula, is basically a way of reintroducing foods avoided for their potential to trigger CD. The LOFFLEX diet helps apply the exclusion of nutrients in a well-structured protocol. Paleolithic, maker’s, and vegan diets are all regimens applied with some presumed efficacy and generally promoted by the media or the lay press, although devoid of actual scientific evidence.

Among elimination diets, the gluten-free diet (GFD) has undoubtedly sparked interest. Indeed, a genetic predisposition for celiac disease may evoke the onset of IBD, although a causative relationship between celiac disease and IBD has never been fully established [ 96 , 97 ]. To date, despite some experimental data on animal models showing that gluten triggers intestinal inflammation and increases epithelial barrier permeability, no clinical trials have clearly indicated that a GFD has effects on CD. An internet-based survey of 1647 patients with IBD conducted in the United States reported that 65.6% of patients on a GFD for the first time experienced an improvement of symptoms associated with the disease (nausea, bloating, diarrhea, abdominal pain, fatigue) [ 98 ]. Conversely, a Swiss study did not show any significant clinical improvement following a GFD [ 99 ]; notably, those who adhered to a GFD reported worsening of the psychological condition. Overall, the scarcity of data and the significant dissimilarities among studies prevent a clear answer as to whether a GFD could have an effect on IBD and in particular on CD. More investigations are eagerly awaited on GFD in IBD patients.

The suggested diets for the treatment of CD are summarized in Table 1 and schematically illustrated in Figure 1 .

Synoptic view summarizing the different dietary regimens for the treatment of CD.

Suggested dietary approaches for CD treatment with explanation of mechanisms of action and effects.

Abbreviations: EN, Enteral Nutrition; PN, Parenteral Nutrition; CD, Crohn’s Disease; SCD, Specific Carbohydrate Diet; FODMAP, fermentable, oligosaccharides, disaccharides, monosaccharides and polyols; SVD, Flexitarian or Semi-Vegetarian Diet; LOFFLEX, Low Fat/Fiber Limited Exclusion Diet.

6. Probiotics, Prebiotics, and Symbiotics

Probiotics are bacteria able to reach the small intestine and the colon alive, providing beneficial effects to the gut microbiota of the host. Probiotics exert an antimicrobial effect, and promote intestinal epithelial barrier integrity and the improvement of the host immune response [ 100 ]. For these reasons, they are increasingly recommended in addition to dietary modifications during illness (i.e., diarrhea), antibiotic use, or other conditions evoking gut dysbiosis. Probiotics could also be recommended to healthy people, to maintain physiological functions and/or avoid the onset of pathological conditions [ 101 ]. Today, probiotics are gaining interest and research has focused on their effects in IBD. Although the use of probiotics, alone [ 102 ] or in combination with 5-ASA, seems to be promising [ 103 , 104 ] for the treatment of UC, their efficacy seems to be uncertain for the treatment of CD [ 105 ]. In particular, the VSL#3 formula, containing a mix of eight bacterial species, has been investigated both in UC and CD patients. Although the VSL#3 formula had the same effect of mesalaxine treatment when administered to UC patients [ 106 ], similar results were not achieved in CD. Fedorak et al. [ 107 ] found that the VSL#3 formula reduced the level of inflammatory cytokines in the mucosa and delayed the disease recurrence in CD patients administrated with it for the entire 365 days. However, there was no statistical difference in endoscopic recurrence rates registered at day 90 between patients treated with VSL#3 formula and patients treated with placebo [ 107 ]. The anti-inflammatory properties of this strain suggest its use as a promising probiotic adjuvant to CD therapy.

Results on the use of probiotics in children are contradictory. In children affected by mild to moderate CD, Lactobacillus GG proved to be effective in increasing the intestinal barrier function [ 108 ]. Conversely, another study showed that Lactobacillus GG failed to delay CD recurrences in children with CD [ 109 ].

Yilmaz et al. investigated the effects of Kefir drink, a fermented dairy product, on patients affected by CD and UC [ 110 ]. Kefir contains a mixture of probiotics that degrade the lactose contained in milk, and therefore it can be consumed by patients with lactose intolerance. The researchers isolated and identified six different strains of Lactobacillus in Kefir ( L. pentosus , L. brevis , L. plantarum , L. fermentum , L. kefiri , and L. lindneri ). Patients received 400 mL/day of Kefir, twice a day, for four weeks. After one month, CD patients reported a statistically significant improvement of abdominal pain and bloating along with a higher feeling of wellbeing compared to UC patients. Moreover, Kefir treatment in CD patients elicited a significant reduction of inflammatory parameters, such as erythrocyte sedimentation rate and CRP, associated with hemoglobin level increase. Furthermore, Kefir could have potential immunomodulatory effects, due to the probiotic ability to restore intestinal permeability.

Prebiotics, defined as dietary compounds able to nourish the commensal bacteria, were found to not improve the CD activity index nor the endoscopic score or the immunohistochemistry. A study by Benjamin et al. on 103 CD patients randomized to receive either fructooligosaccharides (FOS) or placebo found that, although FOS enhanced Bifidobacteria and F. prausnitzii in healthy subjects, they do not have the same effects in patients with active CD [ 111 ].

A study by Halmos et al. [ 87 ] investigated the prebiotic effect of a low FODMAP diet vs. CD patients randomized in a cross-over design to receive either a low FODMAP or typical Australian diet for 21 days. Feces were collected at the end of each diet and analyzed for calprotectin, pH, SCFA, and bacterial abundance. Gastrointestinal symptoms were reported daily. Apart from an improvement of gastrointestinal symptoms (i.e., abdominal pain, bloating, and passage of wind), there was no difference in stool pH and total or specific fecal SCFA in patients fed with low FODMAP compared to those following the Australian diet. Gut microbiota abundance was unchanged between the two groups; however, specific bacteria changed in those who were in the FODMAP diet arm. Indeed, A. muciniphila , a bacterial population associated with beneficial effects on CD, diminished, and R. torques , which is abundant in patients with IBD, increased. Lactobacilli and Bifidobacteria spp., typical markers of the prebiotic activity, did not change between the two groups. Thus, a low FODMAP diet in CD patients could relieve the typical functional symptoms, although its use should be approached carefully, as a long-term restriction of FODMAP intake reduces the prebiotic effect, leading to potentially dangerous changes of gut microbiota. Finally, because of the limited number of investigated patients, the results of Halmos’ study should be carefully considered.

The combined use of probiotics and prebiotics, referred to as symbiotics, has led to interesting results. Steed et al. used a symbiotic formula containing Bifidobacterium longum and Synergy1 randomly administered to 35 CD patients vs. a placebo [ 112 ]. The results showed a significant improvement of CDAI (tested at 3 and 6 months) and histological scores. The symbiotic did not exert a significant effect on the mucosal IL-18, INF-γ, and IL-1β, whereas it reduced TNF-α expression (only at 3 months of treatment) and promoted mucosal Bifidobacteria proliferation.

In conclusion, probiotics, prebiotics, and symbiotics represent a possible dietary integration for CD patients, but the existing scientific literature reports a very mild influence on CD patients’ clinical and laboratory improvement, thus requiring more studies to define their actual efficacy.

Dietary supplements are summarized in Table 2 and schematically illustrated in Figure 2 .

Suggested food supplements for the treatment of CD.

Summary of the main features related to prebiotics, probiotics, and symbiotics.

7. Nutrigenomics

The term “nutrigenomics” refers to an area of research that investigates the effects that foods may have on gene expression. According to the concept that “no one-size fits all”, the goal of nutrigenomics is to create a “tailored” nutrition. This personalized approach will make possible the creation of customized diets according to each individual’s genotype, with the help of biochemistry, physiology, epigenetic modifications, microbiome, nutrition, and the “omic” disciplines: genomics, proteomics, metabolomics, and transcriptomics [ 113 ]. Thus, genetics can indicate the gene affected, and a specific food component could be recommended (for example, long-chain n-3 PUFA or fish oil in case the interleukin gene is mutated, or prebiotics/probiotics, should the NOD2 or ATG16L1 gene be affected) [ 114 ]. The effect of foods, alone or in combination with other therapeutic strategies, could be determined using transcriptomics [ 114 , 115 ], while the long-term effects of diet could be investigated using proteomic and/or metabolomic approaches [ 116 , 117 ].

CD was one of the first diseases investigated by genome-wide association studies (GWAS). More than 200 genes have been related to IBD susceptibility, some of which were also involved in the immune-mediated disorders, ankylosing spondylitis and psoriasis, whereas others modulate the host–microbiota interactions [ 118 ]. Research on food components unveiled their pivotal contribution in gene expression modulation, metabolic pathway activation, transcription factors, and epigenetic modification. Micronutrients, such as vitamin D, vitamin E, calcium, folic acid, retinol, and nicotinic acid, have been associated with reduced DNA damage and are highly recommended in an appropriate dose for the treatment of CD patients, as they play a role in inflammation and immune response [ 119 , 120 ]. Indeed, it has been demonstrated that polymorphisms affecting the human receptor of vitamin D promote susceptibility to IBD [ 121 , 122 , 123 ]. Among food components, the green tea polyphenol, epigallocatechin gallate (EGCG), further to its antioxidant properties, is able to influence many functions involved in CD pathogenesis, such as methylation, transduction, transcription factors, mitochondrial function, and autophagy, and limits the activation of the signal transducer and activator of transcription 3 (STAT3) pathway involved in CD development [ 124 ]. Other nutrients, such as fibers, may modulate gene signaling. In CD, dietary fibers are not recommended during the exacerbation of the disease. Thus, the limited intake of fiber reduces the production of SCFAs by dietary fiber fermenting bacteria [ 125 ], down-regulating free fatty acid receptor 2 (FFAR2) gene expression. FFAR2 is involved in the maintenance of healthy gut microbiota, and mutations affecting this gene could aggravate the tolerance to fiber in CD subjects [ 126 ].

However, another study showed that cruciferous (cabbage, broccoli), normally considered a beneficial food for their anti-neoplastic properties, are detrimental for some CD patients. Laing et al. demonstrated that a SNPs on the major histocompatibility complex is responsible for the adverse effects that cruciferous vegetables could exert on CD patients [ 14 ]. As this mutation is common in CD patients, it explains why cruciferous vegetables are generally considered beneficial for most people, but not for CD patients.

In addition, CD subjects carrying a single nucleotide polymorphism (L503F, c. 1672 C > T) of the organic cation transporter gene OCTN1 show a higher sensitivity to mushroom compared to people carrying the same mutation but not affected by CD [ 127 ]. Other dietary components that influence the genome are fructose, artificial sweeteners, infant formula, food emulsifiers, and antibiotics. High consumption of fructose is one of the factors eliciting IBD onset. Indeed, fructose enhances the expression of the thioredoxin-interacting protein (TXNIP) gene, which evokes hepatic inflammation, and contributes to NF-κB regulation [ 128 , 129 , 130 ]. Artificial sweeteners, infant formula, food emulsifiers, and antibiotics are associated with gut dysbiosis, another leading factor promoting IBD onset [ 131 , 132 ].

Genetic assets may provoke or counteract the onset of CD. An example of a genetic variation exerting a protective effect on CD is represented by the PPAR-γ gene involved in fatty acid storage and glucose metabolism regulation, and thus contributing to inflammation processes and cancer cell growth [ 133 ]. In addition, in humans PPAR-γ gene products orchestrate the antimicrobial immunity response, maintaining the epithelial expression of colonic beta-defensin DEFB1, which is reduced in CD. Studies on PPAR-γ found that the Pro12Ala variant was seen to exert a protective role against CD in a European Caucasian population [ 134 , 135 ]. Thus, subjects carrying the variant have a reduced risk of developing the illness with respect to those who do not.

Carrying specific genetic traits could aggravate the CD condition. For example, absorption of beta-carotene, a precursor of vitamin A, is regulated by the 15,15′-monooxygenase gene (BCMO1) [ 136 ]. The enzyme encoded by BCMO1 cleaves beta-carotene into two retinal molecules. Leung et al. discovered that people carrying one of the two gene polymorphisms are not able to convert beta-carotene to retinol [ 137 ]. This genetic variation is common in the general population (e.g., 45% of people in the study carried one of the two polymorphisms). Thus, CD subjects bearing such a genetic trait may display a limited production of vitamin A, leading to the aggravation of the disease, as the appropriate production of vitamin A is necessary for the correct regulation of the adaptive immune system and the innate immune defense response [ 138 ].

Epigenetic alterations play a primary role in CD orchestration. A recent study shed light on the cross-talk between the miRNA and epigenetic mechanisms implicated in CD development, finding 26 miRNAs highly expressed in CD patients and modulating epigenetic modifications putatively involved with CD progression [ 139 ]. In particular, miR-21, which controls the innate and adaptative immune system and hypomethylation of the miR-21 locus, was found to correlate with increased primary miR-21 expression in leucocytes and in inflamed intestinal mucosa [ 140 ]. Besides miR-21, other microRNAs (miR-122, miR-29, miR-192, miR-146a) may play a role in CD development; in particular, high levels of circulating miR-595 and miR-1246 are associated with a more aggressive form of CD [ 141 ].

The Western diet is characterized by a high intake of saturated fatty acids and low consumption of polyunsaturated fatty (PUFAs) and long-chain PUFAs (LC-PUFAs) [ 142 , 143 , 144 , 145 , 146 ], and for this reason it is considered one of the causes of systemic inflammation. In Western populations, the ratio between omega-6 (one of the factors promoting inflammation) and omega-3 has been estimated to be 10:1–20:1, instead of the optimal estimated ratio, which is 4:1 [ 147 ], a condition that is mainly due to the increasing abuse of vegetable oils (e.g., soy, safflower, corn, and sunflower) [ 142 , 148 , 149 ]. However, this ratio also seems to be influenced by personal genotype. Indeed, mutations or variants in fatty acid desaturase genes (FADS1, FADS2), the peroxisome proliferator-activated receptor genes (PPARA, PPARG), the X-ray repair cross-complementing protein 1 gene (XRCC1), and stearoyl-CoA desaturase gene (SCD1) influence the serum levels of LC-PUFA-omega-3 and omega-6 fatty acids, affecting metabolic pathways, inflammation, and cancer risk [ 138 ]. Again, carrying mutations for these genes could become a detrimental factor for CD patients who already have a limited dietary intake of fish and fish oil and a low omega-3:omega-6 PUFA ratio.

Gut dysbiosis could be exacerbated in some genotypes: the loss of function of the fucosyltransferase 2 (FUT2) gene, involved in CD susceptibility [ 137 ], reduces the microbiota richness and abundance. People carrying this genetic trait are defined as “non-secretors” and show low colonization of Bifidobacterium bifidum , B. adolescentis , and B. catenulatum / pseudocatenulatum [ 150 ]. As Bifidobacteria are key factors in healthy infant microbiota development and protect from pathogens [ 151 ], “non-secretors” IBD will have a greater chance of developing gut inflammation. This may be aggravated by some dietary regimens, such as the low-FODMAP diet, that reduces microbiome richness and decreases Bifidobacteria [ 152 ].

Among people suffering from IBD, 10–20% of them show dairy product sensitivity [ 153 ]. This condition is unrelated to the disease activity status and depends on the presence/absence of the lactase enzyme that catalyzes the milk disaccharide lactose into the two monosaccharides, i.e., galactose and glucose. In most mammals, lactase stops being active after weaning; however, in humans, it can persist into adulthood. This condition, called “lactase persistence”, is present in subjects heterozygous or homozygous for the T allele of DNA variant, rs4988235, located 14 kb upstream from the lactase phlorizin hydrolase (LCT) gene locus, whilst those homozygotes for the C allele of rs4988235 show lactase-non persistence [ 154 ]. Nolan et al. demonstrated that Caucasian people in New Zealand have a strong association between lactase persistence genotype and risk of developing CD. Indeed, subjects homozygous for the T allele show a higher risk of developing CD compared to those homozygous for the C allele [ 155 ]. Overall, these findings suggest that CD onset could be induced by a variety of factors including the complex relationships underlying the crosstalk between food components and genotype. The main findings on nutrigenomics and genetic modifications have been summarized in Table 3 and Table 4 , and schematically summarized in Figure 3 and Figure 4 .

Nutrigenomics: effects of food on the modulation of gene expression and their influence on CD evolution. Abbreviations: EGCG, EpiGalloCatechin Gallate; STAT3, Signal Transducer and Activator of Transcription 3; SCFAs, Short-Chain Fatty Acids; FFAR2, Free Fatty Acid Receptor 2 gene; IBD, Inflammatory Bowel Disease; SNPs, Single-Nucleotide Polymorphism; OCTN1, Sodium-Dependent Organic Cation Transporter gene; TXNIP, Thioredoxin-Interacting Protein; NF-κB, Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells.

Effects of genetic variation on CD onset and outcomes. Abbreviations: IBD, Inflammatory Bowel Disease; PPAR-γ Peroxisome proliferator-activated receptor gamma; miR-595, MicroRNA 595; miR-1246, MicroRNA 1246; BCMO1, β,β-carotene-15,15′-monooxygenase 1; FFAR2, Free Fatty Acid Receptor 2; FADS1, Fatty Acid Desaturase 1; FADS2, Fatty Acid Desaturase 2; PPARA, Peroxisome Proliferator Activated Receptor Alpha; PPARG, Peroxisome Proliferator-Activated Receptor Gamma; XRCC1, X-ray Repair Cross Complementing 1; SCD1, Stearoyl-CoA Desaturase-1; LC-PUFA-omega-3 and omega-6, Long Chain Polyunsaturated Fatty Acids-omega-3 and omega-6; FUT2, Fucosyltransferase 2.

Food/dietary components affecting gene expression or other factors with related mechanisms and effects.

Abbreviations: EGCG, EpiGalloCatechin Gallate; STAT3, Signal Transducer and Activator of Transcription 3; SCFAs, Short-Chain Fatty Acids; FFAR2, Free Fatty Acid Receptor 2 gene; IBD, Inflammatory Bowel Disease; SNPs, Single-Nucleotide Polymorphism; OCTN1, Sodium-Dependent Organic Cation Transporter gene; TXNIP, Thioredoxin-Interacting Protein; NF-κB, Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells.

Genetic abnormalities involved in the onset and/or outcomes of CD.

Abbreviations: IBD, Inflammatory Bowel Disease; PPAR-γ Peroxisome proliferator-activated receptor gamma; miR-595, MicroRNA 595; miR-1246, MicroRNA 1246; BCMO1, β,β-carotene-15,15’-monooxygenase 1; FFAR2, Free Fatty Acid Receptor 2; FADS1, Fatty Acid Desaturase 1; FADS2, Fatty Acid Desaturase 2; PPARA, Peroxisome Proliferator Activated Receptor Alpha; PPARG, Peroxisome Proliferator-Activated Receptor Gamma; XRCC1, X-ray Repair Cross Complementing 1; SCD1, Stearoyl-CoA Desaturase-1; LC-PUFA-omega-3 and omega-6, Long Chain Polyunsaturated Fatty Acids-omega-3 and omega-6; FUT2, Fucosyltransferase 2.

8. Conclusions

Consistent data indicate that CD is a condition originating from the complex interplay among different factors, i.e., gene abnormalities, altered immune response, and environmental and gut microbiota changes. In this scenario, nutrition, ranging from dietary manipulation to EN/PN, plays an essential role in the treatment of IBD, and in particular of CD. Indeed, it is becoming clear that food components have the ability to modulate metabolic pathways, stimulate gene expression, and modify the microbiota composition. Liquid diets represent the primary therapy in CD treatment, as they reduce inflammation and promote mucosal healing, as well as reducing post-operative complications. Besides the classical dietary approaches, new functional foods are being explored, and new technologies, defined by the suffix “omic”, are being developed to investigate the underlying relationship between food and genes. Although the application of these technologies to CD is still at its very beginning, the idea that every patient is somehow unique prompts ad hoc treatments based on specific diets and nutrient intake. Hopefully, in the next few years, a holistic strategy will allow the treatment of CD patients through personalized nutritional approaches.

Author Contributions

Conceptualization, G.C. (Giacomo Caio), L.L., F.C. and G.Z.; writing—original draft preparation, L.L.; writing—review and editing, L.L., G.C. (Giacomo Caio), F.G., E.Z., R.D.G. and G.Z.; visualization, G.C. (Giacomo Caio), F.C., E.Z., F.G. and G.C. (Giuseppe Chiarioni); supervision, G.C. (Giacomo Caio), R.D.G. and G.Z.; project administration, G.C. (Giacomo Caio), R.D.G. and G.Z.; funding acquisition, G.C. (Giacomo Caio), R.D.G. G.C. (Giuseppe Chiarioni) and G.Z. All authors have read and agreed to the published version of the manuscript.

Fondi Ateneo Ricerca and Fondi Incentivo Ricerca 2020 from University of Ferrara (FAR and FIR 2020) (to GC and RDG).

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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• As Ozempic’s Popularity Soars, Here’s What to Know About Semaglutide and Weight Loss JAMA Medical News & Perspectives May 16, 2023 This Medical News article discusses chronic weight management with semaglutide, sold under the brand names Ozempic and Wegovy. Melissa Suran, PhD, MSJ
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• What to Know About Wegovy’s Rare but Serious Adverse Effects JAMA Medical News & Perspectives December 12, 2023 This Medical News article discusses Wegovy, Ozempic, and other GLP-1 receptor agonists used for weight management and type 2 diabetes. Kate Ruder, MSJ
• GLP-1 Receptor Agonists and Gastrointestinal Adverse Events—Reply JAMA Comment & Response March 12, 2024 Ramin Rezaeianzadeh, BSc; Mohit Sodhi, MSc; Mahyar Etminan, PharmD, MSc
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• Glucagon-Like Peptide-1 Receptor Agonist Use and Risk of Gallbladder and Biliary Diseases JAMA Internal Medicine Original Investigation May 1, 2022 This systematic review and meta-analysis of 76 randomized clinical trials examines the effects of glucagon-like peptide-1 receptor agonist use on the risk of gallbladder and biliary diseases. Liyun He, MM; Jialu Wang, MM; Fan Ping, MD; Na Yang, MM; Jingyue Huang, MM; Yuxiu Li, MD; Lingling Xu, MD; Wei Li, MD; Huabing Zhang, MD
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Sodhi M , Rezaeianzadeh R , Kezouh A , Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795–1797. doi:10.1001/jama.2023.19574

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Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

• 1 Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
• 2 StatExpert Ltd, Laval, Quebec, Canada
• 3 Department of Ophthalmology and Visual Sciences and Medicine, University of British Columbia, Vancouver, Canada
• Medical News & Perspectives As Ozempic’s Popularity Soars, Here’s What to Know About Semaglutide and Weight Loss Melissa Suran, PhD, MSJ JAMA
• Special Communication Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists Rasha Alhiary, PharmD; Aaron S. Kesselheim, MD, JD, MPH; Sarah Gabriele, LLM, MBE; Reed F. Beall, PhD; S. Sean Tu, JD, PhD; William B. Feldman, MD, DPhil, MPH JAMA
• Medical News & Perspectives What to Know About Wegovy’s Rare but Serious Adverse Effects Kate Ruder, MSJ JAMA
• Comment & Response GLP-1 Receptor Agonists and Gastrointestinal Adverse Events—Reply Ramin Rezaeianzadeh, BSc; Mohit Sodhi, MSc; Mahyar Etminan, PharmD, MSc JAMA
• Comment & Response GLP-1 Receptor Agonists and Gastrointestinal Adverse Events Karine Suissa, PhD; Sara J. Cromer, MD; Elisabetta Patorno, MD, DrPH JAMA
• Research Letter GLP-1 Receptor Agonist Use and Risk of Postoperative Complications Anjali A. Dixit, MD, MPH; Brian T. Bateman, MD, MS; Mary T. Hawn, MD, MPH; Michelle C. Odden, PhD; Eric C. Sun, MD, PhD JAMA
• Original Investigation Glucagon-Like Peptide-1 Receptor Agonist Use and Risk of Gallbladder and Biliary Diseases Liyun He, MM; Jialu Wang, MM; Fan Ping, MD; Na Yang, MM; Jingyue Huang, MM; Yuxiu Li, MD; Lingling Xu, MD; Wei Li, MD; Huabing Zhang, MD JAMA Internal Medicine
• Research Letter Cholecystitis Associated With the Use of Glucagon-Like Peptide-1 Receptor Agonists Daniel Woronow, MD; Christine Chamberlain, PharmD; Ali Niak, MD; Mark Avigan, MDCM; Monika Houstoun, PharmD, MPH; Cindy Kortepeter, PharmD JAMA Internal Medicine

Glucagon-like peptide 1 (GLP-1) agonists are medications approved for treatment of diabetes that recently have also been used off label for weight loss. 1 Studies have found increased risks of gastrointestinal adverse events (biliary disease, 2 pancreatitis, 3 bowel obstruction, 4 and gastroparesis 5 ) in patients with diabetes. 2 - 5 Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ. Randomized trials examining efficacy of GLP-1 agonists for weight loss were not designed to capture these events 2 due to small sample sizes and short follow-up. We examined gastrointestinal adverse events associated with GLP-1 agonists used for weight loss in a clinical setting.

We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus for Academics database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.

Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch. Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors. 6 Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1. Analyses were performed using SAS version 9.4. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.

Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users ( Table 1 ). For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis.

Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR, 9.09 [95% CI, 1.25-66.00]), bowel obstruction (HR, 4.22 [95% CI, 1.02-17.40]), and gastroparesis (HR, 3.67 [95% CI, 1.15-11.90) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]). Exclusion of hyperlipidemia from the analysis did not change the results ( Table 2 ). Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results ( Table 2 ). E-value HRs did not suggest potential confounding by BMI.

This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes. Limitations include that although all GLP-1 agonist users had a record for obesity without diabetes, whether GLP-1 agonists were all used for weight loss is uncertain.

Accepted for Publication: September 11, 2023.

Published Online: October 5, 2023. doi:10.1001/jama.2023.19574

Correction: This article was corrected on December 21, 2023, to update the full name of the database used.

Corresponding Author: Mahyar Etminan, PharmD, MSc, Faculty of Medicine, Departments of Ophthalmology and Visual Sciences and Medicine, The Eye Care Center, University of British Columbia, 2550 Willow St, Room 323, Vancouver, BC V5Z 3N9, Canada ( [email protected] ).

Author Contributions: Dr Etminan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sodhi, Rezaeianzadeh, Etminan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sodhi, Rezaeianzadeh, Etminan.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Kezouh.

Obtained funding: Etminan.

Administrative, technical, or material support: Sodhi.

Supervision: Etminan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by internal research funds from the Department of Ophthalmology and Visual Sciences, University of British Columbia.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement .

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Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease

• Jia Li 1 , 2 ,
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• Jeremy A. Goettel   ORCID: orcid.org/0000-0002-0749-2357 5 , 7 , 10 , 11 ,
• Yash A. Choksi 5 , 10 , 11 , 12 ,
• Dawn B. Beaulieu 5 ,
• Robin L. Dalal 5 ,
• Sara N. Horst 5 ,
• Baldeep S. Pabla 5 ,
• Yuankai Huo   ORCID: orcid.org/0000-0002-2096-8065 8 , 9 ,
• Bennett A. Landman   ORCID: orcid.org/0000-0001-5733-2127 8 , 9 ,
• Joseph T. Roland 3 , 13 ,
• Elizabeth A. Scoville 5 , 11 ,
• David A. Schwartz 5 ,
• M. Kay Washington 6 , 11 ,
• Yu Shyr 1 , 2 ,
• Keith T. Wilson   ORCID: orcid.org/0000-0003-4421-1830 5 , 7 , 10 , 11 , 12 ,
• Lori A. Coburn   ORCID: orcid.org/0000-0003-3249-9806 5 , 10 , 11 , 12 ,
• Ken S. Lau   ORCID: orcid.org/0000-0001-8438-0319 1 , 3 , 4 , 6 , 11 , 13 &
• Qi Liu   ORCID: orcid.org/0000-0001-8892-7078 1 , 2  

Nature Communications volume  15 , Article number:  7204 ( 2024 ) Cite this article

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• Crohn's disease
• Imaging the immune system
• Mucosal immunology
• Systems analysis

Crohn’s disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identify a distinct epithelial cell type in both terminal ileum and ascending colon (hereon as ‘LND’) with high expression of LCN2 , NOS2 , and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, are rare in non-IBD controls but expand in active CD, and actively interact with immune cells and specifically express IBD/CD susceptibility genes, suggesting a possible function in CD immunopathogenesis. Furthermore, we discover early and late LND subpopulations with different origins and developmental potential. A higher ratio of late-to-early LND cells correlates with better response to anti-TNF treatment. Our findings thus suggest a potential pathogenic role for LND cells in both Crohn’s ileitis and colitis.

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Introduction.

Inflammatory Bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic, relapsing inflammation in the gastrointestinal tract 1 . CD can affect any portion of the gastrointestinal tract with inflammation that can span across all layers of the gut, while UC is localized to the colon and rectum and confined to the mucosa. IBD is believed to be driven from the complex interplay between environmental factors and genetic susceptibilities, resulting in dysregulated immune responses to environmental triggers and the breakdown of the epithelial barrier and intestinal homeostasis 2 , 3 , 4 . Genome-wide association studies have revealed more than 200 IBD-susceptiblility genes, which are involved in microbial sensing, antigen presentation, autophagy, T-cell signaling, and other immune-related pathways 5 , 6 , 7 , 8 .

A wide range of cell types orchestrate intestinal host defense to environmental exposures. Characterizing cellular organizations and their rewiring in intestinal development and response to inflammation is of great importance to understanding IBD pathogenesis and to reveal novel potential treatment options. Recent studies utilized single cell and spatial omics profiling to provide an unbiased census of cell lineages and to characterize their functional states in healthy control and IBD samples 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 . These studies successfully identified novel cells, dissected well-known cell types at high resolution, and revealed spatial, temporal, and functional heterogeneity of cellular compositions 9 , 10 , 11 , 12 , 13 , 14 . Comparing cellular differences between IBD and healthy controls, they found molecular and cellular alterations in disease, identified cellular modules associated with drug response, and built transcriptional links between the developing gut and childhood CD 15 , 19 , 22 , 24 . While their main findings centered around immune cell signatures and immune-stromal interactions, few studies have shed light on epithelial cells regulating immune response and driving disease. Moreover, the ileum and colon exhibit distinct cellular compositions and have specialized preferences for nutrient absorption, microbe defenses, and endocrine function 28 . Whether Crohn’s ileitis and Crohn’s colitis/UC act through a common mechanism remains largely unknown.

In this study, we combined bulk and single-cell RNA profiling, multiplexed imaging of proteins and RNAs, and spatial transcriptomics to study molecular and cellular remodeling and reorganization in active/inactive CD compared to non-IBD controls in both the terminal ileum (TI) and ascending colon (AC). We not only discovered rewiring of epithelial, stromal, and immune cells, but also identified a specific epithelial cell type in CD, which we named “LND cells” given their high expression of LCN2 , NOS2 , and DUOX2 . LND cells are present in both the TI and AC of CD patients and expand significantly with disease activity. LND cells specialize in regulating defense responses by recruiting and activating immune cells as signaling senders. Multiplexed imaging, transwell monocyte migration, and spatial transcriptomics further supported cross-talk between LND and immune cells. LND cells are predicted to be a pivotal cell type in CD pathogenesis, evidenced by highly specific expression of IBD susceptibility genes. The presence of the LND cell type in both the TI and AC of CD patients suggests a common link to dysregulated host-environment interactions. A high-resolution view of LND cells detected two subpopulations with different stem-potential and their ratio was associated with anti-TNF treatment response.

Cellular landscape of terminal ileum and ascending colon in non-IBD control and CD

We profiled 82 TI and 88 AC specimens from either endoscopic biopsies or surgical resection specimens across 83 unique individuals (65 CD patients and 18 non-IBD controls) using single-cell RNA-sequencing (scRNA-seq), representing one of the largest cohorts of CD patients profiled (Fig.  1A and Supplementary Data  1 ). Non-IBD endoscopic specimens were collected from individuals presenting for colonoscopy for colorectal cancer screening or colon polyp surveillance without evidence of intestinal inflammation, while non-IBD surgical specimens were taken from normal adjacent tissue from patients undergoing surgical resection of endoscopically unresectable polyps in the cecum or ascending colon. Patient characteristics were as follows: ethnic background (CD: 77% white, 15% African American, 5% Asian, and 3% Hispanic; Control: 83% white, 11% African American, and 6% Hispanic), sex (CD: 63% female, 37% male; Control: 61% female, 39% male), and age (CD: 18–75; Control: 45–70). 6% of CD patients were treatment naive, with the rest currently undergoing various treatments or previously treated for their CD symptoms (Supplementary Data  1 ). Disease severity of each specimen was classified as active CD (31 mild, 9 moderate, and 11 severe) and inactive CD (58 normal and 17 quiescent) based on histopathologic analysis (Fig.  1B ). The non-IBD specimens comprised 20 TI and 24 AC (Fig.  1B ). In 77% of cases, matching TI and AC samples were collected from the same individual (Supplementary Data  1 ).

A Schematic for processing endoscopic and surgical samples from TI and AC for non-IBD controls, inactive and active CD patients. B Summary of the number of samples in each group. C UMAP of 155,093 cells from endoscopy samples colored by cell clusters. D Dotplot showing markers for each cell type. E UMAP of 155,093 cells colored by tissue origin, TI (brown) or AC (blue). F Proportion of each cell cluster in TI (brown) and AC samples (blue). G UMAP of 155,093 cells colored by disease status, controls (tan), inactive (green) or active CD (purple). H MDS plot of cell compositional differences across all endoscopy specimens. Figure 1a was created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license ( https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en ).

After quality control, 155,093 cells from endoscopic specimens and 47,266 cells from surgical specimens were retained, and these datasets were analyzed separately (Supplementary Data  2 ). Louvain clustering on single cells from endoscopic specimens revealed major cell types within the epithelial compartment (enterocytes/colonocytes, transit amplifying (TA) cells, stem cells, goblet cells, goblet proliferating cells, BEST4/OTOP2 cells, tuft cells, enteroendocrine cells (EEC), and Paneth cells—only in the TI), and the non-epithelial compartment (T cells, B cells, plasma cells, myeloid cells, cytotoxic T/natural killer (CTL/NK) cells, mast cells, and stromal cells) (Fig.  1C ). Cell types were manually curated by known marker genes with TI enterocytes expressing APOA1/APOB , AC colonocytes expressing AQP8 , TA cells expressing MKI67 , stem cells expressing LGR5 , goblet cells expressing MUC2 and TFF3 , goblet profilerating cells expressing both MUC2 and MKI67 , BEST4/OTOP2 cells expressing BEST4 and OTOP2 , Paneth cells expressing defensins such as DEFA5 and DEFA6 , T cells expressing CD3D and CD3G , B cells expressing CD79A and CD79B , plasma cells expressing IGHA1 and IGHA2 , myeloid cells expressing C1QA and C1QB , mast cells expressing KIT , CTL/NK cells expressing GZMA , and stromal cells expressing VWF (Fig.  1D ). These results are consistent with cell types identified by previous scRNA-seq studies of the healthy human small intestine and colon 10 , 13 . In addition, rare microfold-like cells were observed in only a few patients in the AC, and a very minor portion of IgG+ plasma cells (1%) were found within IgA+ plasma cells (Supplementary Note  1 ).

The largest transcriptomic difference was observed in absorptive cells from TI or AC (Fig.  1E ), consistent with previous studies 10 , 13 and reflecting tissue-specific functions (Supplementary Note  2 ). Differences in goblet, EEC, and tuft cells between TI and AC revealed genes that were specific to both cell types and regions; for instance, BEST2 was specific to AC goblet cells, while RGS13 was exclusive to TI tuft cells (Supplementary Note  2 ). While the TI and AC had distinct epithelial transcriptional programs, expression profiles of immune and stromal cells between the two sites largely overlapped, with similar cell types identified (Fig.  1C, E ). In addition, the TI and AC exhibited similar composition of epithelial, stromal, and immune cells (Fig.  1F ).

The second largest transcriptomic differences came from disease activity (Fig.  1G ). UMAP co-embedding revealed a shift of epithelial cell transcriptional state from non-IBD control, inactive, to active CD (Fig.  1G ), indicating transcriptional changes driven by disease activity. Quantifying cellular compositional distances between individuals by scUniFrac v0.9.6 29 revealed that disease status was one of the main factors driving compositional shifts (Fig.  1H ). Surprisingly, UMAP co-embedding revealed intermixing of cells from different individuals with the same disease status, suggesting only subtle if any patient-specific variability (Fig.  1G ).

Analysis of 47,266 cells from surgical specimens generated similar results, with similar epithelial and non-epithelial cell types identified by marker genes and gene signatures (Supplementary Fig.  8A , E , G ). The same differences between transcriptional programs of the TI and AC were observed in data generated from biopsies (Fig.  1E ) and surgical resections (Supplementary Fig.  8B ). Furthermore, shifts in cell populations as a function of disease activity were also observed in the two specimen types (Supplementary Fig.  8C , F ). However, cell distributions between biopsies and surgical resections were different, with endoscopic biopsies dominated by epithelial cells and surgical specimens enriched for immune and stromal cells (Supplementary Fig.  8D ). This result reflects the superficial mucosal sampling of biopsies versus deeper submucosal sampling of surgical resections. For the rest of the analysis, we mainly focused on endoscopic specimens, which had a larger sample size with more evenly distributed disease status compared with surgical specimens.

Distinct immune and stromal cellular organizations in active CD

Because CD is inherently characterized as an inflammatory disease, we set out to delineate changes within the immune and stromal compartments as a function of disease activity. High resolution clustering revealed 12 populations of immune and stromal cells (Fig.  2A ), encompassing pre-characterized T cells, CTL/NK cells, B cells, and plasma cells. Proliferative T and B cells were also marked by a proliferative signature including TOP2A and MKI67 . Within myeloid cells, mast cells were annotated by high expression of KIT and FCER1A , and neutrophils were marked by high expression of S100A8 , S100A9 , and CXCR2 (Fig.  2B ). We also recovered two types of macrophages. Resident macrophages expressed tissue residency markers MRC1 and complement genes C1QA and C1QB , while recruited macrophages highly expressed inflammatory molecules, such as NFKBIA , NFKBI , CXCL16 , and CXCL9 (Fig.  2B ). We identified fibroblasts expressing PDGFRA and ECM genes, such as COL1A1 , COL1A2 , and COL6A1 and endothelial cells expressing VWF and PECAM1 (Fig.  2B ).

A UMAP of immune and stromal cells. B Dotplot of markers in each cell type. C Proportional changes of each immune and stromal cell type from non-IBD controls to inactive and active CD patients in TI (two-sided Wilcoxon test with FDR adjustment). D Proportional changes of each immune and stromal cell type from non-IBD controls to inactive and active CD patients in AC (two-sided Wilcoxon test with FDR adjustment). Data are represented as the mean ± SD ( C , D ).

As expected, cellular composition within the immune and stromal compartments differed significantly between inactive and active CD (Supplementary Data  3 ). Almost all immune and stromal cell numbers increased significantly in active compared to inactive CD (Fig.  2C, D ), with the exception of B cells, proliferating B cells, and CTL/NK cells in the TI (Fig.  2C ), and mast cells, B cells, proliferating B cells, and T cells in the AC (Fig.  2D ). Among them, neutrophils and recruited macrophages showed the most significant elevation in active CD, in both TI and AC. The proportion of neutrophils increased from 0% to 1.3% (FDR = 2.0e−6) in TI and from 0.06% to 0.7% in AC (FDR = 1.5e−3), which is not surprising as the presence of neutrophils is a hallmark of histologically active disease, while the proportion of recruited macrophages increased from 0% to 2.7% in TI (FDR = 1.1e−4) and from 0.19% to 1.5% in AC (FDR = 1.5e−3) (Fig.  2C, D ). Beyond cellular compositional changes, transcriptional upregulation of pro-inflammatory genes was observed in active CD compared to inactive CD within each cell type (Supplementary Note  3 ).

Immune and stromal cell compositions were mostly unchanged between inactive CD and controls, with the exception of T proliferating cells in the AC, which was slightly increased in inactive CD (from 0% to 0.17%, FDR = 0.024) (Fig.  2D ). However, transcriptional upregulation of pro-inflammatory genes was still observed in a cell type-specific manner (Supplementary Note  3 ).

Analysis of surgical samples revealed similar cell types (Supplementary Fig.  9A ). Furthermore, we identified three subtypes of fibroblasts, PDGFRA+ fibroblasts, ABCA8+ fibroblasts, and PDPN+ fibroblasts in both the TI and AC (Supplementary Fig.  9A ). The three subtypes had distinct expression profiles. ABCA8+ fibroblasts had high expression of ABCA8 , CFD and SFRP2 , PDGFRA+ fibroblasts had enriched expression of PDGFRA , CXCL14 , and ADGRL3 , and PDPN+ fibroblasts were marked by high expression of PDPN , MMP1 , and SOD2 (Supplementary Fig.  9B ). The PDGFRA+ fibroblasts in the surgical samples were similar to fibroblasts identified in TI and AC endoscopic biopsies (Supplementary Fig.  9C ). The PDPN+ fibroblasts, also called activated or inflammatory fibroblasts, reside in the submucosa of the inflamed intestine outside of the lamina propria 15 . They have been proposed as a central hub in IBD with an essential role in hematopoietic-stromal interactions 15 , 19 , 30 . An increasing trend was observed for most stromal cell types in the TI (not implemented in the AC due to only two active CD surgical samples), especially PDPN+ fibroblasts (Supplementary Fig.  9D ). Increases in recruited macrophages and neutrophils were observed in surgical specimens similar to the endoscopic biopsies (Supplementary Fig.  9D ). However, the increases were not statistically significant due to limited sample sizes in the TI surgical samples.

An LND subpopulation specialized in regulating mucosal immunity

Deep annotation of epithelial cells revealed a continuum of cells consisting of stem, TA, early, intermediate, and mature enterocytes/colonocytes (Fig.  3A, C ) 10 , 13 . Early, intermediate, and mature enterocytes/colonocytes were distinguished based on markers previously defined for each cell type 13 and predicted crypt-axis scores 14 (Supplementary Fig.  10 ; details in “Methods”). Most interestingly, we identified a distinct absorptive cell type that emerges and then expands during active inflammation in both the TI and AC. This subpopulation was marked by high expression of LCN2 , NOS2 , and DUOX2 , therefore, we named it LND (Fig.  3B, D ). LND cells were present in 73.6% and 87.2% of CD samples in TI and AC, respectively (Supplementary Data  3 ). LND cells were rare in non-IBD control tissues, increased marginally in inactive CD (0.3% to 1.3%, FDR = 0.5 in TI; 0.06% to 0.6%, FDR = 0.1 in AC), and expanded significantly in active CD (1.3% to 18.9%, FDR = 1.7e−6 in TI; 0.6% to 17.8%, FDR = 1.0e−5 in AC) (Fig.  3E, F ; Supplementary Data  3 ). The increase was observed both in the TI and AC, even though absorptive cells from both regions, as well as LND cells, have distinct transcriptomes. The proportion of LND cells was not associated with medication exposures (Supplementary Fig.  11 ). LND cells increased at the expense of early, intermediate, and mature enterocytes/colonocytes, as well as BEST4/OTOP2 cells as CD progresses from inactive to active disease (Fig.  3E, F ; Supplementary Data  3 ). The emergence and expansion of the LND subpopulation in active CD was also observed in surgical TI samples (Supplementary Fig.  12 ). Beyond cellular composition alterations, cell-specific transcriptional changes with disease activity were also observed (Supplementary Note  3 and Supplementary Data  4 ).

A UMAP of 13 epithelial cell types in TI. B UMAP labeled with expression of LCN2 , NOS2 , and DUOX2 in TI. C UMAP of 12 epithelial cell types in AC. D UMAP labeled with expression of LCN2 , NOS2 , and DUOX2 in AC. E Proportional changes of each epithelial cell type from controls to inactive and active CD patients in TI (two-sided Wilcoxon test with FDR adjustment). F Proportional changes of each epithelial cell from controls to inactive and active CD patients in AC (two-sided Wilcoxon test with FDR adjustment). G Proportional changes of LND cells with disease status in six independent cohorts (two-sided Wilcoxon test with FDR adjustment). H Heatmap of high expression of immune-related genes in the LND in both TI (top) and AC (bottom). I Representative HCR-FISH Co-staining of LCN2 (green), NOS2 (pink), and DUOX2 (red) on non-IBD controls, CD with low LND and CD with high LND in TI and AC tissues ( N  = 2–5 per group). The scale bar represents 100 μm. Data are represented as the mean ± SD ( E – G ).

We verified the emergence and expansion of LND cells in CD in six independent studies with clinical activity, including five microarray studies 31 , 32 , 33 , 34 , 35 and one bulk RNA-seq dataset 36 . Consistently, LND cells were rare in healthy controls and emerged in uninflamed CD and expanded significantly in inflamed CD (Fig.  3G ). Significant expansion of LND cells was observed from uninflamed to inflamed CD in both TI and AC in GSE179285 31 (FDR = 2.3e−4 in TI and FDR = 2.2e−8 in AC) (Fig.  3G ). In GSE75214 32 , LND cells also expanded from healthy controls to inactive CD in TI (FDR = 8.5e−6) and to active CD in AC (FDR = 2.2e−3) (Fig.  3G ). A similar trend was detected in four other independent studies (GSE186582 33 and GSE112366 34 in TI, and GSE20881 35 and GSE66207 36 in AC) (Fig.  3G ). The increase of LND cells at the expense of mature enterocytes/colonocytes was also observed in the six studies (Supplementary Figs.  13 and 14 ).

Genes defining the LND cell cluster, LCN2 , NOS2 , and DUOX2 are all involved in the host response to microbiota, generating products that can damage tissues. LCN2, lipocalin 2, acts as an antimicrobial protein, which attenuates bacterial growth by binding and sequestering iron-scavenging siderophores 37 . LCN2 is a serum and fecal biomarker for intestinal inflammation 38 , and it has been reported to be increased in serum from CD patients 39 . Importantly, LCN2 is implicated in a form of programmed cell death termed ferroptosis, which has been hypothesized to contribute to colitis-associated mucosal damage 40 . NOS2 , or nitric oxide synthase 2, also known as inducible NOS or iNOS, is an enzyme that catalyzes the production of nitric oxide (NO), a broad-spectrum anti-bacterial agent 41 . NOS2 has been reported to be increased in colonic tissues 42 , 43 , 44 and specifically in the colonic epithelium 45 , 46 from both CD and UC patients. The contribution of NOS2 to IBD pathogenesis has been studied in several experimental models 47 , 48 , 49 . DUOX2 , or dual oxidase 2, produces hydrogen peroxide, which is then metabolized by lactoperoxidase to oxidize pseudohalide into potent antimicrobial reactive oxygen species (ROS) 50 . Dysregulated ROS production has been implicated as a driving factor in IBD and variants of DUOX2 have been identified in very early-onset IBD 51 , 52 . Moreover, DUOX2 has been found to be upregulated in intestinal inflammation in a TLR-4-dependent manner 53 and is involved in NOD2-mediated antibacterial response 54 . In addition to these marker genes, LND cells also express a high level of anti-microbial peptides (AMPs), including DMBT1 , REG1A , REG1B , REG3G , PI3 , S100A9 , LYZ , SAA1 , and SAA2 , and upregulate transmembrane mucins ( MUC13 , MUC17 , and MUC3A ) that form the glycocalyx, which acts a physical barrier to luminal antigens (Fig.  3H ). Downstream of immediate microbial defense, LND cells also overexpress genes that orchestrate immune responses. These include pattern recognition receptors TLR3 and its interacting partner TICAM1 , inflammatory signaling and immunity modulator BIRC3 , antigen-presenting machinery ( HLA-B , HLA-A , HLA-DPA1 , HLA-E , HLA-F , HLA-DQA1 , HLA-DQB1 , HLA-DQA2 , and TAPBP ), and cytokines ( CCL20 , CCL28 , CXCL1 , CXCL2 , CXCL3 , CXCL5 , CXCL16 , TNF , IFNG , IL13A , and IL17C ) (Fig.  3H ). Functional analysis of genes upregulated only in LND cells compared to other epithelial cells found that they were enriched in antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, HIF-1 signaling pathway, and TNF signaling pathway (Supplementary Fig.  15 ). These results suggest that the LND subpopulation that expands in active inflammation serves specialized functions of antimicrobial response and immunoregulation.

To confirm the presence and location of LND cells, we employed hybridization chain reaction-fluorescene in-situ hybridization (HCR-FISH) on tissues from TI and AC of non-IBD controls and CD patients with low and high proportions of LND cells (Fig.  3I and Supplementary Fig.  16 ). Generally, LCN2, NOS2 , and DUOX2 expression was undetectable in non-IBD controls (Fig.  3I ). Consistent with the scRNA-seq results in both TI and AC, LCN2, NOS2 , and DUOX2 colocalized in a subset of epithelial cells in the high LND tissues but were barely detected in the low LND tissues (Fig.  3I and Supplementary Fig.  16 ). The epithelial protein expression of LCN2, NOS2, and DUOX2, as well as their colocalization in the high LND tissues, was confirmed by immunohistochemistry (Supplementary Fig.  17 ) and multiplex immunofluorescence (Supplementary Fig.  18 ). In summary, multiplex RNA and protein imaging validate the presence of LCN2, NOS2, and DUOX2 co-expressing epithelial cells in CD.

Developmental origins of LND cells

To infer the developmental origin of LND cells, we applied RNA velocity v0.6, an algorithm that predicts the future transcriptional states of each individual cell by the ratio of unspliced to spliced gene isoforms over the transcriptome 55 . As expected, we observed a cycling pattern for TA cells and a strong directional flow originating from stem cells, passing through early enterocyte, intermediate enterocyte, and ending in mature enterocytes in the TI (Fig.  4A ). Interestingly, we noted two potential origins that point toward LND cell development, one was from early enterocytes/stem cells, and the other was from mature/intermediate enterocytes, which paralleled the two subclusters of LND cells from high resolution clustering (Fig.  4B ). The subcluster that might originate from early enterocytes/stem cells was labeled “early LND”, while the other was labeled “late LND”. Partition-based graph abstraction (PAGA) analysis, which defines total connection strength between progenitor and differentiated cell populations 56 , also showed that early LND cells were associated strongly with early enterocytes, while late LND cells were linked to intermediate and mature enterocytes, as well as early LND cells (Fig.  4C ). CytoTRACE v0.3.3 analysis to infer the developmental potential of cell populations 57 predicted that stem and TA cells had the highest inferred stemness score, followed by early enterocytes, early LND, intermediate enterocytes, late LND, and finally mature enterocytes (Fig.  4D ). Our results indicate that LND cells may differentiate directly from stem/progenitor cells (early LND), or they may arise later (late LND) from intermediate/mature enterocyte or from early LND cells themselves.

A RNA velocity results mapped on the UMAP plot showing the predicted future transcriptional state of each cell. B UMAP of early (light red) and late (medium red) LND clusters in the TI. C PAGA results mapped on the UMAP plot showing connectivity between cell types. D Histogram plot comparing the developmental potential of enterocytes predicted by CytoTRACE (two-sided Wilcoxon test with FDR adjustment). E Comparison of the expression of CXCL5 , TNFRSF1A, and TNFRSF1B between early and late LND cells (two-sided Wilcoxon test with FDR adjustment). F Comparison of the ratio of late to early LND cells between anti-TNF responders (tan) and non-responders (pink) after the first dose of medication (two-sided Wilcoxon test). Data are represented as the mean ± SD ( D – F ).

Differential expression analysis between early and late LND cells found that early LND cells were enriched in neutrophil chemoattractants ( CXCL3 and CXCL5 ), mucin ( MUC1 and MUC4 ), and anti-microbial genes ( DMBT1 , PL2AG2A , REG4 , and PIGR ), while late LND cells were enriched in lipid-metabolic genes (such as APOC3 , APOA4 , APOB , and APOA1 ), cytokines ( CCL20 and CCL25 ), MUC3A, REG3G , and TNF receptors ( TNFRSF1A , TNFRSF10B , and TNFRSF1B ) (Fig.  4E and Supplementary Fig.  19A ). They shared similar expression levels of SAA1 and CCL28 . Both early and late LND cells were increased as a function of disease activity, from normal non-IBD controls, inactive CD, to active CD (Supplementary Fig.  19B ). The ratio of early to late LND cells was also associated with disease activity (Supplementary Fig.  19C ), with early LND cells being enriched along the CD progression spectrum.

Since late LND cells expressed TNF receptors, we were curious whether the proportion of LND subclusters can predict anti-TNF response. We utilized the GSE16879 dataset 58 , which included 18 CD ileum patients assessed before and after their first anti-TNF treatment. In the Arijs et al. study, patients were classified as responders or non-responders based on endoscopic and histologic findings at 4–6 weeks after the initial treatment. We estimated the proportion of early and late LND cells by deconvolving bulk gene expression profiles through CIBERSORT v1.05 59 . Despite the limited sample sizes ( n  = 10 responders and n  = 8 non-responders), we observed that patients with higher proportions of late LND cells were more likely to respond to anti-TNF treatment ( p  = 0.05) (Supplementary Fig.  20 ). The proportions of early LND cells and other epithelial cells were not correlated with anti-TNF response (Supplementary Fig.  20 ); however, the ratio of late vs. early LND cells showed a significant association with anti-TNF response ( p  = 0.012) (Fig.  4F ).

LND cells actively interact with immune cells

To identify the potential immunomodulatory function of the LND cells, we inferred cell–cell communications between LND and any other cell types using CellChat v1.4.0 60 . We found that LND cells are likely to actively interact with immune cells as both signaling senders and receivers with similar patterns in the TI and AC (Fig.  5A, B ). Compared with other epithelial cells, LND cells showed much stronger cytokine-receptor interactions to recruit a variety of immune cells (Fig.  5A, B ; Supplementary Note  4 ). The strong ligand–receptor interactions between LND and immune cells suggest a specialized role of LND in regulating mucosal immunity.

Scatterplot of incoming and outgoing interaction strength of each cell type in the TI ( A ) and AC ( B ). C Representative multiplex images of CD8+ (red), CD4+ (green), and CD45+ (yellow) cells in low ( N  = 7) and high LND ( N  = 10) in the TI and AC. D DotPlot of marker genes in infiltrating lymocytes (ILs). E The proportion differences of ILs between low (orange) and high (purple) LND patients (one-sided Wilcoxon test). Data are represented as the mean ± SD. F Representative 40X images from Transwell monocyte migration assays from non-IBD control, inactive CD, active CD with low LND, and active CD with high LND. The migrated monocytes are stained in purple. G Violin Plot of the number of migrated monocytes in non-IBD control, inactive CD, active CD with low LND, and active CD with high LND. Statistical test was performed using a negative binomial mixed model ( n  = 21 measurements per group from 4 independent experiments; 6 quantified images from two wells in the first experiment and 5 images from one well in the next three experiments). Data are represented as the mean ± SEM.

We performed multiplexed protein imaging analysis on 55 tissues, of which 38 had single-cell RNAseq profiling (17 CD and 3 controls in TI, 15 CD and 3 controls in AC). We classified the multiplex imaging of CD patients into two categories based on the LND proportion reported in the single-cell RNAseq data, low and high LND. We observed those with a high LND proportion had a significantly higher infiltration of lymphocytes into the epithelial submucosa in both TI and AC compared to those with a low LND proportion (Fig.  5C, E ) ( p  = 0.018 and p  = 0.012, respectively). These infilitrating lymphocytes (ILs) were characterized by association of both epithelial (PANCK, NAKATPASE, and BCATENIN) and lymphocyte markers (CD3D, CD4, CD8, and CD45) (Fig.  5D ). These results strengthen the association between CD activity, LND expansion, and immune cells infiltration. Since LND releases a variety of chemokines and cytokines (Fig.  3H ) and actively interacts with immune cells (Fig.  5A, B ), they likely play a role in immune cell recruitment and infiltration.

Next, we investigated the impact of LND cells on monocyte migration. Human colon organoids were generated from patients with normal histology (non-IBD control), inactive CD, active CD with low LND, and active CD with high LND (Supplementary Fig.  21 ). These organoid lines were then used to produce conditioned media for monocyte migration assays. Freshly isolated human monocytes from four normal blood donors were added above Transwell TM filters, with the organoid medium in the wells below. The number of migrated cells was quantified repeatedly in different fields, and differential analysis was performed using a negative binomial mixed model as described in the “Methods”. As expected, medium from active CD led to significantly increased monocyte migration compared to inactive CD and controls ( p  < =2e−4), while inactive CD showed a subtle increase in monocyte migration compared to controls ( p  = 0.02) (Fig.  5F, G ). Importantly, active CD with high LND resulted in significantly higher monocyte migration than active CD with low LND ( p  = 0.001) (Fig.  5F, G ), supporting the role of LND cells in enhancing monocyte migration.

In addition, we investigated spatial organization and crosstalk between LND and immune cells using spatial transcriptome from four CD samples selected for relatively high proportions of LND cells. The four samples consisted of two with active TI disease (GCA092 and GCA033) and two with active AC disease (GCA089 and GCA099) (Fig.  6A ). As expected, LND marker genes, including LCN2 , NOS2 , DUOX2 , and CCL20/CCL28 , were coexpressed across spots in all four samples, indicating the existence of LND cells (Supplementary Fig.  22 ). In contrast, expression of LND marker genes were not correlated with immune cell signatures, including CD3D for T cells, CD8A and GZMB for CD8 + T/NK, MRC1 for resident macrophages, NFKBIA and NFKBIB for recruited macrophages, and S100A8 for neutrophils (Supplementary Fig.  22 ). Instead, high expression of LND marker genes in one spot was significantly correlated to high expression of immune cell signatures in its neighboring spots in all four samples using SpaGene v0.1.0 61 (Fig.  6B ), suggesting heterotypic interaction between LND and immune cells (Fig.  6B ). Specifically, NOS2 , LCN2 , and DUOX2 all showed a very significant colocalization with GZMB , S100A8 , and NFKBIA in the GCA092_TI (FDR < 3e−16). DUOX2 colocalized with CD8A (FDR = 2e−8) and NOS2 with NFKBIA (FDR = 2e−8), CD8A (FDR = 2e−5), and GZMB (FDR = 8e−5) in the GCA033_TI. LCN2 colocalized with NFKBIB (FDR = 3e−9) in the GCA089_AC. NOS2 colocalized with NFKBIA (FDR = 2e−9), and LCN2 colocalized with S100A8 (FDR = 4e−8), NFKBIA (FDR = 1e−5), and NFKBIB (FDR = 2e−5) in the GCA099_AC. In comparsion, only marginally significant or insignificant colocalizations were found between the general epithelial genes ( KRT8 and KRT18 ) and immune markers in these samples (Fig.  6B ). To uncover cellular spatial organizations, we further deconvoluted cellular components in each spot based on our scRNA-seq data using RCTD 62 and evaluated colocalization between epithelial cells and immune cells by SpaGene v0.1.0 61 (Fig.  6C ). In the GCA092_TI, the most significant association was found between late LND and CTL/NK (FDR = 8e−35), followed by early LND-CTL/NK (FDR = 2e−27) and late LND-Neutrophils (FDR = 3e−16). In the GCA033_TI, significant association was observed between late LND-CTL/NK (FDR = 3e−8). In the GCA089_AC, early LND and neutrophils were signficiantly colocalized (FDR = 5e−24). In the GCA099_AC, LND and resident macrophages (FDR = 1e−3) were significantly colocalized (Fig.  6C ). In summary, LND cells were much more significantly colocalized with immune cells in all four inflamed specimens as compared to other epithelial cells, further suggesting their specialized ability to interact with immune cells.

A H&E images for the four patient samples overlaid and colored by the expression of DUOX2 . B Dotplot of colocalization of LND markes ( LCN2 , NOS2 , and DUOX2 ) and the general epithelial genes ( KRT8 and KRT18 ) with immune signatures. Only significant colocalization (FDR < 0.01) is included. Dot size denotes the z-value and color denotes the colocalization significance compared to random distribution. C Dotplot of colocalization between epiethial and immune cells. Only significant colocalization (FDR < 0.01) is included. Dot size denotes the z-value and color denotes the colocalization significance compared to random distribution.

LND is a CD/IBD-critical cell type

Genome-wide association studies (GWAS) on IBD have reported more than 200 genes involving 300 risk loci in multiple pathways 5 , 6 , 7 , 8 . Previous studies applying these SNPs in a cell-type-specific manner identified that these alterations in immune cells, especially T cells, are most strongly associated with IBD 14 . We combined GWAS-identified SNPs with single-cell RNA profiling to investigate the role of each cell type in CD. We utilized SNPsea v1.0.3 63 to infer cell type-disease association by evaluating expression specificity of CD/IBD-associated risk genes in our scRNAseq data, with the assumption that risk genes specifically expressed in a cell type are likely driving disease by affecting a function unique to this cell type. Consistent with previous results 14 , we found T cells to be the most CD/IBD-associated cell type (FDR = 0.001 in TI, FDR = 9e−5 in AC), followed by recruited macrophages (FDR = 0.001 in TI, FDR = 0.03 in AC) and CTL/NK cells (FDR = 0.02 in TI, FDR = 0.03 in AC) in both TI and AC (Fig.  7A, B ) (Supplementary Data  5 ). T cell-disease association was driven by specific expression of FYN , PTPRC , CD28 , CD5 , CD6 , CARD11 , and other immune-related genes (Supplementary Fig.  23A ). The macrophage-disease relationship was contributed to by specific expression of LITAF , HCK , SLC11A1 , MMP9 , FCGR2A , and TNFAIP3 , and CTL/NK involvement was indicated by KIF2DL4 , IKZF3 , TNFRSF18 , CTSW , and PTPN22 (Supplementary Fig.  23A ).

A Significance of cell-type specific expression of IBD/CD-risk genes in TI. B Significance of cell-type specific expression of IBD/CD-risk genes in AC. C Significance of cell-type specific expression of IBD/CD-risk genes in each CD TI tissue. D Significance of cell-type specific expression of IBD/CD-risk genes in each CD AC tissue.

Among epithelial and stromal cells, only LND cells were associated with CD/IBD, with marginal significance in both TI and AC (FDR = 0.1) (Fig.  7A, B ). NOS2 was highly upregulated in LND compared to other cell types (Supplementary Fig.  23A ). A NOS2 variant rs2297518 resulting in increased NO production has been associated with IBD (both CD and UC) 64 . CCL20 was also highly upregulated in LND cells (Supplementary Fig.  23A ), and one of its gene variants, rs111781203, has been reported to decrease the risk of IBD 6 . Other CD/IBD-risk genes with high expression in LND cells were shown in Supplementary Fig.  23A , such as TNFRSF1A , STAT3 , PLA2G2A , IRF1 , TMBIM1 , and PIGR . Although genes highly expressed in LND cells, such as DUOX2 and LCN2 , have not been identified as CD/IBD-risk genes in large-scale GWAS studies, they have been reported to be associated with IBD risk or demonstrated to contribute to intestinal inflammation. Rare loss-of-function variants in DUOX2 have been associated with increased plasma levels of IL-17C in patients, and Duox2 -deficient mice had altered microbiota composition and high Il-17c expression in the intestine 65 . Biallelic mutations in DUOX2 have been reported to be associated with very early-onset IBD 51 , 52 . Depletion of LCN2 in mice leads to dysbiosis with increased intestinal inflammatory activity and an induction of Th17 cell differentiation 66 .

We observed extensive transcriptional heterogeneity of key genes in LND cells across CD patients. For example, NOS2 was expressed highly in some patients, but its expression was low in others, although this gene was upregulated globally in the LND cluster (Supplementary Fig.  23B ). To address patient heterogeneity, we further evaluated disease association of each cell type on a per patient basis. We found T cells were significantly associated with CD in 43 out of 46 patients in TI, and 33 out of 43 patients in AC (FDR <= 0.1). LND cells were significantly related to CD in 13 out of 31 patients in TI and 8 out of 25 patients in AC (FDR <= 0.1) (Fig.  7C, D ). In one CD patient (GCA062) with severe TI involvement, LND was significantly associated with CD, superceding the involvement of immune cells outside of recruited macrophages (FDR = 0.001 for LND, FDR = 0.001 for T cells, FDR = 0.0008 for recruited macrophages). LND cells in this patient expressed high levels of NOS2 and CXCL5 , suggesting that this population is likely disease-critical (Supplementary Fig.  23C ). In contrast, no significant patient-specific association was observed for any other epithelial cell types, endothelial cells, or fibroblasts. These findings support the conclusion that LND cells might drive a significant portion of CD via dysregulated LND-immune cell communication.

In this study, we present a comprehensive single-cell atlas of 170 specimens from 83 individuals, consisting of 202,359 cells from the terminal ileum and ascending colon of human gut in non-IBD controls and inactive and active CD patients. We confirmed prior findings about region-specific transcriptomics to maintain physiologic function of the intestine and colon. Despite the distinct epithelial transcriptome between the TI and AC, we identified similar cellular rewiring in epithelial, immune, and stromal cell proportions with CD activity. For example, T cells, Mast, and recruited macrophages expand from inactive to active CD. In addition to histology-based classification, we investigated changes in cellular compositions using the Clinical Disease Activity Index (CDAI), the most commonly used non-invasive standard for assessing disease activity (Supplementary Data  1 ). However, we did not observe significant correlations between the proportions of any cell types and CDAI scores (Supplementary Fig.  24 ). This outcome is likely attributed to inherent limitations in the CDAI, including subjective questions based on patient reported symptoms/overall well-being and variability when incorportating ideal versus actual body weight.

Most interestingly, we uncovered a special epithelial cell type, named LND, in both the TI and AC with high expression of LCN2, NOS2 , and DUOX2 . LND cells were rarely detected in non-IBD controls, but expanded significantly in active CD. While the LND proportion indicates CD activity, its direct application in clinical settings is not straightforward. Notably, we found a significant correlation between the average expression of LCN2 , NOS2 , and DUOX2 and LND proportions ( r  > 0.8). Moreover, there was substantial upregulation of the average expression in active CD compared to inactive CD, as well as inactive CD compared to non-IBD controls ( p  < 0.001), in both the TI and AC (Supplementary Fig.  25 ). These findings suggests that the average expression levels of these three genes could potentially serve as reliable surrogates in clinical settings to estimate the LND population and provide additional insights into disease activity beyond histology. Moreover, we observed a significant increase in the chemokines CXCL1 and CXCL9, and the cytokine IL6 in the serum from patients with high LND proportion compared to those with low LND proportion (Supplementary Fig.  26 ), suggesting LND status may predict differences in the level of systemic inflammation.

Compared to other enterocytes/colonocytes, LND cells had high expression of anti-microbial proteins (such as REG1A , REG1B , LYZ , PLA2G2A , SAA1 / SAA2 ), inflammatory cytokines (such as CXCL2 , CXCL3 , CXCL5 , CCL20 , CCL28 ), as well as antigen-presentation and processing genes, STAT3 and STAT1 , indicating a specialized immunoregulatory role. Cell–cell communication analysis supported that LND cells may actively interact with a variety of immune cells as signaling senders. Transwell migration assays provided evidence supporting the role of LND status in monocyte recruitment and spatial transcriptomics further showed the colocalization of LND and immune cells. The cross-talk between LND and immune cells highlights the role of LND in regulating mucosal immunity.

The intestinal epithelium is known to be the central coordinator of mucosal Immunity, which requires a synergy of distinct epithelial cell types to promote homeostasis. These cell types carry out unique and specialized functions, including enterocytes/colonocytes for nutrient and water absorption, goblet cells for secreting mucins, Paneth cells for releasing antimicrobial peptides, and enteroendocrine cells for producing hormones. LND cells, in comparison, highly expressed some host defense-related genes which are cell-type specific in homeostatic conditions. For example, REG1B, LYZ , and PLA2G2A , which are antimicrobial peptides specifically released from Paneth cells, are highly expressed in LND cells. Consistently, previous studies found that expression of genes that are cell-type specific in homeostatic conditions was broadened across multiple cell types during infection 11 . Therefore, LND cells are highly likely to be derived from enterocytes/colonocytes under chronic inflammatory stress, leading to specialized functions in immunoregulation. Studying the developmental origins of LND cells also supports that LND cells may originate from early enterocytes or intermediate/mature enterocytes.

LND cells not only had high expression of cell-type specific genes as mentioned above, but also showed high expression of IBD/CD GWAS-risk genes, such as NOS2 , CCL20 , TNFRSF1A , and STAT3 . The specific expression of IBD/CD-risk genes suggest LND cells are a critical disease cell type. The disease-association of LND cells was quite heterogenous across patients. In TI, LND cells in ~30% of CD patients showed significant disease association and were ranked the second most important cell type. The heterogeneity of LND cells also reflects the complex and multifactorial pathogenesis of CD. In addition to IBD/CD-risk genes, LND cells were marked by high expression of additional genes previously demonstrated to modulate colitis, indicating their potential pathogenic role. Our studies identified that hematopoietic-LND cell interactions play an important role in regulating host response and driving CD, which extends previous findings emphasizing hematopoietic-stromal interactions as a central hub in IBD pathology 15 , 19 , 30 .

Taken together, our study identified a special LND cell population with unique molecular features enriched in immunoregulation, providing a better understanding of the mechanisms sustaining the pathogenic process in Crohn’s disease. Our results indicate that LND marker genes and their cellular proportion could have clinical significance as markers of disease activity, risk for disease progression, or likelihood of anti-TNF response. Our findings establish the possibility of meet evolving clinical needs with characterization and personalized treatment of CD at the molecular level, which would greatly benefit future clinical studies.

Human specimen collection and processing

The study protocol was approved by the Institutional Review Board at Vanderbilt University Medical Center. Written informed consent was obtained from non-IBD control and CD subjects to obtain serum samples, as well as, terminal ileum (TI) and ascending colon (AC) tissues at the time of scheduled endoscopic procedures. TI and AC tissues from non-IBD control and CD subjects undergoing surgical resection were also obtained from under a separate IRB protocol in coordination with the Comparative Human Tissue Network (CHTN). All samples were obtained as a part of the clinical trial “Combinatorial Single Cell Strategies for a Crohn’s Disease Gut Cell Atlas”, identifier NCT04113733 ( clinicaltrials.gov ).

Between December 2019 and January 2022, endoscopy subjects were prospectively recruited in the IBD clinic or GI endoscopy unit at Vanderbilt University Medical Center prior to colonoscopy for CD disease activity assessment or non-IBD indications including colorectal cancer screening or polyp surveillance. Surgical resection subjects were those undergoing resection for CD-related complications or other non-inflammatory indications, including endoscopically unresectable polyps. Patient participation in the current study ended after serum and/or tissue samples were obtained. Exclusion criteria for the study were: pregnancy, known coagulopathy or bleeding disorders, known renal or hepatic impairment, history of organ transplantation, or inability to give informed consent. After appropriate exclusions, there were 65 CD subjects with varying disease activity and 18 non-IBD controls.

For all participants, demographics including age, gender, medical history, and medication use were determined from participant reporting and review of the electronic medical record. Serum samples were obtained at the time of colonoscopy and were snap frozen with dry ice and then stored at −80 °C 39 , 67 . Tissue biopsies for research purposes in the TI and AC were obtained as follows: fresh tissue biopsies were placed in chelation buffer (4 mM EDTA, 0.5 mM DTT in DPBS) for further processing and scRNAseq analysis, and an adjacent set of tissue biopsies were formalin-fixed and paraffin-embedded (FFPE) for research blocks. 5 µm sections were used from each FFPE block and stained with hematoxylin and eosin (H&E) and examined in a blinded manner by a gastrointestinal pathologist (MKW) and graded accordingly as: inactive (normal_CD, quiescent) or active (mild, moderate, or severe activity). All associated study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at Vanderbilt 68 , 69 , including Clinical Data Interoperability Services, such as Clinical Data Pull 70 and e-consent 71 .

Single-cell encapsulation and library generation

Single-cell RNA-sequencing was performed on human biopsies and surgical specimens 72 , 73 . For surgical specimens that were large (>2 mm 2 ), a representative portion (~2 mm 2 ) of the tissue was used, while smaller tissues and biopsies were processed directly. Briefly, tissues were incubated in a chelating buffer (0.5 M EDTA, 0.1 M DTT in DPBS) for 1.25 h, and then transferred to cold active protease (5 mg/ml Protease from Bacillus licheniformis, 2.5 mg/mL dNase in PBS) and incubated with rotation for 25 min at 4 ˚C. Tissues were then pipetted 10–20 times to yield single cells. Cell suspensions were filtered, washed, and inspected for count and quality before loading onto a microfluidics platform for inDrops single-cell encapsulation using standard inDrops scRNA-seq gel-beads 74 , 75 . We targeted 2–3000 cells captured per sample, at a rate of encapsulation not exceeding 15 min total time. Single-cell libraries were prepared for sequencing using the Trudrop library structure to enable dual indexing 76 . Libraries (consisting of an estimated 2000–3000 cell transcriptomes) were sequenced at ~125 million reads each on the Novaseq6000.

HCR FISH was performed for three targets mRNAs using three DNA probe sets DUOX2, LCN2, and NOS2, using the HCR™ RNA-FISH Protocol for FFPE tissue sections 77 . Tissue slides were baked at 60 °C for 1 h, followed by tissue deparaffinization by immersing slides in Xylenes, 3X for 5 min. After deparaffinization, slides were incubated in 100% Ethanol, 2X for 3 min. Rehydration of tissue slides was done by series of graded ETOH washes at 95%, 70%, and 50% concentrations followed by nanopure water wash. After the rehydration steps, slides were immersed for 15 min in Tris-EDTA buffer (pH 9.0) at 95 °C. Tris-EDTA buffer temperature was slowly cooled down to 45 °C in 20 min, by adding nanopure water every 5 min. Slides were kept in nanopure water for 10 min at room temperature, followed by PBS1X wash. Proteinase K was introduced at 0.5 µL of 20 mg/1 mL PBS1X concentration, for 10 min at 37 °C, followed by PBS1X washes. 200 µL of Probe Hybridization Buffer was added on top of each tissue sample for pre-hybridization and slides were kept in humidified chamber, at 37 °C, for 10 min. Probe solution was prepared by adding 0.4 µL of 1 µM Stock/100 µL of probe hybridization buffer at 37 °C for DUOX2 and LCN2 probe sets and 0.8 µL of 1 µL of 1 µM stock/100 µL of probe hybridization buffer at 37 °C for NOS2 probe set. Pre-hybridization solution was removed from tissue slides and 100 µL of the Probe solution was added on top of each tissue sample. Sample slides were covered with parafilm and incubated overnight at 37 °C in the humidified chamber. Excess probes were washed by incubating slides at 37 °C in: (a) 75% of probe wash buffer/25% 5X SSCT for 15 min, (b) 50% of probe wash buffer/50% 5X SSCT for 15 min, (c) 25% of probe wash buffer/75% 5X SSCT for 15 min, (d) 100% 5X SSCT for 15 min. Slides were immersed in 5X SSCT for 5 min at room temperature. For pre-amplification, 200 µL of amplification buffer was added on top of each tissue sample for 30 min at room temperature. 2 µL of 3 µM stock hairpins h1 and h2 (per slide), for each probe set, were separately heated at 95 °C for 90 s and cooled to room temperature in the dark for 30 min. Hairpin solution was prepared by adding snap-cooled hairpins h1 and snap-cooled hairpins h2 to 100 µL of amplification buffer at room temperature. Pre-amplification buffer was removed and 100 µL of the hairpin solution was added on top of each tissue sample. Slides were incubated overnight ≥12 h at Room temperature. Excess hairpins were removed by incubating slides in 5X SSCT at room temperature for 1 × 5 min, 2 × 15 min and lastly 1 X for 5 min. Slides were dried by blotting edges on a kimwipe. 100 µL of Hoechst stain (1:100 dilution) was added on top of each tissue slide and slides were incubated at room temp for 5 min. Cover slipping was done by using Invitrogen Prolong™ Gold antifade reagent. Slides were imaged using the Aperio Versa slide scanner (Leica). Probe sets were designed by Molecular Instruments: LCN2 Probe set: probe set size 13 targeting NM_005564.5, DUOX2 Probe set: probe set size 20 targeting NM_014080.5, NOS2 Probe set: probe set size 20 targeting NM_000625.4.

Multiplex immunofluorescence and image analysis

Multiplex immunofluorescence (MxIF) imaging was performed on FFPE sections at 4 μm after standard histological processing and antigen retrieval. Slides were iteratively stained using a fluorescence-inactivation protocol 78 , 79 , using directly labeled or bench-conjugated antibodies incubated overnight at 4 °C. Slides were scanned using the Aperio Versa (Leica) at ×20 magnification, and then were photo-inactivated with an alkaline peroxide solution for repeated staining and imaging cycles until images for all analytes were acquired. A validated antibody panel was used, including DAPI, NAKATPASE, PANCK, CD8, CD4, and CD45 72 . The following antibodies were used for LND: LCN2 (Novus Biologicals, Cat. number NB100-1503) with secondary (Jackson ImmunoResearch, Cat. number 705-547-003), NOS2 (Novus Biologicals, Cat. number NBP2-22119AF750), and DUOX2 (Novus Biologicals, Cat. Number NB110-61576AF647). Images were computationally registered and corrected for illumination and autofluorescence against the interlaced blank imaging rounds. Cells were segmented with an algorithm modified from one published 80 , using a combination of machine learning, computed membrane completion, and image watershed using a combination of multiple membrane markers. Cells meeting a certain quality thresholds of size were kept. The mean, standard deviation, median, and maximum staining intensity for each protein was quantified with respect to the whole cell, cell membrane, cytoplasm, and nucleus. Location, area, and shape metrics were obtained. Cells were clustered based on the similarity of protein intensity profiles and each cluster was annotated by positive expression of known marker genes.

Immunohistochemistry

IHC was performed for three targets LCN2, NOS2, DUOX2. Tissue slides were baked at 60 °C for 1 h, followed by tissue deparaffinization by immersing slides in Xylene. After deparaffinization, slides were incubated in 100% ethanol. Rehydration was done by a series of graded ethanol washes at 95%, 90%, and 80% concentrations followed by a distilled water wash. Antigen retrieval was performed by rinsing slides in PBS, then slides were immersed in retrieval solution (DAKO target retrieval, pH 9) under pressure using a Biocare Decloaking Chamber. Slides were then rinsed with PBS. 3% hydrogen peroxide was applied to the slides for 15 min followed by Universal Protein Block (DAKO, Cat. #X0909) for 40 min at room temperature. The protein block was removed, and the slides rinsed with PBS for 5 min. Diluted primary antibody was applied to the slides and allowed to incubate overnight at 4 °C. Antibodies used were: LCN2 (Sigma, Cat. #HPA002695, 1:300), NOS2 (Novus Biologicals, Cat. Number NBP2-99091, 1:600), and DUOX2 (Novus Biologicals, Cat. Number NB110-61576, 1:300). The slides were rinsed with PBS. HRP-labeled polymer anti-Rabbit (DAKO, Cat. #K4003) was allowed to incubate at room temperature for 45 min, then the slides were rinsed with PBS. DAB+ substrate (DAKO, Cat. #K3468) was applied for 3–5 min at room temperature, then the slides were rinsed with PBS. Counterstain with CAT hematoxylin (Biocare Medical, Cat. #CATHE-MM) was applied for 1 min. The slides were rinsed with deionized water 6–10 times for 1 min each. Tacha’s bluing solution (Biocare Medical, Cat. #HTBLU-MX) was applied for 45 s at room temperature. The slides were rinsed with deionized water 6–10 times for 1 min each. Next slides were dehydrated with xylene and ethanol. Cover slipping was done by using cytoseal (Epredia, Cat. #8312-4). Slides were imaged using the Aperio AT2 Bright Field slide scanner (Leica).

Spatial transcriptomics

Spatial transcriptomics was performed using the Human FFPE Visium platform version 1 81 . FFPE sections (5 μm) of biospies were cut and directly placed onto 6.5 mm × 6.5 mm capture areas of Visium FFPE spatial gene expression slides (10X Genomics). Visium slides were stained with hematoxylin and eosin, temporarily coverslipped, and imaged in brightfield at ×20 magnification using Aperio Versa (Leica) prior to tissue permeabilization, probing, and library prep according to the Human Visium FFPE protocol (10X Genomics). Sample libraries were sequenced on the NovaSeq6000 sequencer (Illumina) adjusted to ~50,000 reads per spot. Resulting sequencing data were aligned using 10X Genomics Space Ranger version 1.3.0 (10X Genomics).

Single-cell RNAseq alignment and quality control

Single-cell RNAseq reads were filtered, demultiplexed, and quantified by dropEst v0.8.6 82 to generate cell-by-gene count matrices. Specifically, reads with expected structure were kept, and cell barcodes and UMI were extracted by dropTag. Demultiplexed reads were aligned to the human reference transcriptome GRCh38 using STAR v2.7.9a 83 . Uniquely mapped reads were quantified into UMI-filtered counts by dropEst v0.8.6. Cells with >40% mitochondria reads, or <500 UMI counts, or <200 or >6000 genes expressed were considered as low quality and excluded. After this rough quality control, each sample was manually checked to remove those clusters of empty droplets (low number of UMI and genes, and no distinct markers) and clusters of doublets (high number of UMI and genes, and markers from two different cell types). Samples with cells less than 100 were excluded from the downstream analysis. Outliers and batch effects were detected using scRNABatchQC v0.10.3 84 .

Single-cell RNAseq data analysis

Single-cell RNAseq count matrices were normalized to 10,000 and the top 2000 highly variable genes were selected by fitting the variance-mean relationship in the Seurat v4.1.0 package 85 , 86 . The normalized data were scaled to z-scores and principal component analysis was performed to reduce dimension. The top 30 principle compoents were used to generate the UMAP embedding for visualization and to to build the k -nearest neighbor graph (k = 20). Louvain clustering at a resolution of 0.8 was applied on the graph to partition cells into non-overlapping groups by the Seurat v4.1.0. Cell clusters were automatically annotated by a marker-based approach scMRMA v1.0 87 and were further manually curated using cluster-specific genes from the differential expression analysis. Specifically, the categorization of early, intermediate, and mature enterocytes/colonocytes was established through a multi-perspective approach. Firstly, we considered markers identified in previous studies, such as high expression of FREM1 , PCCA , and DMBT1 in early enterocytes, RBP2 in intermediate enterocytes, and APOA1 , APOC3 , APOA4 , and GUCA2B in mature enterocytes 13 . Similarly, early colonocytes were defined by high expression of B3GNT7 , ABR , and ADH1C , intermediate colonocytes by ATP5G1 and PCNP , and mature colonocytes by AQP8 , GUCA2A , CA4 , and CEACAM1 13 (Supplementary Fig.  10 ). Moreover, differentiation among early, intermediate, and mature colonocytes was determined using a crypt-axis score as proposed by Parikh et al. 14 , where mature colonocytes, locate at the crypt-top with the highest scores, contrast with early clonotypes situate at the crypt-bottom with the lowest scores (Supplementary Fig.  10 ). Secondly, we employed cell differentiation state and trajectory analysis, with detailed methods outlined in the Developmental Trajectory analysis. The clustering and annotation results served as the input to scUnifrac v0.9.6 29 to quantify cell compositional distances across samples, which considered both cellular compositions and similarities. Multidimensional scaling was used to map each sample into a space based on pairwise distances from scUniFrac v0.9.6.

Cell type deconvolution for bulk transcriptomics data

CIBERSORT v1.05 59 was applied to characterize the cell composition of bulk RNAseq data using single-cell transcriptional profiles of each cell type from TI and AC as the reference. The signature matrix was created from average expression of the top 100 marker genes in each cell type. Default parameters were used to implement CIBERSORT v1.05, except that the parameter of quantile normalization of bulk mixture was set to False.

Cell–cell interaction analysis

CellChat v1.4.0 60 was used to infer communications between cell types through ligand–receptor interaction analysis from single-cell RNAseq data of TI and AC separately. The standard workflow was followed with the normalized data and the annotated cell types as inputs. The built-in database CellChatDB.human involving 1939 interactions was used as a reference to screen potential ligand–receptor interactions. The communication probablility was quantified between cell types having at least 10 cells. The average gene expression per cell type was caculated without trimming.

Development trajectory analysis

RNA velocity v0.6 55 was applied to infer lineage relationships between epithelial cell populations and predict future transcriptional state of a single cell. First, the loom file including spliced/unspliced matrices was generated from the bam file using Velocyto. Then velocity was calculated by the function RunVelocity in the SeuratWrapper v0.3.0 package with default parameters. The velocity was plotted on the pre-computed UMAP embedding and colored by the annotated cell types. As anticipated, we observed a pronounced directional flow starting from stem cells, progressing through early enterocytes, intermediate enterocytes, and culminating in mature enterocytes (Fig.  4A ).

CytoTRACE v0.3.3 57 was performed to predict stemness status from single-cell RNAseq data based on the assumption that the number of genes expressed in a cell decreases during differentiation. CytoTRACE v0.3.3 was implemented with default parameters and the raw count matrix of each sample as the input. A CytoTRACE score was assigned to each cell based on its differentiation potential, with higher score indicating higher stemness. CytoTRACE scores from different samples were grouped by cell types and score differences between two cell types were compared by Wilcoxon rank-sum test. As anticipated, stem cells exhibit the highest score, indicating undifferentiated status, followed by early and intermediate enterocytes, while mature enterocytes register the lowest score, signifying full differentiation (Fig.  4D ).

Partition-based graph abstraction (PAGA) v1.3.3 56 was used to reconstruct lineage relationships of epithelial cell populations. First, the Seurat object was converted to h5ad file for the PAGA input. Then, a neighborhood graph was computed based on the size of local neighborhood of 50 and the number of PCs of 30 using scanpy. Finally, the connections between cell types were quantified. The connections of weight less than 0.2 were removed.

Cell types associated with CD/IBD-risk Loci

SNPsea algorithm v1.0.3 63 was used to identify cell types associated with CD/IBD-risk SNPs based on the assumption that genes specificity to a cell type is an indicator of its importance to the cell type function. Thus if one cell type have significant enrichment of specific genes associated with GWAS risk loci, this cell type is highly likely to be pathogenic and critical to the disease. The CD/IBD-risk SNPs were compiled from two GWAS studies 5 , 6 , which reported 344 loci in total. A pseudobulk dataset for each cell type with greater than nine cells in CD was generated by summing all UMI counts for each gene in each cell type and adding pseudocount of 1. The data were then normalized by DESeq2 to remove the effects introduced by cell cluster-sizes. SNPsea was run with defult parameters and all genes in a SNP’s linkage interval are accounted when calculating scores. The p -values were further adjusted by the Benjamini-Hochberg multiple testing procedure.

Cell type deconvolution and spatial colocalization

Robust Cell-Type Decomposition (RCTD) 62 in the spacexr v2.2.1 package was applied to deconvolve cell type compositions of each spot. Single-cell RNAseq data and cell types annotations from all TI and AC samples were used as the reference to decompose spatial TI and AC samples, respectively. The anchor-based integration workflow in the Seurat v4.1.0 was also used to predict the underlying composition of cell types in each spot and similar results were obtained.

SpaGene v0.1.0 61 was used to quantify colocalization of markers of epithelial genes ( KRT8 and KRT18 ) and LND ( LCN2 , NOS2 , and DUOX2 ) with immune cell signatures ( CD3D , CD8A , GZMB , MRC1 , S100A8 , NFKB1A , and NFKB1B ). Z-scores and FDR values were generated to estimate the significance of spatial connections of two genes (such as NOS2 and CD8A ) compared to random distributions. SpaGene v0.1.0 was also performed to quantify colocalization between epithelial and immune cells based on the inferred composition of each cell type from RCTD 62 . Z-scores and FDR values were produced to estimate the significance of spatial colocalizations of two cell types (such as LND and Neutrophils) compared to random connections.

Human colon organoids

Colonoscopic biopsies were obtained from patients in these groups: non-IBD controls with normal histology, inactive CD, and active CD under a VUMC IRB protocol. Fresh tissues were used to generate and maintain colon organoids as follows 88 . Tissues were incubated in 10 mM EDTA in PBS at 4 °C for 30 min. Tissues were then transferred to dissociation buffer (43.5 mM sucrose and 54.9 mM D-sorbitol in PBS) and shaken to release the crypts. After centrifugation, the crypts were resuspended and plated in Matrigel, which was overlaid with IntestiCult™ Organoid Growth Medium (Stemcell Technologies) supplemented with penicillin-streptomycin-gentamicin, 10 μM Y-27632 (Tocris) and 4 μM CHIR 99021 (Tocris). Then, cells were maintained in the same media without gentamicin or Y-27632, for a maximum of 10 passages. For experiments, the organoids were cultured in 24-well plates in Matrigel with IntestiCult TM Organoid Differentiation Medium supplemented with antibiotics with the media changed daily. On day 7, the entire 500 µl of conditioned media was collected from each well.

RNA expression in human colon organoids

Organoids maintained in Matrigel were treated with Cell Recovery Solution TM (Corning) and pelleted by centrifugation. Total RNA was isolated using the RNeasy Mini kit (Qiagen). For RT-real-time PCR, reverse transcription was first performed using the Superscript IV Reverse Transcriptase kit (Invitrogen) and Oligo dT (Invitrogen); then mRNAs were amplified using the PowerUp SYBR Green Master Mix (Invitrogen) 88 . The primer sets used were listed in Supplementary Data  6 .

Transwell TM monocyte cell migration assays

CD14+ monocytes were isolated from human peripheral blood mononuclear cells (PBMCs) from four healthy donors with the EasySep™ Human CD14 Positive Selection Kit II (STEMCELL Technologies, #17858) per the manufacturer’s protocol. Cells were counted and 100,000 live cells diluted in 200 µL of serum-free RPMI 1640 media (Gibco, #11875093) were added to the apical compartments of 8.0 µm pore size ThinCert™ inserts (Greiner Bio-One, #662638) in the 24-well plate. The basolateral compartments contained 400 µL colonoid conditioned media. Cells were allowed to migrate for 90 min at 37 °C, and then inserts were removed, washed once with PBS, and stained with the Hema 3™ Manual Staining System (Fisher Scientific, #23-123869) per the manufacturer’s protocol. Stained inserts were imaged on a brightfield microscope at ×20 or ×40 magnification. Migrated cells inside the pores of the inserts were manually counted by an observer blinded to the conditioned media source, and were then normalized to total image area in cm 2 .

The negative binomial mixed model using the glmmTMB package was performed to estimate the difference in the number of migrated cells between control, inactive CD, active CD with low LND, and active CD with high LND. The negative binomial distribution fitted the count data well and the mixed model considered repeated measurements from different fields and different wells within each experiment.

Serum cytokine analysis

Serum cytokines were measured using Luminex technology with Milliplex MAP (Millipore, Billerica, MA) multiplex magnetic bead-based antibody detection kits, which were used according to the manufacturer’s protocol 39 , 67 . Serum samples were analyzed with a pre-mixed cytokine analyte kit. Samples were run in duplicate and quality control samples were run across plates and assayed on a FLEXMAP 3D machine 39 , 67 .

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

The scRNA-seq data generated in this study have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database under accession number GSE266546 . The five microarray datasets and one bulk RNA-seq dataset for CD and control patients, as well as the microarray dataset for anti-TNF treatment, were downloaded from public source under accession numbers GSE179285 , GSE75214 , GSE186582 , GSE112366 , GSE20881 , GSE66207 , and GSE16879 , respectively.  Source data are provided with this paper.

Code availability

The code used for the analysis is available at GitHub [ https://github.com/JiaLiVUMC/GCA_LND ].

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Acknowledgements

We thank Dr. Nicholas Zachos and I-Ling Chiang for their helpful contributions. This work is part of the Gut Cell Atlas Crohn’s Disease Consortium funded by The Leona M. and Harry B. Helmsley Charitable Trust and is supported by a grant from Helmsley to Vanderbilt University Medical Center (G-1903-03793) ( http://www.helmsleytrust.org/gut-cell-atlas/ ) (K.T.W., L.A.C., K.S.L., Q.L. and B.A.L.). This work was also funded National Institutes of Health (NIH) grants P01AI139449 (Q.L.), R01DK103831 (K.S.L.), R01 DK128200 (K.T.W.), P50CA236733 (Y.S. and Q.L.), P01CA229123 (Q.L.), P01CA116087 (K.T.W.), and U54 CA274367 (Q.L.); Veterans Affairs Merit Review grants I01BX004366 (L.A.C.), I01CX002171 (K.T.W.), and I01CX002473 (K.T.W.), Department of Defense PRCRP Impact Award W81XWH-21-1-0617 (K.T.W.), Crohn’s & Colitis Foundation Senior Research Award 703003 (K.T.W.), the James Rowen Fund (K.T.W.), Cure for IBD (K.T.W.), and NCI/NIH Cancer Center Support Grant P30CA068485 (Y.S.). Additional support was provided by NIH grant P30DK058404 (Vanderbilt Digestive Disease Research Center) (K.T.W.). Use of REDCap was supported by NCATS/NIH grant UL1TR000445 (Vanderbilt Institute for Clinical and Translational Research and REDCap). Whole slide imaging and quantification were performed in the Digital Histology Shared Resource of the Vanderbilt University Medical Center Digestive Disease Research Center. Surgical resection specimens were provided by the Cooperative Human Tissue Network (CHTN), which is funded by National Cancer Institute grant UM1CA183727 (M.K.W.). De-identified human PBMCs from four healthy donors were provided by the Vanderbilt Center for Immunobiology.

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Contributions

Q.L., K.S.L., L.A.C. and K.T.W. conceived the project and acquired funding. J.L. performed the main analysis and generated figures. A.J.S., N.T. and Y.X. contributed to data curation on single cell RNA-seq and spatial transcriptomics. H.K. and P.N.V. performed the formal analysis. N.T. and H.K. contributed to validation on HCR-FISH. M.A.R. performed the alignment of single cell RNA-seq data. Y.S. guided the experimental design and analysis. J.T.R contributed to data curation on MxIF data. J.L., S.B., C.C., L.A.C., Y.H. and B.A.L. performed the analysis for MxIF data. L.A.C., S.C., R.N.T. and L.W.R screened and consented patients, collected human samples. S.C. and R.N.T. maintained REDCap database. D.B.B., R.L.D., S.N.H., B.S.P., E.A.S. and D.A.S. obtained tissue biopsies. K.T.W., J.A.G. and Y.A.C. designed experiments. C.V.H., F.R., J.M.P., J.J., K.M.M., M.M.A. and M.A. performed experiments. A.N.C., G.A.R. and A.P.G. performed the analysis for experiment data. M.K.W. reviewed and graded tissue histopathology. Q.L. guided and performed the analysis and drafted the manuscript. Q.L., K.S.L., L.A.C. and K.T.W. wrote and revised the manuscript. All authors approved the final manuscript.

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Correspondence to Keith T. Wilson , Lori A. Coburn , Ken S. Lau or Qi Liu .

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Li, J., Simmons, A.J., Hawkins, C.V. et al. Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease. Nat Commun 15 , 7204 (2024). https://doi.org/10.1038/s41467-024-51580-7

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Received : 28 August 2023

Accepted : 13 August 2024

Published : 22 August 2024

DOI : https://doi.org/10.1038/s41467-024-51580-7

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Crohn's and Colitis UK: Inflammatory Bowel Disease Patient Involvement in Research Day 2024

Date: 06/11/2024 to 06/11/2024 Venue: Online, Zoom

This year, Crohn's and Colitis UK's Inflammatory Bowel Disease (IBD) Patient Involvement in Research Day will be held on Saturday 16 November 2024 on Zoom

This is an opportunity for people affected by Crohn’s or Colitis to hear from pioneering researchers about their latest projects and have the chance to actively shape that research by responding to questions from the researchers through live voting.

The keynote speaker this year is Dr James Lee whose recent research into the causes of IBD has been widely reported.

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