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  • Review Article
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Revisiting fibrosis in inflammatory bowel disease: the gut thickens

Nature Reviews Gastroenterology & Hepatology volume 19, pages 169–184 (2022)Cite this article

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Abstract

Intestinal fibrosis, which is usually the consequence of chronic inflammation, is a common complication of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In the past few years, substantial advances have been made in the areas of pathogenesis, diagnosis and management of intestinal fibrosis. Of particular interest have been inflammation-independent mechanisms behind the gut fibrotic process, genetic and environmental risk factors (such as the role of the microbiota), and the generation of new in vitro and in vivo systems to study fibrogenesis in the gut. A huge amount of work has also been done in the area of biomarkers to predict or detect intestinal fibrosis, including novel cross-sectional imaging techniques. In parallel, researchers are embarking on developing and validating clinical trial end points and protocols to test novel antifibrotic agents, although no antifibrotic therapies are currently available. This Review presents the state of the art on the most recently identified pathogenic mechanisms of this serious IBD-related complication, focusing on possible targets of antifibrotic therapies, management strategies, and factors that might predict fibrosis progression or response to treatment.

Key points

  • Intestinal fibrosis — the excessive deposition of extracellular matrix (ECM) components by activated cells of mesenchymal origin in the intestinal wall — is a common complication of inflammatory bowel disease (IBD).

  • The main drivers of intestinal fibrosis are soluble molecules (for example, cytokines and growth factors), G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota.

  • Identification of biomarkers (such as antimicrobial antibodies, ECM components and clinical, endoscopic or environmental factors) might aid in the prediction or assessment of fibrosis in patients with Crohn’s disease.

  • No treatments are currently available for intestinal fibrosis in patients with IBD; however, several preclinical studies have shown the antifibrotic effect of newly identified compounds that might represent novel therapeutic approaches.

  • Standardized criteria for the diagnosis of small-bowel strictures and standardized definitions of outcome measures and treatment end points have now been published by a multidisciplinary panel of experts.

  • Fibrosis in patients with ulcerative colitis remains an underestimated issue; given its serious clinical implications, an urgent need exists for further studies to characterize, diagnose and treat this complication.

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Fig. 1: Molecular and cellular components involved in the pathogenesis of intestinal fibrosis.
Fig. 2: Microbial components that contribute to intestinal fibrosis.
Fig. 3: A possible approach to histopathological scoring of Crohn’s disease.
Fig. 4: Histopathological features of intestinal fibrosis in Crohn’s disease and ulcerative colitis.

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  1. These authors contributed equally: Silvia D’Alessio, Federica Ungaro.

Authors and Affiliations

  1. PhoenixLAB, Lodi, Italy

    Silvia D’Alessio

  2. Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy

    Federica Ungaro & Silvio Danese

  3. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy

    Daniele Noviello

  4. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Sara Lovisa

  5. IBD Centre, Laboratory of Gastrointestinal Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Sara Lovisa

  6. INSERM NGERE, University of Lorraine, Vandoeuvre-les-Nancy, Nancy, France

    Laurent Peyrin-Biroulet

  7. Nancy University Hospital, Vandoeuvre-les-Nancy, Nancy, France

    Laurent Peyrin-Biroulet

  8. University Vita-Salute San Raffaele, Milan, Italy

    Silvio Danese

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S.D. made a substantial contribution to discussion of content and reviewed or edited the manuscript before submission. S.D.’A. researched data for the article, made a substantial contribution to discussion of content, wrote, and reviewed or edited the manuscript before submission. F.U. researched data for the article, made a substantial contribution to discussion of content and wrote the article. D.N. researched data for the article and wrote the article. S.L. and L.P.-B. reviewed or edited the manuscript before submission.

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S.D. declares that she has served as a speaker, consultant, and advisory board member for Abbott (AbbVie), Actelion, Alfa Wasserman, Astra Zeneca, Cellerix, Ferring, Genentech, Grunenthal, Johnson and Johnson, Merck and Co, Millennium Takeda, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, UCB Pharma and Vifor. L.P.-B. declares that he has received personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boerhinger Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Merck Sharp & Dohme, Mylan, Nestlé, Norgine, Oppilan, OSE Immunotherapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots and Vifor; L.P.-B. also declares that he has received research grants from Abbvie, Merck Sharp & Dohme and Takeda and that he owns stock options in Clinical Trials Mobile Application (CTMA). The other authors declare no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks R. Mao, who co-reviewed with X. Zhuang, G. Latella and G. Bamias for their contribution to the peer review of this work.

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D’Alessio, S., Ungaro, F., Noviello, D. et al. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol 19, 169–184 (2022). https://doi.org/10.1038/s41575-021-00543-0

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