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Intestinal fibrosis in IBD—a dynamic, multifactorial process

Abstract

Intestinal fibrosis is a common and potentially serious complication of IBD that results from the reaction of intestinal tissue to the damage inflicted by chronic inflammation. The traditional view that fibrosis is inevitable or irreversible in patients with IBD is progressively changing in light of improved understanding of the cellular and molecular mechanisms that underlie the pathogenesis of fibrosis in general, and, in particular, intestinal fibrosis. These mechanisms are complex and dynamic, and involve multiple cell types, interconnected cellular events and a large number of soluble factors. In addition, owing to a breakdown of the epithelial barrier during inflammation of the gut, luminal bacterial products induce an innate immune response, which is triggered by activation of immune and nonimmune cells alike. Comprehension of the mechanisms of intestinal fibrosis will create a conceptual and practical framework that could achieve the specific blockade of fibrogenic pathways, allow for the estimation of risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, enable the development of treatments customized to the type and stage of each patient's IBD.

Key Points

  • Intestinal fibrosis is a common complication of IBD and represents a response of mesenchymal cells to injuries inflicted by chronic inflammatory insults

  • In addition to fibroblasts, several other cell types contribute to intestinal fibrosis, including stellate cells, bone marrow-derived cells, fibrocytes and pericytes

  • Events such as epithelial-to-mesenchymal and endothelial-to-mesenchymal transitions contribute to fibrosis

  • A large number of soluble factors present in IBD-affected tissue mediate intestinal fibrosis, among which transforming growth factor β1, interleukin 13, selected chemokines and proteolytic enzymes predominate

  • The enteric, commensal microbiota contribute to intestinal fibrosis by inciting an innate immune response mediated by immune and nonimmune cells

  • Experimental evidence indicates that blockade of selective signaling pathways can prevent or reverse fibrosis; therefore, intestinal fibrosis should not be considered an inevitable or irreversible component of chronic inflammation

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Figure 1: Schematic representation of the various cell types, cellular transformations, soluble mediators, and innate immune stimuli involved in the initiation and mediation of fibrogenesis in the inflamed intestine.

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Acknowledgements

The authors acknowledge the support of the Deutsche Forschungsgemeinschaft, Germany (F Rieder), and of the National Institutes of Health, Bethesda, MD, USA (C Fiocchi), and the technical assistance of J Kanasz, Cleveland Clinic Foundation, in illustrating this manuscript. The authors also acknowledge the contributions of several other colleagues whose work could not be cited due to space limitations.

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Correspondence to Claudio Fiocchi.

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Rieder, F., Fiocchi, C. Intestinal fibrosis in IBD—a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol 6, 228–235 (2009). https://doi.org/10.1038/nrgastro.2009.31

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