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Review
. 2021 Jul;302(1):211-227.
doi: 10.1111/imr.12974. Epub 2021 May 16.

Novel mechanisms and clinical trial endpoints in intestinal fibrosis

Jie Wang  1   2 , Sinan Lin  2   3 , Jonathan Mark Brown  4 , David van Wagoner  4 , Claudio Fiocchi  2   5 , Florian Rieder  2   5
Affiliations
Review

Novel mechanisms and clinical trial endpoints in intestinal fibrosis

Jie Wang et al. Immunol Rev. 2021 Jul.

Abstract

The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti-fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non-immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host-microbiome interactions, creeping fat, and their translation for endpoint development in anti-fibrotic clinical trials.

Keywords: creeping fat; cytokine; inflammatory bowel disease; intestinal fibrosis; myofibroblasts; single-cell RNA sequencing.

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Conflict of interest statement

Competing interests:

F.R. is consultant to Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, UCB. None of the other authors has any competing interest to declare.

Figures

Figure 1.
Figure 1.
The main cell types and cell differentiation mechanisms involved in ECM secretion and fibrosis in intestine. EMT, epithelial-mesenchymal transition; EndoMT, endothelial-to-mesenchymal transition; TLR, Toll-like receptor; NLR, Nod-like receptor; IL, interleukin; TNF, tumor necrosis factor; TGF-β1, transforming growth factor beta 1.
Figure 2.
Figure 2.
Novel mechanisms underlying intestinal fibrosis. IL, interleukin; TLR, Toll-like receptor; LOX, lysyl oxidases; TNFSF14, tumor necrosis factor superfamily member 14; PDPN, podoplanin; CTHRC1, collagen triple-helix repeat-containing 1; CHI3L1, chitinase-3-like 1.
Figure 3.
Figure 3.
Proposed pathway to develop anti-fibrotic medications in IBD
See this image and copyright information in PMC

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