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ABSTRACT
Introduction
Intestinal fibrosis is a common and serious complication of inflammatory bowel diseases (IBD) driving stricture formation in Crohn’s disease patients and leading to submucosal damage in ulcerative colitis. Recent studies provided novel insights into the role of immune and nonimmune components in the pathogenesis of intestinal fibrosis. Those new findings may accelerate the development of anti-fibrotic treatment in IBD patients.
Areas covered
This review is designed to cover the recent progress in mechanistic research and therapeutic developments on intestinal fibrosis in IBD patients, including new cell clusters, cytokines, proteins, microbiota, creeping fat, and anti-fibrotic therapies.
Expert opinion
Due to the previously existing major obstacle of missing consensus on stricture definitions and the absence of clinical trial endpoints, testing of drugs with an anti-fibrotic mechanism is just starting in stricturing Crohn’s disease (CD). A biomarker to stratify CD patients at diagnosis without any complications into at-risk populations for future strictures would be highly desirable. Further investigations are needed to identify novel mechanisms of fibrogenesis in the intestine that are targetable and ideally gut specific.
Article highlights
New cell clusters of activated fibroblasts and other mesenchymal cell populations were identified by single-cell RNA-sequencing and are summarized.
Recent study on the role of creeping fat and muscle hyperplasia in intestinal fibrosis is detailed.
New therapeutic developments for intestinal fibrosis and the largest gaps in this field are discussed.
Abbreviations
| AIEC | = | Adherent invasive E-coli |
| Akt | = | Protein kinase B |
| ASCs | = | Adipose tissue-derived stem cells |
| CDH11 | = | Cadherin-11 |
| CD | = | Crohn’s disease |
| CXCL14 | = | CXC motif chemokine ligand-14 |
| DR3 | = | Death domain receptor 3 |
| DSS | = | Dextran sodium sulfate |
| ECM | = | Extracellular matrix |
| EMT | = | Epithelial to mesenchymal transition |
| ER | = | Endoplasmic reticulum |
| HIMCs | = | Human intestinal muscle cells |
| IBD | = | Inflammatory bowel diseases |
| IL | = | Interleukin |
| MC | = | Mast cell |
| MMP | = | Matrix metalloproteinase |
| mTOR | = | Mammalian target of rapamycin |
| MyD88 | = | Myeloid differentiation protein 88 |
| PAMPs | = | Pathogen-associated molecular patterns |
| PAR-2 | = | Protease-activated receptor-2 |
| scRNA | = | Single-cell RNA |
| SIRT4 | = | Silent information regulator |
| ST2 | = | Interleukin-1 receptor like-1 |
| STAR | = | Stenosis Therapy and Anti-Fibrotic Therapy |
| TGF-β | = | Transforming growth factor-β |
| TLR | = | Toll-like receptor |
| TNBS | = | 2,4,6-Trinitrobenzene sulfonic acid |
| TNF0 | = | Tumor necrosis factor |
| TL1A | = | Tumor necrosis factor-like cytokine 1A |
| UC | = | Ulcerative colitis |
Declaration of interest
F Rieder is consultant to Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jansen, Koutif, Metacrine, Morphic, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Takeda, Techlab, Thetis, UCB, 89Bio. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Author’s contribution
Study design: F Rieder, J Wang; Execution/data collection: All authors; Data compilation and analysis: All authors; Oversight/advisory: All authors; Wrote and edited manuscript: All authors; Acquired funding, regulatory approvals: F Rieder
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.