Fibrosis and Inflammation in Inflammatory Bowel Disease—More Than 2 Sides of the Same Coin?

See “Th17 cell–derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts,” by Zhao X, Yang W, Yu T, et al, on page 89. See “Th17 cell–derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts,” by Zhao X, Yang W, Yu T, et al, on page 89. Although the therapeutic management of inflammatory bowel disease (IBD) has improved with the advent of novel therapeutic agents (eg, JAK inhibitors and anti–interleukin [IL]-23), handling of disease-related complications still represents a large unmet clinical need. Intestinal fibrosis thereby represents a major complication of IBD that mainly affects patients with Crohn’s disease (CD), and manifests in the form of strictures and stenoses, causing reduced intestinal functionality and ultimately obstruction.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350.e6Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar As the pathophysiological processes driving fibrosis remain only partly understood, standardized fibrosis definitions; clinical trial design; and identification of biomarkers continue to be major challenges causing unavailability of antifibrotic drugs.2Bettenworth D. Rieder F. Medical therapy of stricturing Crohn’s disease: what the gut can learn from other organs – a systematic review.Fibrogenesis Tissue Repair. 2014; 7: 5Crossref PubMed Scopus (64) Google Scholar,3Rieder F. Lawrance I.C. Leite A. et al.Predictors of fibrostenotic Crohn’s disease.Inflamm Bowel Dis. 2011; 17 (2000–7)Crossref PubMed Scopus (59) Google Scholar Therapeutic approaches to this may only indirectly target fibrosis by exerting anti-inflammatory features, with endoscopic or surgical interventions as remaining treatment options, which have high recurrence and complication rates.4Rieder F. Managing intestinal fibrosis in patients with inflammatory bowel disease.Gastroenterol Hepatol (N Y). 2018; 14: 120-122PubMed Google Scholar As chronic intestinal inflammation causes repetitive unphysiological healing of injured tissue, it represents a major driver of intestinal fibrosis.5Friedman S.L. Sheppard D. Duffield J.S. et al.Therapy for fibrotic diseases: nearing the starting line.Sci Transl Med. 2013; 5: 167sr1Crossref PubMed Scopus (502) Google Scholar Fibrotic changes can persist once inflammatory stimuli are eliminated and, despite beneficial effects of biologic therapy (eg, tumor necrosis factor–α antibodies or vedolizumab) on fibrosis, surgery rates have diminished only slightly since biologics were approved for IBD treatment.6Johnson L.A. Luke A. Sauder K. et al.Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a “top-down” approach to intestinal fibrosis in mice.Inflamm Bowel Dis. 2012; 18: 460-471Crossref PubMed Scopus (87) Google Scholar, 7Olivera P. Spinelli A. Gower-Rousseau C. et al.Surgical rates in the era of biological therapy: up, down or unchanged?.Curr Opin Gastroenterol. 2017; 33: 246-253Crossref PubMed Scopus (53) Google Scholar, 8Allocca M. Bonifacio C. Fiorino G. et al.Efficacy of tumour necrosis factor antagonists in stricturing Crohn’s disease: a tertiary center real-life experience.Dig Liver Dis. 2017; 49: 872-877Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 9Bouhnik Y. Carbonnel F. Laharie D. et al.Efficacy of adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study.Gut. 2018; 67: 53-60Crossref PubMed Scopus (165) Google Scholar, 10Engel T. Ungar B. Yung D.E. et al.Vedolizumab in IBD-lessons from real-world experience; a systematic review and pooled analysis.J Crohns Colitis. 2018; 12: 245-257Crossref PubMed Scopus (107) Google Scholar Importantly, the effectiveness of anti-inflammatory drugs in IBD does not generally lead to improvement of fibrosis severity in the gastrointestinal tract,11Ma C. Fedorak R.N. Kaplan G.G. et al.Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn’s disease: real world experience from a multicentre cohort.Aliment Pharmacol Ther. 2017; 45: 1232-1243Crossref PubMed Scopus (120) Google Scholar which emphasizes the unmet scientific need to understand the underlying processes of both inflammation and fibrosis independently. In their latest study published in this issue of Gastroenterology, Zhao et al12Zhao X. Yang W. Yu T. et al.Th17 cell-derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts.Gastroenterology. 2023; 164: 89-102Abstract Full Text Full Text PDF Scopus (6) Google Scholar used an elegant way to disentangle the pathophysiology of intestinal inflammation from the mechanism of intestinal fibrosis by means of assessing the role of gut microbiota antigen-specific T helper (Th) 17 cells in colitis-associated intestinal fibrosis. In fact, although Th1 and Th17 cells are crucial contributors to IBD pathogenesis, their implications for fibrotic processes are incompletely unraveled.13Imam T. Park S. Kaplan M.H. et al.Effector T helper cell subsets in inflammatory bowel diseases.Front Immunol. 2018; 9: 1212Crossref PubMed Scopus (140) Google Scholar,14Latella G. Viscido A. Controversial contribution of Th17/IL-17 toward the immune response in intestinal fibrosis.Dig Dis Sci. 2020; 65: 1299-1306Crossref PubMed Scopus (23) Google Scholar By employing a T-cell transfer mouse model of chronic colitis (Tcrβxδ-–/–), the authors presented the striking finding that both Th1 and Th17 cells contribute to intestinal inflammation, but only Th17 cells instigated intestinal fibrosis. Conducting a microarray of CD4+ T cells, they identified strong up-regulation of the epidermal growth factor receptor ligand amphiregulin (Areg) in Th17 cells. Vice versa, fibrosis induction was abrogated in chronic colitis on Areg deficiency, which underscores a crucial role for Areg in colitis-associated fibrosis, and highlights the authors’ remarkable observation of Th17 cells promoting intestinal fibrosis via inflammation-independent Areg expression. Areg belongs to a family of cytokines that signal via the epidermal growth factor. It is expressed mainly in epithelial cells, immune cells, and MFs, and promotes regeneration after tissue injury.15Minutti C.M. Modak R.V. Macdonald F. et al.A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation.Immunity. 2019; 50: 645-654.e6Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Importantly, Areg silencing has already been shown to be effective in murine kidney fibrosis, indicating a potential druggable mechanism of Areg for intestinal fibrosis as well.16Son S.S. Hwang S. Park J.H. et al.In vivo silencing of amphiregulin by a novel effective self-assembled-micelle inhibitory RNA ameliorates renal fibrosis via inhibition of EGFR signals.Sci Rep. 2021; 11: 2191Crossref PubMed Scopus (9) Google Scholar The authors further demonstrated mechanistically that Areg expression in Th17 cells was dependent on IL-6 and IL-21 signaling, and IL-23, IL-1β, and IL-17 stimulation had no effect on Th17-expressed Areg. These findings were validated via augmented Areg expression in fibrotic intestinal tissues from patients with CD compared with biopsies from healthy controls or patients with CD without fibrosis. Of note, Areg expression was heightened in fibrotic compared with nonfibrotic lesions of the same patients with CD, caused by a specific increase of lamina propria Th1 and Th17 cells. In addition, peripheral blood CD4+ cells from healthy controls and patients with CD exhibited significantly augmented Areg expression in Th17 cells, with Areg expression in CD-Th17 cells being higher than in Th17 cells from healthy controls. Given the fact that the IL-6/IL-21–dependent Areg expression in Th17 cells indicates a unique molecular link between a proinflammatory circuit and the manifestation of intestinal fibrosis, it needs to be explored to what extent this pathophysiological switch can be exploited for therapeutic purposes. Zhao et al12Zhao X. Yang W. Yu T. et al.Th17 cell-derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts.Gastroenterology. 2023; 164: 89-102Abstract Full Text Full Text PDF Scopus (6) Google Scholar delineated IL-6– and IL-21–mediated Areg expression in Th17 cells to be governed by Stat3 (signal transducer and activator of transcription 3) in vitro and showed Stat3 inhibition to effectively reduce intestinal fibrosis after Th17 cell transfer into Tcrβxδ–/– mice. These findings suggest that targeted tackling of specific pathways involved in Th17 cell activation or function may harbor a greater potential to reduce fibrosis than general blockade of IL-17. Inhibition of JAK/STAT signaling by either pan-JAK (tofacitinib) or JAK1 (upadacitinib, filgotinib) inhibitors has emerged as a powerful target for ulcerative colitis therapy. In addition, targeted inhibition of the IL-6 trans-signaling pathway has also been shown to interfere robustly with JAK/STAT signaling and alleviate mucosal inflammatory responses.17Schreiber S. Aden K. Bernardes J.P. et al.therapeutic interleukin-6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease.Gastroenterology. 2021; 160: 2354-2366.e11Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Consequently, these novel molecular tools of IBD management might play an additional role in specifically inhibiting the manifestation of IBD-related complications, such as fibrosis. Along the same line, the authors opened the avenue for another molecular way to precisely intercept fibrosis manifestation. Translating their preclinical findings into human intestinal inflammation, Zhao et al12Zhao X. Yang W. Yu T. et al.Th17 cell-derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts.Gastroenterology. 2023; 164: 89-102Abstract Full Text Full Text PDF Scopus (6) Google Scholar demonstrated Areg to direct CD patients–derived myofibroblast activity in an the epidermal growth factor receptor/mTOR/MEK-guided manner, a pathway essential in pulmonary or dermal fibrosis.18Seykora J.T. Grabbing amphiregulin by the tail to better understand keratinocyte growth.J Invest Dermatol. 2010; 130: 1966-1968Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,19Zhou Y. Lee J.-Y. Lee C.-M. et al.Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis.J Biol Chem. 2012; 287: 41991-42000Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Although antifibrotic drugs shown to be effective in other organs are only partially transferable to intestinal fibrosis,2Bettenworth D. Rieder F. Medical therapy of stricturing Crohn’s disease: what the gut can learn from other organs – a systematic review.Fibrogenesis Tissue Repair. 2014; 7: 5Crossref PubMed Scopus (64) Google Scholar mTOR inhibition re-established epithelial homeostasis in a murine model of epithelial damage, reduced fibrotic changes in murine colitis, and diminished strictures in upper CD-related fibrosis,20Mathur R. Alam M.M. Zhao X.-F. et al.Induction of autophagy in Cx3cr1+ mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis.Mucosal Immunol. 2019; 12: 612-623Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 21Zhong M. Cui B. Xiang J. et al.Rapamycin is effective for upper but not for lower gastrointestinal Crohn’s disease-related stricture: a pilot study.Front Pharmacol. 2020; 11617535Google Scholar, 22Welz L. Kakavand N. Hang X. et al.Epithelial X-box binding protein 1 coordinates tumor protein p53-driven DNA damage responses and suppression of intestinal carcinogenesis.Gastroenterology. 2022; 162: 223-237.e11Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar rendering mTOR pathways an additive therapeutic target for simultaneous immunosuppressive and antifibrotic therapy in stricturing CD. Collectively, Zhao et al12Zhao X. Yang W. Yu T. et al.Th17 cell-derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts.Gastroenterology. 2023; 164: 89-102Abstract Full Text Full Text PDF Scopus (6) Google Scholar described how IL-6/IL-21–Stat3 signaling drives Areg production in Th17 cells, compromising a novel pathomechanism of intestinal fibrosis. Importantly, the authors revealed a pro-fibrotic mechanism that, contrary to current approaches, acts independently of intestinal inflammation, demanding further research to distinctly differentiate between fibrosis as a bystander of inflammation and fibrosis as an autonomous process. On the clinical side, these novel insights will further steer our efforts to understand and identify molecular subentities of IBD that precipitate into individual, possibly unexpected clinical manifestations. To ensure an optimal targeted treatment for patients with IBD and from intestinal fibrosis, we need to establish an independent assessment of fibrotic changes because inflammation does not necessarily evolve into the same phenotype every time, but can turn out to be quite “Areg”-ularly fibrotic! Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal MyofibroblastsGastroenterologyVol. 164Issue 1PreviewTh17 cells induce more severe intestinal fibrosis through the production of Areg, which promotes human intestinal myofibroblast proliferation and migration. Full-Text PDF