Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD) without specific treatment. As macrophages are the key actors in inflammatory responses and the wound healing process, they have been extensively studied in chronic diseases these past decades. By their exceptional ability to integrate diverse stimuli in their surrounding environment, macrophages display a multitude of phenotypes to underpin a broad spectrum of functions, from the initiation to the resolution of inflammation following injury. The hypothesis that distinct macrophage subtypes could be involved in fibrogenesis and wound healing is emerging and could open up new therapeutic perspectives in the treatment of intestinal fibrosis. Gut microbiota and diet are two key factors capable of modifying intestinal macrophage profiles, shaping their specific function. Defects in macrophage polarisation, inadequate dietary habits, and alteration of microbiota composition may contribute to the development of intestinal fibrosis. In this review, we describe the intriguing triangle between intestinal macrophages, diet, and gut microbiota in homeostasis and how the perturbation of this discreet balance may lead to a pro-fibrotic environment and influence fibrogenesis in the gut.

Background: Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD) patients without specific treatment. Aryl hydrocarbon receptor (AhR) activation is associated with better outcomes in intestinal inflammation. Development of novel therapies targeting fibrogenic pathways is required and we aimed to screen dietary AhR ligands for their anti-fibrotic properties in TGF-β1-stimulated human colonic fibroblast cells. Methods: The study was conducted using TGF-β1-stimulated CCD-18Co, a human colonic fibroblast cell line in response to increased concentrations of dietary ligands of AhR such as FICZ, ITE, L-kynurenine and curcumin. Fibrosis markers such as α-SMA, COL1A1, COL3A1 and CTGF were assessed. AhR and ANRT RNA were evaluated. Results: TGF-β1 at 10 ng/mL significantly induced mRNA levels for ECM-associated proteins such as CTGF, COL1A1 and COL3A1 in CCD-18Co cells. FICZ from 10 to 1000 nM, L-kynurenine from 0.1 to 10 μM, ITE from 1 to 100 μM or curcumin from 5 to 20 μM had no significant effect on fibrosis markers in TGF-β1-induced CCD-18Co. Conclusions: Our data highlight that none of the tested dietary AhR ligands had an effect on fibrosis markers in TGF-β1-stimulated human colonic fibroblast cells in our experimental conditions. Further studies are now required to identify novel potential targets in intestinal fibrosis.

The natural history of inflammatory bowel diseases, especially Crohn’s disease, is frequently complicated by intestinal fibrosis. Because of the lack of effective treatments for intestinal fibrosis, there is an urgent need to develop new therapies. Factors promoting intestinal fibrosis are currently unclear, but diet is a potential culprit. Diet may influence predisposition to develop intestinal fibrosis or alter its natural history by modification of both the host immune response and intestinal microbial composition. Few studies have documented the effects of dietary factors in modulating IBD-induced intestinal fibrosis. As the mechanisms behind fibrogenesis in the gut are believed to be broadly similar to those from extra-intestinal organs, it may be relevant to investigate which dietary components can inhibit or promote fibrosis factors such as myofibroblasts progenitor activation in other fibrotic diseases.