Introduction: Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing disorder characterized by inflammation of the gastrointestinal tract. Ulceration of the intestinal epithelium is a central factor in IBD, and preservation of its homeostasis appears crucial to prevent disease progression. A well-established feature of IBD is gut microbiome dysbiosis, which is characterized by a shift in microbial composition, leading to alterations in bacterial metabolites. Among these metabolites are secondary bile acids (BAs), pivotal in regulating intestinal and host physiology. BAs, initially synthesized in the liver as primary BAs and released into the intestine postprandially for lipid solubilization, undergo reabsorption and recycling in the small intestine. However, a fraction reaches the colon, where resident bacteria catalyze primary BA conversion into a variety of secondary BAs with different biological activities. Of particular importance are BA 7alpha-dehydroxylating bacteria which convert the primary BAs cholic acid and chenodeoxycholic acid into deoxycholic acid and lithocholic acid, respectively, which are potent agonists of the BA-responsive membrane receptor Takeda G-coupled receptor 5 (TGR5). TGR5 activation drives multiple host processes, including gut hormone secretion, immunomodulation and stem cell-induced intestinal renewal. Since secondary BA production is diminished in IBD patients, we hypothesized that restoring 7alpha-dehydroxylated BA levels may enhance the regenerative capacity of the colonic epithelium in mouse models and human patients with impaired or delayed intestinal repair capacity.
Aims and objectives: In this study, we investigated whether restoration of 7alpha-dehydroxylated BA levels through colonization with the most characterized human-derived 7alpha-dehydroxylating bacterium, Clostridium scindens (C. scindens), could re-establish epithelial intestinal homeostasis following colon injury. In addition, we analyzed omics datasets from UC patients and non-IBD individuals to translate our results to humans.
Methods: We colonized gnotobiotic Oligo-MM12 and conventional C57BL/6J specific-pathogen free (SPF) mice with C. scindens and quantified fecal BAs. In both mouse models, colonic lesions were induced by administration ofdextran sulfate sodium (DSS) and disease severity was assessed. SPF TGR5 knock-out mice and wild-type controls were also subjected to chemically-induced experimental colitis to evaluate the impact of the BA receptor TGR5. In addition, we reanalyzed public multi-omics datasets from a cohort of UC patients and controls to increase the relevance of our preclinical results.
Results and conclusion: Our study revealed that the amendment of C scindens confers protection to DSS-induced colitis in both a prophylactic and therapeutic manner. Mechanistically, C. scindens improved the integrity of intestinal epithelium by promoting TGR5-mediated tissue regeneration. Finally, we observed that UC patients displayed dampened intestinal cell renewal and differentiation, and genes involved in those pathways showed a robust positive correlation with 7alpha-dehydroxylated BAs levels. Our study reports C. scindens administration as a promising biotherapeutic strategy to foster epithelial regeneration and healing following colon injury by restoring the secondary to primary BA ratio.