IDDF2024-ABS-0043 Alistipes putredinis alleviates murine experimental colitis through 2-methylbutyric acid-mediated immune tolerance

Background While Alistipes putredinis (AP) abundance in the faeces of patients with inflammatory bowel disease (IBD) decreases, its role in IBD is not well understood. We, therefore, investigated the effects and potential mechanisms of AP on colitis in mice. Methods Metagenome sequencing was performed to analyse AP abundance in the faeces of patients with CD and healthy controls. Dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced murine models of colitis were performed to explore the role of AP on colitis. Transcriptome analyses and flow cytometry were performed to explore the mechanism of the AP on colitis. Metabolomics analyses were conducted to identify the metabolites of AP. T cell and dendritic cell (DC) cultures were used to analyse the effects of AP-derived 2-methylbutyric acid (2-MA) on DCs' immune tolerance and regulatory T (Treg) cell differentiation. G protein-coupled receptors (GPCR) inhibitor and TGF-b-neutralizing antibody were used to explore the intrinsic mechanisms of 2-MA. Results AP abundance in faeces was lower in patients with CD than in HCs. The therapeutic effects of AP on mice with DSS or TNBS-induced colitis were observed. AP could catabolise leucine to 2-MA, which had beneficial effects on colitis remission in mice. Moreover, AP and 2-MA induced CD103+ DC and Treg-mediated immune tolerance in vivo. Furthermore, 2-MA activated CD103+ DC cells to upregulate transforming growth factor beta through GPCR, thereby promoting Treg cell differentiation. (IDDF2024-ABS-0043 Figure 1. Diagram of the mechanisms involved in the therapeutic effects of AP on colitis) Conclusions AP protects against murine experimental colitis by inducing CD103+ DC and Treg-mediated immune tolerance. Moreover, AP-derived 2-MA activates CD103+ DC via GPCR, leading to Treg cell differentiation. Thus, administration of AP or 2-MA is a promising therapeutic strategy for treating IBD.