Title : Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis
Abstract:
Ulcerative Colitis (UC) is a relapsing-remitting inflammatory disorder of the gastrointestinal tract driven by complex interactions between the gut microbiota and dysregulated mucosal immune pathways. In this study, we identify microbiota-derived succinate as a key metabolic driver of colitogenic immune responses in UC. We observed a distinctive dysbiosis characterized by a marked enrichment of succinate-producing bacteria, particularly Bacteroides vulgatus, along with a substantial depletion of succinate-consuming taxa such as Phascolarctobacterium and Dialister. This microbial imbalance leads to elevated luminal succinate, which activates the succinate receptor SUCNR1 on CD4? T cells, promoting the differentiation of IL-9-secreting CD4? T cells that contribute to epithelial barrier disruption and inflammation. Strategies that increased colonic succinate including dietary FOS supplementation, PEG-mediated succinate elevation, or colonization with succinate- producing bacteria consistently exacerbated colitis and expanded IL-9-producing CD4? T cells. Conversely, interventions that reduced succinate availability, such as colonization with succinate-metabolizing bacteria, retinoic acid supplementation to suppress B. vulgatus, IL-9 neutralization, or pharmacological inhibition of SUCNR1, significantly ameliorated disease severity. Together, these findings highlight the succinate-SUCNR1-Th9 axis as a central pathogenic pathway in UC and underscore the therapeutic potential of targeting succinate metabolism and its microbial regulators to develop next-generation microbiome-based interventions.
