Gut microbiome promotes succinate-induced ulcerative colitis by enhancing glycolysis through SUCNR1/NF-κB signaling...

Ulcerative colitis (UC) is a chronic recurrent inflammatory disease. Previous studies demonstrate that excessive accumulation of gut microbial metabolites, especially succinate, increases the risk of disease progression. However, the role of succinate and its molecular mechanism have not been explored. We investigated the effects of succinate on colonic inflammation and intestinal microbiota and their association with succinate receptor (SUCNR1) signaling in 3% dextran sodium sulfate (DSS)-induced acute UC in C57BL/6J mice. After treatment, fecal bacteria from UC mice were evaluated by 16S rRNA sequencing. Colon tissues and cell lysates were collected and prepared for histological evaluation, immunohistochemistry, Western blotting, and inflammatory activity cytokine analysis. It was found that Phascolarctobacterium spp. (Phascolarctobacterium faecium), which consumed succinate, significantly decreased SUCNR1 expression, relieved colonic damage, reduced cytokine levels, and restored the integrity of the intestinal epithelial barrier in UC mice. In addition, the results of flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay indicated that succinate deficiency markedly suppressed secretion of proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α). Moreover, the SUCNR1 inhibitor (NF-56-EJ40) inhibited glycolysis of intestinal epithelial cells (IECs) in the coculture system with Th17 cells, including downregulation of oxygen consumption rate and increased extracellular acidification rate reflecting overall glycolytic flux, and regulated the expression of glycolysis-related proteins, such as GLUT1, HK-II, and LDHA. Collectively, our findings indicate that microbiota consumption of succinate can ameliorate DSS-induced UC through suppressing Th17, reducing IEC glycolysis, lowering the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving dysbiosis.NEW & NOTEWORTHY The gut microbiota contributes to host physiology through the production of a myriad of metabolites. Owing to the high degree of cross talk both within and between biological kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. In this study, we demonstrated that the microbiota consumption of succinate can alleviate DSS-induced UC in mice responses by modulating glycolytic metabolism through the SUCNR1/NF-κB signaling pathway.