Prevotella copri leads to colonic barrier dysfunction via the succinate receptor 1-FoxM1-IL-6 axis.

Prevotella copri, a key commensal bacterium in the human gut microbiome, exhibits both positive and negative abundance correlations with various disorders. Although multiple studies have suggested an association between P. copri and intestinal pathologies, the mechanistic basis remains elusive. In this study, we examined P. copri's effects on colonic physiology in healthy mice, revealing its capacity to compromise intestinal barrier integrity. This was demonstrated through downregulation of colonic tight junction proteins (Occludin and ZO-1) and elevated serum levels of gut permeability markers (LPS and D-LA). We identified succinate as the primary microbial metabolite mediating P. copri's barrier-disrupting effects, with succinate receptor 1 (SUCNR1) being essential for this pathological process. Notably, both P. copri colonization and succinate administration activated the IL-6-STAT3 signaling pathway, leading to transcriptional suppression of the tight junction-related gene, Occludin. Through mechanistic studies, we identified Forkhead box M1 (FoxM1) as a crucial transcription factor regulating P. copri- or succinate-induced Il-6 expression. Clinical relevance was established through human cohort analyses showing significant positive correlations between fecal succinate levels and plasma markers of gut permeability. These findings elucidate a novel mechanistic pathway through which P. copri impairs colonic function, suggesting therapeutic potential in colitis through strategies targeting either P. copri abundance or microbial succinate production.