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The intestinal epithelial barrier is important to mucosal immunity, although how it is maintained after damage is unclear. Here, we show that G protein-coupled receptor 109A (GPR109A) supports barrier integrity and decreases mortality in a mouse cecum ligation and puncture (CLP) sepsis model. Data from 16S RNA sequencing showed that the intestinal microbiota of WT and Gpr109a−/− mice clustered differently and their compositions were disrupted after CLP surgery. GPR109A-deficient mice showed increased mortality, intestinal permeability, altered inflammation, and lower tight junction gene expression. After eliminating the intestinal flora with antibiotics, all experimental mice died within 48 h of CLP surgery. This demonstrates the critical role of the gut microbiota in CLP-induced sepsis. Importantly, mortality and other pathologies in the model were decreased after Gpr109a−/− mice received WT gut microbiota. These findings indicate that GPR109A regulates the gut microbiota, contributing to intestinal epithelial barrier integrity and decreased mortality in CLP-induced sepsis.