Tas2r105 ameliorates gut inflammation, possibly through influencing the gut microbiota and metabolites

Inflammatory bowel disease (IBD) is an immune-mediated gastrointestinal disorder that significantly impacts the life quality of people worldwide. Genetic factors play crucial roles in the development of IBD. Tas2rs, members of the G protein-coupled receptor (GPCR) superfamily, are known for their roles in bitter taste perception. However, Tas2rs have also been identified in the gut, where they help sense luminal contents and regulate gastrointestinal hormones. Periodontal Tas2r105 has been shown to modulate innate immunity by interacting with metabolites produced by oral bacteria. In this study, we observed increased Tas2r105 in the inflammatory colons induced by dextran sulfate sodium salt (DSS). We also noted that α-gustducin, the α-subunit of GPCRs, is present in the intestine, and that α-gustducin knockout mice exhibit aggravated colitis. Based on these findings, we hypothesize that Tas2r105 may play a role in immune regulation during IBD pathogenesis. To test this hypothesis, we used Tas2r105 knockout (KO) mice in a colitis model. Our results show that the KO mice had significantly shorter colon length, more severe colon inflammation, and greater destruction of the gut barrier compared with control mice. We also observed increased recruitment of macrophages to the lamina propria mucosa in the KO mice. Microbiological analysis revealed a significant increase in <i>Proteobacteria</i> and <i>Bacteroidota</i>, with a concomitant decrease in <i>Firmicutes</i> after Tas2r105 knockout. Metabolomic analysis showed a significant reduction in lysophosphatidylethanolamine (LPE) levels in the KO mice, which is known to have anti-inflammatory effects. Based on these findings, we speculate that Tas2r105 may help protect the intestine from inflammation by influencing the gut microbiota composition and LPE production.IMPORTANCEIncreased Tas2r105 was detected in the inflamed colon of mice outside the tongue. Tas2r105 deletion aggravated mice colon colitis. Tas2r105 might alleviate mice colitis by downregulating the <i>Proteobacteria</i> and the <i>Bacteroidota</i> abundance in the colon. Lysophosphatidylethanolamine (LPE) might be the key metabolite that mediated the intestinal protection of Tas2r105.