G Protein-Coupled Receptor 109A Maintains the Intestinal Integrity and Protects Against ETEC Mucosal Infection by...

Several studies have reported an intricate link between the G protein-coupled receptor 109A (GPR109A) and intestinal health. Upon activation, induced by butyric acid and β-hydroxybutyric acid, GPR109A regulates the expression of tight junction proteins, exerts anti-inflammatory effects, and maintains the integrity of the intestinal barrier. However, its function and the mechanism of action in combating the infection caused by exogenous pathogenic microorganisms remain unclear. This study established an animal model of infection by oral enterotoxigenic Escherichia coli (ETEC) gavage to examine the underlying mechanism(s) and protective effects of GPR109A on the intestinal tract. Experimental GPR109A^-/-and GPR109A^+/+ mice were orally administered with 1 × 10⁹ colony-forming units (CFUs) of ETEC, and changes in body weight were then observed. The colonization and translocation of ETEC in the intestine were detected by the plate counting method. The expression of tight junction proteins and the levels of inflammatory factors and secretory IgA (SIgA) in the intestine were detected by quantitative real-time polymerase chain reaction (q-PCR), western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The results demonstrated that GPR109A^-/-mice were more susceptible to ETEC infection, showing more severe inflammatory reactions and intestinal damage. Moreover, the secretion of IgA in the intestinal tract of GPR109A^+/+ mice was significantly increased after ETEC infection, whereas the IgA levels in GPR109A^-/-mice did not change significantly. We added 5 g/L sodium butyrate to the drinking water of all mice. The GPR109A^+/+ mice were protected against ETEC infection and no effect was observed in GPR109A^-/-mice. Similarly, sodium butyrate increased the SIgA content in the gut of the GPR109A^+/+ mice and no effect was observed in GPR109A^-/-mice. In conclusion, activated GPR109A is effective against the colonization and translocation of ETEC in the gut and maintains the integrity of the intestinal barrier, possibly by promoting the secretion of intestinal IgA.