Functional Role of Microbiota‐derived Metabolites in the GPCR‐mediated Regulation of Intestinal Wound Healing and Barrier Function

Abstract

The mammalian intestine houses a complex and abundant ensemble of commensal bacteria, which are in constant cross‐talk with the intestinal epithelial cells, and thereby, ensure gut homeostasis, development, permeability, and repair. Wound regeneration is a complex but coordinated cellular events to repair injured gut mucosa, which involves both cellular proliferation and migration. Gut barrier function is central to the health and is critical in a wide variety of diseases including inflammatory bowel diseases (IBD). Our recent metagenomics study discovered a consortium of novel gut mucosa‐associated proregenerative symbiotic bacteria, which preferentially enrich in and colonize the injured mucosa to augment epithelial repair. The resident microbiota of the gut is endowed with over a hundred times more genes than those in our genome. However, the microbiota's more than nine million genes, and their metabolic functions remained mostly unrecognized. We performed an unbiased screening analysis by mass spectrometry‐based metabolomic profiling of intact and wounded mucosa in germ‐free and conventional mice. Unlike the germ‐free animals, the colon of the conventional mice demonstrated increased amounts of acidic microbial metabolites, which established an extracellular pH gradient with more acidic pH at the apex of the colonic crypt. We found that the murine and human intestinal epithelial cells express the proton‐sensing G‐protein coupled‐receptor GPCR68. Intriguingly, the murine colonic contents of the conventional mouse or a specific metabolite, 2‐hydroxy‐4‐methylpentanoic acid (HMP) decreases the extracellular pH to modulate claudin‐4 dependent paracellular permeability and to regulate the proliferation of intestinal epithelial cells in a GPCR68‐dependent manner. Importantly, our findings highlighted that the HMP‐stimulated intestinal epithelial wound closure requires GPR68. Collectively, our data underscore the significance of intestinal metabolites in modulating the extracellular proton concentration in the gut mucosal microenvironment. Furthermore, our findings demonstrate that the GPCR68 functions as the sensor of microbially modulated proton gradient that is potentially involved in the maintenance of gut mucosal homeostasis, wound healing, and restoration of the intestinal barrier function.Support or Funding InformationK01DK114391 (National Institute of Diabetes and Digestive and Kidney Diseases), R01DK089763 (National Institute of Diabetes and Digestive and Kidney Diseases), R01AI064462 (National Institute of Allergy and Infectious Diseases)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.