The Microbial Metabolite δ-Valerobetaine Strengthens the Gut Epithelial Barrier

Metabolic processes within gut microbes generate bioactive metabolites that impact intestinal epithelial barrier function. Herein, gnotobiotic mice and mass spectrometry-based metabolomics were used to identify novel metabolites in host tissues of microbial origin. Of those detected, the gut microbe-generated metabolite δ-valerobetaine (δ-VB) is a potent inhibitor of l-carnitine biosynthesis and a modulator of fatty acid oxidation by mitochondria in liver cells. The bioactivity of δ-VB toward gut epithelial barrier function was assessed. Germ-free mice are devoid of δ-VB, and administration of δ-VB to germ-free mice induced the enrichment of transcript sets associated with gut mitochondrial respiration and fatty acid oxidation in colonic tissue. Furthermore, δ-VB induced the differential expression of genes that function in barrier function in germ-free and conventionally raised mice. Functionally, δ-VB decreased gut barrier permeability and augmented wound healing in cultured gut epithelial cells and elicited cytoprotective and prorestitutive effects in a mouse model of colonic injury. These data indicate that the microbial-derived metabolite δ-VB is a modulator of gut epithelium function, and thus is a molecular target to potentially manage microbiome-host dysbiosis in intestinal health and disease.