Microbiota-derived metabolite promotes HDAC3 activity in the gut

The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of a symbiotic host-microbiota relationship(1). Epigenetic machinery permits mammalian cells to integrate environmental signals(2), however, how these pathways are finely tuned by diverse cues from commensal bacteria is not well understood. Here, we reveal a highly selective pathway through which microbiota-derived inositol phosphate regulates histone deacetylase 3 (HDAC3) activity in the intestine. Despite abundant HDAC inhibitors in the intestine such as butyrate, we unexpectedly found that HDAC3 activity was sharply increased in intestinal epithelial cells (IECs) of microbiota-replete mice compared to germ-free mice. This discordance was reconciled by finding that commensal bacteria, including E. coli, stimulated HDAC activity through metabolism of phytate and inositol trisphosphate production. Intestinal exposure to inositol trisphosphate and phytate ingestion both promoted recovery following intestinal damage. Remarkably, inositol trisphosphate also induced growth of patient-derived intestinal organoids, stimulated HDAC3-dependent proliferation, and countered butyrate inhibition of colonic growth. Collectively, these data reveal inositol trisphosphate as a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a converging epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals.