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.

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SUMMARY Mucosal tissues are constantly in direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating complex microbial signals to sustain effective host defense. Here we show an essential role for intestinal epithelial cell expression of histone deacetylase 3 (HDAC3) in responding to pathogenic microbes and activating protective innate immunity. Mice lacking HDAC3 in intestinal epithelial cells were more susceptible to Citrobacter rodentium when under tonic stimulation by the commensal microbiota. This impaired host defense reflected significantly decreased IFNγ production by intraepithelial CD8+ T cells early during infection. Further, HDAC3 was necessary for infection-induced epithelial expression of the IFNγ-inducing factor IL-18 and administration of IL-18 restored IFNγ activity to resident CD8+ T cells and reduced infection. Thus, HDAC3 mediates communication between intestinal epithelial cells and resident lymphocytes, revealing that epithelial priming by an epigenetic modifier may direct mucosal regulation of host defense against pathogenic microbes.

US28 transcripts have been detected in primary monocytes and in THP-1 monocytes infected with HCMV but US28 protein expression has not yet been demonstrated in these cell types. Moreover, the mechanism(s) by which US28 signals and contributes to viral pathogenesis in monocytes remains unclear. Here, we show that US28 protein is robustly expressed in HCMV infected THP-1 monocytes and that US28 can trigger Gαq dependent signaling in THP-1 cells infected with HCMV and in THP-1 cells stably expressing US28. US28 signaling in these cells is dependent on G-protein coupling, but independent of chemokine binding. Importantly, we demonstrate that this US28 signaling is functionally important as it stimulates the adhesion of monocytes to an endothelial monolayer. Our studies, which demonstrate that US28-driven Gαq signaling has profound effects on monocyte biology, suggest that US28 driven phenotypic changes in HCMV infected monocytes may play important roles in HCMV dissemination and/or pathogenesis.