Microbiota-derived metabolite promotes HDAC3 activity in the gut

Shu-en Wu, Seika Hashimoto-Hill, Vivienne Woo, Emily M. Eshleman, Jordan Whitt, Laura Engleman, Rebekah Karns, Lee A. Denson, David B. Haslam and Theresa Alenghat ()
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Shu-en Wu: Cincinnati Children’s Hospital Medical Center
Seika Hashimoto-Hill: Cincinnati Children’s Hospital Medical Center
Vivienne Woo: Cincinnati Children’s Hospital Medical Center
Emily M. Eshleman: Cincinnati Children’s Hospital Medical Center
Jordan Whitt: Cincinnati Children’s Hospital Medical Center
Laura Engleman: Cincinnati Children’s Hospital Medical Center
Rebekah Karns: Cincinnati Children’s Hospital Medical Center
Lee A. Denson: Cincinnati Children’s Hospital Medical Center
David B. Haslam: University of Cincinnati College of Medicine
Theresa Alenghat: Cincinnati Children’s Hospital Medical Center

Nature, 2020, vol. 586, issue 7827, 108-112

Abstract: Abstract The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of symbiotic host–microbiota relationships1. Epigenetic machinery permits mammalian cells to integrate environmental signals2; however, how these pathways are fine-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 the abundant presence of HDAC inhibitors such as butyrate in the intestine, we found that HDAC3 activity was sharply increased in intestinal epithelial cells of microbiota-replete mice compared with germ-free mice. This divergence was reconciled by the finding that commensal bacteria, including Escherichia coli, stimulated HDAC activity through metabolism of phytate and production of inositol-1,4,5-trisphosphate (InsP3). Both intestinal exposure to InsP3 and phytate ingestion promoted recovery following intestinal damage. Of note, InsP3 also induced growth of intestinal organoids derived from human tissue, stimulated HDAC3-dependent proliferation and countered butyrate inhibition of colonic growth. Collectively, these results show that InsP3 is a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a convergent epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals.

Date: 2020
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DOI: 10.1038/s41586-020-2604-2

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