Author
Listed:
- 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
University of Cincinnati College of Medicine)
- David B. Haslam
(University of Cincinnati College of Medicine
Cincinnati Children’s Hospital Medical Center)
- Theresa Alenghat
(Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati Children’s Hospital Medical Center)
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.
Suggested Citation
Shu-en Wu & Seika Hashimoto-Hill & Vivienne Woo & Emily M. Eshleman & Jordan Whitt & Laura Engleman & Rebekah Karns & Lee A. Denson & David B. Haslam & Theresa Alenghat, 2020.
"Microbiota-derived metabolite promotes HDAC3 activity in the gut,"
Nature, Nature, vol. 586(7827), pages 108-112, October.
Handle:
RePEc:nat:nature:v:586:y:2020:i:7827:d:10.1038_s41586-020-2604-2
DOI: 10.1038/s41586-020-2604-2
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Cited by:
- Alberto Díez-Sánchez & Håvard T. Lindholm & Pia M. Vornewald & Jenny Ostrop & Rouan Yao & Andrew B. Single & Anne Marstad & Naveen Parmar & Tovah N. Shaw & Mara Martín-Alonso & Menno J. Oudhoff, 2024.
"LSD1 drives intestinal epithelial maturation and controls small intestinal immune cell composition independent of microbiota in a murine model,"
Nature Communications, Nature, vol. 15(1), pages 1-20, December.
- Marjolein Heddes & Baraa Altaha & Yunhui Niu & Sandra Reitmeier & Karin Kleigrewe & Dirk Haller & Silke Kiessling, 2022.
"The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis,"
Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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