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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 comm...

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Autores principales: Wu, Shu-en, Hashimoto-Hill, Seika, Woo, Vivienne, Eshleman, Emily M., Whitt, Jordan, Engleman, Laura, Karns, Rebekah, Denson, Lee A., Haslam, David B., Alenghat, Theresa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529926/
https://www.ncbi.nlm.nih.gov/pubmed/32731255
http://dx.doi.org/10.1038/s41586-020-2604-2
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author Wu, Shu-en
Hashimoto-Hill, Seika
Woo, Vivienne
Eshleman, Emily M.
Whitt, Jordan
Engleman, Laura
Karns, Rebekah
Denson, Lee A.
Haslam, David B.
Alenghat, Theresa
author_facet Wu, Shu-en
Hashimoto-Hill, Seika
Woo, Vivienne
Eshleman, Emily M.
Whitt, Jordan
Engleman, Laura
Karns, Rebekah
Denson, Lee A.
Haslam, David B.
Alenghat, Theresa
author_sort Wu, Shu-en
collection PubMed
description 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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spelling pubmed-75299262021-01-30 Microbiota-derived metabolite promotes HDAC3 activity in the gut Wu, Shu-en Hashimoto-Hill, Seika Woo, Vivienne Eshleman, Emily M. Whitt, Jordan Engleman, Laura Karns, Rebekah Denson, Lee A. Haslam, David B. Alenghat, Theresa Nature Article 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. 2020-07-30 2020-10 /pmc/articles/PMC7529926/ /pubmed/32731255 http://dx.doi.org/10.1038/s41586-020-2604-2 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wu, Shu-en
Hashimoto-Hill, Seika
Woo, Vivienne
Eshleman, Emily M.
Whitt, Jordan
Engleman, Laura
Karns, Rebekah
Denson, Lee A.
Haslam, David B.
Alenghat, Theresa
Microbiota-derived metabolite promotes HDAC3 activity in the gut
title Microbiota-derived metabolite promotes HDAC3 activity in the gut
title_full Microbiota-derived metabolite promotes HDAC3 activity in the gut
title_fullStr Microbiota-derived metabolite promotes HDAC3 activity in the gut
title_full_unstemmed Microbiota-derived metabolite promotes HDAC3 activity in the gut
title_short Microbiota-derived metabolite promotes HDAC3 activity in the gut
title_sort microbiota-derived metabolite promotes hdac3 activity in the gut
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529926/
https://www.ncbi.nlm.nih.gov/pubmed/32731255
http://dx.doi.org/10.1038/s41586-020-2604-2
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