Microbiota-derived butyrate is an endogenous HIF prolyl hydroxylase inhibitor

The gut microbiota is essential for human health. Microbial supply of short-chain fatty acids (SCFAs), particularly butyrate, is a well-established contributor to gut homeostasis and disease resistance. Reaching millimolar luminal concentrations, butyrate is sequestered and utilized in the colon as...

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Published in:Gut microbes Vol. 13; no. 1; p. 1938380
Main Authors: Wang, Ruth X., Henen, Morkos A., Lee, J. Scott, Vögeli, Beat, Colgan, Sean P.
Format: Journal Article
Language:English
Published: United States Taylor & Francis 01.01.2021
Taylor & Francis Group
Subjects:
Animals
Bacteria - classification
Bacteria - genetics
Bacteria - metabolism
butyrate
Butyrates - chemistry
Butyrates - metabolism
Colon - enzymology
Colon - metabolism
Colon - microbiology
Fatty Acids, Volatile - metabolism
Female
Gastrointestinal Microbiome
Humans
hypoxia-inducible factor
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases - chemistry
Hypoxia-Inducible Factor-Proline Dioxygenases - genetics
Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism
inhibition
Intestinal Mucosa - enzymology
Intestinal Mucosa - metabolism
Intestinal Mucosa - microbiology
Male
Mice
Mice, Inbred C57BL
Microbiota
Oxidation-Reduction
Oxygen - metabolism
prolyl-hydroxylase
Prolyl-Hydroxylase Inhibitors - chemistry
Prolyl-Hydroxylase Inhibitors - metabolism
Research Paper
short-chain fatty acids
inhibition
Microbiota
hypoxia-inducible factor
butyrate
short-chain fatty acids
prolyl-hydroxylase
ISSN:1949-0976, 1949-0984, 1949-0984
Online Access:Get full text
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Summary:The gut microbiota is essential for human health. Microbial supply of short-chain fatty acids (SCFAs), particularly butyrate, is a well-established contributor to gut homeostasis and disease resistance. Reaching millimolar luminal concentrations, butyrate is sequestered and utilized in the colon as the favored energy source for intestinal epithelia. Given the steep oxygen gradient across the anoxic lumen and the highly oxygenated lamina propria, the colon provides a particularly interesting environment to study oxygen sensing. Previous studies have shown that the transcription factor hypoxia-inducible factor (HIF) is stabilized in healthy colonic epithelia. Here we show that butyrate directly inhibits HIF prolyl hydroxylases (PHDs) to stabilize HIF. We find that butyrate stabilizes HIF in vitro despite eliminating β-oxidation and resultant oxygen consumption. Using recombinant PHD protein in combination with nuclear magnetic resonance and enzymatic biochemical assays, we identify butyrate to bind and function as a unique, noncompetitive inhibitor of PHDs relative to other SCFAs. Butyrate inhibited PHD with a noncompetitive K i of 5.3 ± 0.5 mM, a physiologically relevant concentration. We also confirm that microbiota-derived butyrate is necessary to stabilize HIF in mice colonic tissue through antibiotic-induced butyrate depletion and reconstitution experiments. Our results suggest that the co-evolution of mammals and mutualistic microbiota has selected for butyrate to impact a critical gene regulation pathway that can be extended beyond the mammalian gut. As PHDs are a major target for drug development in the stabilization of HIF, butyrate holds great potential as a well-tolerated endogenous inhibitor with far-reaching therapeutic impact.
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These authors contributed equally to this work.
ISSN:1949-0976
1949-0984
1949-0984
DOI:10.1080/19490976.2021.1938380