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Research Article

The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition

Pamela V. Chang, Liming Hao, Stefan Offermanns, and Ruslan Medzhitov
PNAS February 11, 2014 111 (6) 2247-2252; https://doi.org/10.1073/pnas.1322269111
Pamela V. Chang
Departments of aImmunobiology and
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Liming Hao
bPathology, Yale University School of Medicine, New Haven, CT 06520;
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Stefan Offermanns
cDepartment of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany; and
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Ruslan Medzhitov
Departments of aImmunobiology and
dHoward Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
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  • For correspondence: ruslan.medzhitov@yale.edu
  1. Contributed by Ruslan Medzhitov, December 3, 2013 (sent for review October 13, 2013)

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Significance

The mammalian intestines contain an enormous number of microorganisms within the lumen. Given the constant exposure to these microbes, the intestinal immune system has the difficult task of maintaining tolerance to commensal bacteria while remaining responsive to potential pathogens. The mechanisms by which this balance is achieved are relatively unknown. Here, we identify a bacterial metabolite, n-butyrate, that exerts immunomodulatory effects on intestinal macrophages and renders them hyporesponsive to commensals that reside in the colon. Our studies elucidate a possible mechanism that contributes to immune homeostasis in the intestines.

Abstract

Given the trillions of microbes that inhabit the mammalian intestines, the host immune system must constantly maintain a balance between tolerance to commensals and immunity against pathogens to avoid unnecessary immune responses against otherwise harmless bacteria. Misregulated responses can lead to inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. The mechanisms by which the immune system maintains this critical balance remain largely undefined. Here, we demonstrate that the short-chain fatty acid n-butyrate, which is secreted in high amounts by commensal bacteria, can modulate the function of intestinal macrophages, the most abundant immune cell type in the lamina propria. Treatment of macrophages with n-butyrate led to the down-regulation of lipopolysaccharide-induced proinflammatory mediators, including nitric oxide, IL-6, and IL-12, but did not affect levels of TNF-α or MCP-1. These effects were independent of toll-like receptor signaling and activation of G-protein–coupled receptors, two pathways that could be affected by short-chain fatty acids. In this study, we provide several lines of evidence that suggest that these effects are due to the inhibition of histone deacetylases by n-butyrate. These findings elucidate a pathway in which the host may maintain tolerance to intestinal microbiota by rendering lamina propria macrophages hyporesponsive to commensal bacteria through the down-regulation of proinflammatory effectors.

  • inflammation
  • microbiome

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: ruslan.medzhitov{at}yale.edu.
  • Author contributions: P.V.C. and R.M. designed research; P.V.C. performed research; S.O. contributed new reagents/analytic tools; P.V.C., L.H., and R.M. analyzed data; and P.V.C. and R.M. wrote the paper.

  • The authors declare no conflict of interest.

  • See Commentary on page 2058.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1322269111/-/DCSupplemental.

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Inhibition of macrophage responses by n-butyrate
Pamela V. Chang, Liming Hao, Stefan Offermanns, Ruslan Medzhitov
Proceedings of the National Academy of Sciences Feb 2014, 111 (6) 2247-2252; DOI: 10.1073/pnas.1322269111

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Inhibition of macrophage responses by n-butyrate
Pamela V. Chang, Liming Hao, Stefan Offermanns, Ruslan Medzhitov
Proceedings of the National Academy of Sciences Feb 2014, 111 (6) 2247-2252; DOI: 10.1073/pnas.1322269111
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