Study Title:

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Study Abstract

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell1, 2, 3, 4, 5. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses3. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4+ CD45RBhi T cells in Rag1−/− mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host–microbe interactions establish immunological homeostasis in the gut.

From press release:

New research from the RIKEN Center for Integrative Medical Sciences in Japan sheds light on the role of gut bacteria on the maturation of the immune system and provides evidence supporting the use of butyrate as therapy for inflammatory bowel diseases like Crohn's disease.

Published in the journal Nature today, the Japanese study shows that butyrate, a by-product of the digestion of dietary fiber by gut microbes, acts as an epigenetic switch that boosts the immune system by inducing the production of regulatory T cells in the gut.

Previous studies have shown that patients suffering from inflammatory bowel disease lack butyrate-producing bacteria and have lower levels of butyrate in their gut. However, butyrate's anti-inflammatory properties were attributed to its role as main energy source for the cells lining the colon. This study is the first to provide a molecular basis for the role of butyrate on the production of regulatory T lymphocytes.

The Japanese team, lead by Dr Hiroshi Ohno from RIKEN in collaboration with the University of Tokyo and Keio University, investigated the molecular mechanisms by which commensal microbes augment the number of regulatory T cells (Treg cells) present in the colon of mice that were bred germ-free.

Their research demonstrates that butyric acid, a short-chain fatty acid produced by commensal bacteria acts on naïve T cells to promote their differentiation into Treg cells. It achieves this through epigenetic changes that regulate the expression of the genes responsible for differentiation of naïve T cells into Treg cells.

The study shows that mice suffering from colitis see their levels of Treg cells increase and their symptoms improve after administration of butyrate as part of their diet.

"Regulatory T cells are important for the containment of excessive inflammatory responses as well as autoimmune disorders. Therefore these findings could be applicable for the prevention and treatment of inflammatory bowel disease (IBD), allergy and autoimmune disease," said Dr Hiroshi Ohno.

"Butyrate is natural and safe as a therapy and in addition to that it is cheap, which could reduce costs for both patients and society," Dr Ohno added.

Study Information

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, et al.
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
2013 November
University of Tokyo and Keio University

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