Short chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway

By Jeongho Park, Myunghoo Kim, S. Kang, A. Jannasch, B. Cooper, J. Patterson, Chang H. Kim. Mucosal Immunology, 2014

1,143 citations recorded by the source corpus.

Microbial metabolites, such as short-chain fatty acids (SCFAs), are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in the regulation of T-cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T-cell differentiation into T cells producing interleukin-17 (IL-17), interferon-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41 or GPR43, but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17 (T helper type 17), Th1, and IL-10+ T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during Citrobacter rodentium infection, but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T-cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.

Subfields: Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/5edf268a730f88a71d19a48a82206672e4f913bd

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In Immunology

1. S. Ghosh
2. T. Postler
3. N. Perkins
4. Shizuo Akira
5. M. Hayden

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1. Severine Vermeire

Citations in the corpus

• Short chain fatty acids and its producing organisms: An overlooked therapy for IBD? (2021, background): “These effects were again mediated by HDAC inhibition, nevertheless, mTOR (mammalian target of rapamycin) activation was also proposed to be involved [57].”
• Butyrate: A Double-Edged Sword for Health? (2018, background): “In addition to acting as an antitumor agent, butyrate achieves the anti-inflammatory effects partly through HDAC inhibition as well (58, 59).”
• Gut Microbial Metabolites Fuel Host Antibody Responses. (2016, background): “SCFAs support epithelial cell integrity, innate immune functions, and the generation of regulatory and effector T cells (Arpaia et al., 2013; Furusawa et al., 2013; Kim et al., 2013; Park et al., 2015; Sakata, 1987; Schauber et al., 2003).”
• Dietary Fiber Confers Protection against Flu by Shaping Ly6c− Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism (2018, background): “…properties by either binding to G protein-coupled receptors (GPRs), principally FFAR3 (also known as GPR41) and FFAR2 (also known as GPR43) (Le Poul et al., 2003; Maslowski et al., 2009), or functioning as histone deacetylase (HDAC) inhibitors (Aoyama et al., 2010; Park et al., 2015).”
• Microbiota metabolite short chain fatty acids, GCPR, and inflammatory bowel diseases (2016, background): “This effect of SCFA is primarily dependent on HDAC inhibitor activity, but independent of GPR43 [37].”
• Short chain fatty acids in human gut and metabolic health. (2020, positive): “In T-cells, SCFA promoted differentiation depending on the cytokine milieu (Park et al. , 2015).”
• Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “The regulation of T cell biology may be even more complex, however, as SCFAs have also been reported to promote generation of both effector and regulatory T cells, depending on the immunological context (Park et al., 2015).”