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Microbiota or short-chain fatty acids: which regulates diabetes?

Cellular & Molecular Immunology volume 15, pages 88–91 (2018)Cite this article

Anti-inflammatory effects of DF and RS on inflammatory diseases were identified decades ago. SCFAs, fed generally via drinking water or as starch-conjugated forms, can suppress inflammatory diseases in the intestine, lungs, joints and central nervous system (CNS). SCFAs have profound effects on intestinal epithelial cells because they are absorbed and partially consumed by enterocytes as a major energy source. SCFAs strengthen epithelial barrier function by promoting epithelial growth and innate responses to damages, as well as invading microbes. SCFAs make macrophages and dendritic cells more tolerogenic and efficient in inducing regulatory T cells.5, 6 Induction of FoxP3+ T cells by C4 has been observed in many studies. Regardless of FoxP3+ T cell induction, all major SCFAs, such as C2, C3 and C4, induce IL-10 production in T cells.7 In addition, SCFAs promote the generation of significant effector T cell subsets such as Th1 and Th17 cells. SCFAs boost Th1 and Th17 responses during infection and inflammatory processes. Moreover, SCFAs boost antibody production by promoting B cell activation and differentiation into plasma B cells.8 Unlike retinoic acid, which selectively induces IgA production, SCFAs boost most types of antibody isotypes, including IgG and IgA.8 Therefore, SCFAs not only function as anti-inflammatory microbial metabolites but also serve as immune boosters to prepare tissue and immune cells to better eliminate pathogens.

Functions of SCFAs are mediated by several different mechanisms involving G-protein-coupled receptors (GPCR) receptors, histone deacetylase (HDAC) inhibition and metabolic integration. GPR43, GPR41, GPR109A and Olfr78 have been identified as SCFA receptors.9 GPR43 and GPR41 are activated by all three major SCFAs (C2, C3, and C4), whereas GPR109A is selected activated by C4 and niacin. Olfr78 is activated by C2 and C3. Expression of these SCFA receptors is restricted to specific cell types such as intestinal epithelial cells (GPR43 and GPR41), enteroendocrine cells (GPR43 and GPR41), adipocytes (GPR41), renal endothelial cells (Olfr78) and certain myeloid cells (GPR43 for neutrophils and GPR109A for certain dendritic cells and macrophages). Activation of the intestinal epithelial cell GPR43 by SCFAs promotes the production of immunity-related cytokines such as IL-1, IL-6, IL-12 and IL-18.10 Actually, inflammasome activation is supported by GPR43 in intestinal epithelial cells.11 In addition, GPR43 functions as a neutrophil chemotactic receptor, possibly mediating neutrophil chemotaxis to SCFA-rich environments such as the gut lamina propria and lumen. GPR109A activation in macrophages and dendritic cells make them efficient inducers of Tregs, suppressing experimental colitis and colon cancer.5 While exact roles and cell types are unclear, GPR41 and GPR43 are highly expressed in the pancreas.12, 13

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Acknowledgements

This study was supported partly from NIH grants (R01AI074745, R01DK076616, R01AI080769 and R01AI121302).

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  1. Department of Comparative Pathobiology and Biological Sciences, Laboratory of Immunology and Hematopoiesis, Weldon School of Biomedical Engineering, Purdue Institute of Inflammation, Immunology and Infectious Diseases, Purdue Center for Cancer Research, Purdue University, West Lafayette, 47907, IN, USA

    Chang H Kim

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Kim, C. Microbiota or short-chain fatty acids: which regulates diabetes?. Cell Mol Immunol 15, 88–91 (2018). https://doi.org/10.1038/cmi.2017.57

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