Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: Focused on host defense peptides

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Abstract

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d1284210e83">The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs. </p>

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From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites.

Ara Koh, Filipe De Vadder, Petia Kovatcheva-Datchary … (2016)

A compelling set of links between the composition of the gut microbiota, the host diet, and host physiology has emerged. Do these links reflect cause-and-effect relationships, and what might be their mechanistic basis? A growing body of work implicates microbially produced metabolites as crucial executors of diet-based microbial influence on the host. Here, we will review data supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs). SCFAs can directly activate G-coupled-receptors, inhibit histone deacetylases, and serve as energy substrates. They thus affect various physiological processes and may contribute to health and disease.

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The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Patrick M. Smith, Michael R. Howitt, Nicolai Panikov … (2013)

Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

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

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda … (2013)

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. 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 responses. 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(+) CD45RB(hi) 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.