Are Short Chain Fatty Acids in Gut Microbiota Defensive Players for Inflammation and Atherosclerosis?

Abstract

Intestinal flora (microbiota) have recently attracted attention among lipid and carbohydrate metabolism researchers. Microbiota metabolize resistant starches and dietary fibers through fermentation and decomposition, and provide short chain fatty acids (SCFAs) to the host. The major SCFAs acetates, propionate and butyrate, have different production ratios and physiological activities. Several receptors for SCFAs have been identified as the G-protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3), GPR43/FFAR2, GPR109A, and olfactory receptor 78, which are present in intestinal epithelial cells, immune cells, and adipocytes, despite their expression levels differing between tissues and cell types. Many studies have indicated that SCFAs exhibit a wide range of functions from immune regulation to metabolism in a variety of tissues and organs, and therefore have both a direct and indirect influence on our bodies. This review will focus on SCFAs, especially butyrate, and their effects on various inflammatory mechanisms including atherosclerosis. In the future, SCFAs may provide new insights into understanding the pathophysiology of chronic inflammation, metabolic disorders, and atherosclerosis, and we can expect the development of novel therapeutic strategies for these diseases.

Keywords: Atherosclerosis; Butyrate; Inflammation; Microbiota; Short chain fatty acids.

Fig 1.

Hypothetical pathways based on the results of the suppressive effect of butyrate depends on the prostaglandin E2 (PGE2)-mediated pathway Cited from the reference 73 (A) The effect of butyrate on PGE2 production in the interaction between co-cultured macrophages and adipocytes. Co-culture elevates calcium-dependent cytosolic phospholipase A2 (cPLA2) activity in macrophages, secretory PLA2 (sPLA2) activity in adipocytes and macrophages, and the expression of adipose-specific PLA2 (AdPLA2) protein and mRNA in adipocytes. Butyrate elevates cPLA2 activity to a greater degree in macrophages. Co-culture elevates cyclooxygenase-2 (COX2) expression in both cells, and butyrate further enhances COX2 expression in both cells. Butyrate increases PGE2 production more than coculture alone. (B) The effects of butyrate and PGE2 on lipolysis in co-cultured adipocytes. Co-culture increases cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) levels in adipocytes and increases the release of free fatty acids (FFAs) and free glycerol into the medium (lipolysis). Butyrate suppresses cAMP and PKA levels, and exogenous PGE2 via prostaglandin E receptor 3 (EP3) has a lesser effect than butyrate. These suppressive effects may reduce the activities of lipases, including adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), thus resulting in inhibition of lipolysis. (C) The effects of butyrate and exogenous PGE2 on cAMP- and nuclear factor-kappa B (NF-κB)–mediated lipolysis in tumor necrosis factor-α (TNF-α)–stimulated 3T3-L1 adipocytes. Co-culture increases TNF-α production. TNF-α increases cAMP, leading to increased lipolysis. Anti–TNF-α antibody, butyrate, or exogenous PGE2 decrease cAMP levels and reduce lipolysis in TNF-α–stimulated 3T3-L1 cells. The GPR109A-mediated pathway may be the predominant pathway regulating the effect of butyrate on lipolysis in TNF-α–stimulated 3T3-L1 cells. PTX (pertussis toxin), an inhibitor blocking G-protein coupled receptor (GPR) 41- and/or GPR109A-mediated signaling; SC 58635, COX2 selective inhibitor; L798106, EP3 selective antagonist; SQ22536, adenylyl cyclase selective inhibitor; BAY11-7082, NF-αB–selective inhibitor