Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages

Abstract

The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis.

Short‐chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43

“…Other potential mechanisms by which SCFAs could affect the cells might be via effects mediated by a transporter or pursuant to direct passage of the SCFAs across the cell membrane. Once inside the cell, SCFAs might affect signal transduction or transcriptional events, as reported elsewhere . It has been reported that SCFAs can act as histone deacetylase inhibitors (HDACi), and HDACi can also enhance t‐PA induction in endothelial cells.…”

“…SCFAs are produced at concentrations of ~100 mmol/L in the gut lumen, and the major components are acetic acid (C2), propionic acid (C3) and butyric acid (C4) . Previous studies have highlighted the variety of functions of SCFAs in inflammation, carcinogenesis, metabolism and allergy . There is interest in SCFA receptors as attractive pharmaceutical targets having a broad range of potential therapeutic applications .…”

“…SCFAs produced in the gut lumen are readily absorbed by intestinal epithelial cells, circulate in the body and can be used as an energy source in peripheral tissues . Many recent reports have discovered diverse functions of SCFAs in inflammation, carcinogenesis, metabolism and allergic diseases . SCFAs are now recognized to be key molecules that regulate beneficial effects on human health .…”

“…21 Many recent reports have discovered diverse functions of SCFAs in inflammation, carcinogenesis, metabolism and allergic diseases. [22][23][24][25][26][27][28] SCFAs are now recognized to be key molecules that regulate beneficial effects on human health. 29 They can perform their functions via intermediary metabolism or via specific SCFA receptors, namely G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/ FFAR2, which are 7-transmembrane-spanning G protein-coupled receptors.…”

Metabolic regulation of macrophage phenotype and function

“…For example, commensal bacteria secretes large amounts of n‐butyrate which modulates the pro‐inflammatory functions of LPS‐stimulated macrophages by down regulating NO, IL‐6, and IL‐12 . N‐butyrate was also shown to suppress the expression of M2 markers, limit macrophage‐induced IL‐17A expression by T‐regulatory cells and enhance anti‐bacterial effects in IL‐4‐treated M2 macrophages . An epigenetic role of n‐butyrate in controlling macrophage gene expression has been indicated .…”