Microbial metabolite butyrate facilitates M2 macrophage polarization and function

Abstract

Metabolites from intestinal microbes modulate the mucosal immune system by regulating the polarization and expansion of T cells. Whether the microbial metabolites influence macrophage polarization, however, is poorly understood. Here, we show that the large bowel microbial fermentation product, butyrate, facilitates M2 macrophage polarization, in vitro and in vivo. The supernatant from butyrate-treated M2 macrophage increased the migration and enhanced the wound closure rate of MLE-12 cells. Butyrate attenuated intestinal inflammation in mice with dextran sulfate sodium (DSS)-induced colitis, with a significant increase in colonic expression of the M2 macrophage-associated protein, Arg1. M2 macrophage treated with butyrate, had increased activation of the H3K9/STAT6 signaling pathway, suggesting a mechanism for butyrate facilitated M2 macrophage polarization. Collectively, our study indicated that commensal microbe-derived butyrate is a novel activator of STAT6-mediated transcription through H3K9 acetylation driving M2 macrophage polarization, and delineated new insights into the immune interplay underlying inflammatory bowel disease.

Host–microbiota interactions: epigenomic regulation

“…These genes, among others, were also downregulated in macrophages from antibiotic-treated mice, and exhibited impaired interferon signaling and anti-viral function compared to conventionally-housed mice [33]. Recent work also demonstrated a novel role for butyrate in facilitating colitis-protective M2 macrophage polarization in vivo , as well as reducing TNF-α and IL-1β production to suppress inflammation [34]. Moreover, in vitro experiments on bone marrow-derived macrophages indicated that M0 to M2 differentiation was induced by butyrate, potentially through inhibition of HDACs and enhanced histone H3K9 acetylation and Il-4/STAT4 signaling [34].…”

“…Recent work also demonstrated a novel role for butyrate in facilitating colitis-protective M2 macrophage polarization in vivo , as well as reducing TNF-α and IL-1β production to suppress inflammation [34]. Moreover, in vitro experiments on bone marrow-derived macrophages indicated that M0 to M2 differentiation was induced by butyrate, potentially through inhibition of HDACs and enhanced histone H3K9 acetylation and Il-4/STAT4 signaling [34]. Importantly, decreased gene expression in response to butyrate is not consistent with the generally expected outcome of HDAC inhibition and increased histone acetylation, indicating that butyrate is possibly functioning through other mechanisms in addition to HDACs or that butyrate-induced increased histone acetylation at specific genes mediates decreased gene expression.…”

Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm

“…Interestingly, anti-inflammatory effects of butyrate are independent of TLR signaling and are mediated by inhibition of histone deacetylases (HDACs)(139). In addition to suppressing pro-inflammatory response by activated myeloid cells, SCFAs can also facilitate M2 polarization of macrophages by directly activating STAT6 signaling(141). Whether SCFAs can influence innate control of T cell responses has not been directly tested however, butyrate-producing Clostridia was shown to attenuate GVHD(142), a disease with a strong T cell component.…”

Short Chain Fatty Acids from Fermentation By Endophytic Bacteria in Aloe Vera Leaf Rind and Gel

“…Present study reveals the key to understand how an in-vitro-of lumen pH and to exert many beneficial extra-intestinal effects through epigenetic mechanisms [15] . Ji J. group showed that the large bowel microbial fermentation product, butyrate, facilitates M2 macrophage polarization, in vitro and in vivo [16] . Chang PV.…”