Butyrate increases IL-23 production by stimulated dendritic cells

Abstract

The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL-17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration.

Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells

“…mRNA relative expression of pro-inflammatory chemokines/cytokines genes: A-CCL20, B-IL-8 and C-ITF of Caco-2 cells in basal condition (mock), pre-incubated with lactate and SCFAs solutions100 mM pH 7, non-treated and stimulated with flagellin. Statistically significative differences with control cells stimulated with flagellin obtained by Student t test are indicated as * for p-value < 0.05, **p-value < 0.01. human or mouse dendritic cells were also reported (Berndt et al, 2012;Liu et al, 2012). This work evidenced changes in CD40 expression levels upon BMDC activation, whereas changes in CD80 and CD86 were not detected ( Figs.…”

“…In particular, the administration of probiotic bacteria with the capacity to produce butyrate has been shown to improve the symptoms in IBD models (Eeckhaut et al, 2013). These modulatory effects in vivo are probably due to the capacity that show different SCFA to downregulate specific inflammatory cell functions that has been partially described so far (Tedelind et al, 2007;Berndt et al, 2012;Liu et al, 2012). SCFAs have effects in different cell types mediated by different mechanisms.…”

The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease

“…For example, SCFAs inhibit the development of myeloid dendritic cells from their progenitors [118], as well their functional maturation [119,120]. A key mechanism is the attenuation of histone deacetylase activity.…”

Epigenomic regulation of host–microbiota interactions

“…Further, while loss of HDAC3 expression in IECs impairs microbiota-dependent intestinal barrier function, inhibition of HDACs by commensal bacteria-derived SCFAs in Tregs generally protects from pathologic intestinal inflammation, possibly underlying why multiple outcomes and mechanisms have been suggested for butyrate treatment during colitis [68, 84–87]. These seemingly opposing effects of HDACs in different intestinal cell populations warrant a more thorough examination of the differential effects of SCFAs on specific HDAC isoforms in different host cells, in the context of protective and pathologic immunity [66, 68, 84, 85, 87]. …”