Butyrate and Class I Histone Deacetylase Inhibitors Promote Differentiation of Neonatal Porcine Islet Cells into Beta Cells

Abstract

Neonatal porcine islets-like clusters (NPICCs) are a promising source for cell therapy of type 1 diabetes. Freshly isolated NPICCs are composed of progenitor cells and endocrine cells, which undergo a maturation process lasting several weeks until the normal beta cell function has developed. Here, we investigated the effects of short-chain fatty acids on the maturation of islet cells isolated from two to three day-old piglets. NPICCs were cultivated with acetate, butyrate and propionate (0–2000 µM) for one to eight days. Incubation with butyrate resulted in a significant upregulation of insulin gene expression and an increased beta cell number, whereas acetate or propionate had only marginal effects. Treatment with specific inhibitors of G-protein-coupled receptor GPR41 (β-hydroxybutyrate) and/or GPR43 (GPLG0974) did not abolish butyrate induced insulin expression. However, incubation of NPICCs with class I histone deacetylase inhibitors (HDACi) mocetinostat and MS275, but not selective class II HDACi (TMP269, MC1568) mimicked the butyrate effect on beta cell differentiation. Our study revealed that butyrate treatment has the capacity to increase the number of beta cells, which may be predominantly mediated through its HDAC inhibitory activity. Butyrate and specific class I HDAC inhibitors may represent beneficial supplements to promote differentiation of neonatal porcine islet cells towards beta cells for cell replacement therapies.

Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity

“…C4 suppressed nuclear factor kappa B (NF-κB) and inflammatory cytokine production by β cells [ 96 ]. Moreover, C4 had positive effects on the differentiation of pancreatic islet cells to β cells in vitro and promoted insulin secretion from pancreatic islets [ 97 , 98 ]. In nonobese diabetic (NOD) mice, long-term antibiotic treatment depleted SCFA-producing bacteria, accelerated disease activity and increased the diabetogenic intestinal microbiome [ 99 ].…”

Butyrate and obesity: Current research status and future prospect

“…A possible mechanism involves butyrate inhibition of the recruitment of HDACs to the promoter by the transcription factors specificity protein 1/specificity protein 3 (Sp1/ Sp3), leading to histone hyperacetylation (112). In addition, studies have shown that, as a histone deacetylase inhibitor, butyrate promoted pancreatic b-cell differentiation, which was seen as having potential for the treatment of diabetes (114,115).…”

The therapeutic potential of targeting cardiac RGS4

“… 73 These findings suggest a protective role for cardiac RGS4 in reverse remodeling and in mitigation of sympathetic nervous system hyperactivity induced by gut microbiota-derived nutrient metabolites, such as propionic and butyric acids. 73 , 77 Of note, ketone bodies like β-hydroxybutyrate have been reported to antagonize FFAR3, 76 , 80 so it appears that RGS4 can mimic (at least some of) the beneficial actions of ketone bodies in the heart.…”