Butyrate functions as a histone deacetylase inhibitor to protect pancreatic beta cells from IL‐1β‐induced dysfunction

Abstract

Butyrate, a gut microbial metabolite, has beneficial effects on glucose homeostasis and has become an attractive drug candidate for type 2 diabetes (T2D). Recently, we showed that butyrate protects pancreatic beta cells against cytokine‐induced dysfunction. In this study, we explored the underlying mechanisms of butyrate action. Pancreatic mouse islets were exposed to a non‐cytotoxic concentration of interleukin‐1β (IL‐1β) for 10 days to mimic low‐grade inflammation in T2D. Similar to the effect of butyrate, an isoform‐selective histone deacetylase 3 (HDAC3) inhibitor normalized IL‐1β‐reduced glucose‐stimulated insulin secretion and insulin content. In contrast, free fatty acid receptor 2 and 3 (FFAR2/3) agonists failed to normalize IL‐1β‐induced beta cell dysfunction. Furthermore, butyrate inhibited HDAC activity and increased the acetylation of histone H3 and H4 by 3‐ and 10‐fold, respectively. Genome‐wide analysis of histone H3 lysine 27 acetylation (H3K27ac) revealed that butyrate mainly increased H3K27ac at promoter regions (74%), while H3K27ac peaks regulated by IL‐1β were more equally distributed at promoters (38%), introns (23%) and intergenic regions (23%). Gene ontology analysis showed that butyrate increased IL‐1β‐reduced H3K27ac levels near several genes related to hormone secretion and reduced IL‐1β‐increased H3K27ac levels near genes associated with inflammatory responses. Butyrate alone increased H3K27ac near many genes related to MAPK signaling, hormone secretion, and differentiation, and decreased H3K27ac at genes involved in cell replication. Together, these results suggest that butyrate prevents IL‐1β‐induced pancreatic islet dysfunction by inhibition of HDACs resulting in changes in H3K27ac levels at genes relevant for beta cell function and inflammatory responses.

Exploring the Role of G Protein Expression in Sodium Butyrate-Enhanced Pancreas Development of Dairy Calves: A Proteomic Perspective

“…In the context of the current research on butyrate, it is conceivable that its SB addition to milk can augment PROX1 expression in the calf pancreas through several potential mechanisms: (1) metabolic regulation: SB, as a readily absorbable and utilizable energy source, can increase the energy availability for intestinal epithelial cells . This direct energy provision may alter the cellular metabolic status, activating metabolic sensors such as AMPK, which in turn could influence the activity and expression of nuclear transcription factors, including PROX1. , (2) Epigenetic regulation: As a short-chain fatty acid, butyrate serves as a histone deacetylase inhibitor, modifying chromatin structure and potentially regulating the expression of various genes, such as PROX1. , Such epigenetic alterations might change the transcriptional landscape of pancreatic cells, thereby affecting their development and function. Although we have proposed these potential pathways through which butyrate may influence PROX1, the specific impacts and functional ramifications in the calf pancreas require further exploration and validation through detailed experimental studies.…”

Effect of Akkermansia muciniphila on pancreatic islet β-cell function in rats with prediabetes mellitus induced by a high-fat diet

“…(2) A. muciniphila can also upregulate short-chain fatty acids in the gut through the metabolic interactions between A. muciniphila and butyrogenic bacterial taxa, perhaps especially butyrate (Belzer et al 2017 ). Butyrate has been extensively shown to afford protection in pancreatic islet β cells (Pedersen et al 2024 ). Whether the effects of A. muciniphila regulated butyrate are mediated via the upregulation of β-cell sirtuin-3 (Zhang et al 2016 ), thereby optimizing pancreatic β-cell mitochondrial function and decreasing oxidant production will be important to clarify (Anderson and Maes 2020 ).…”