The Gut Microbial Metabolite Butyrate Alleviates IL-1β-Induced Mitochondrial Dysfunction and Oxidative Stress in Pancreatic Islets

Abstract

Butyrate, a gut microbiota-derived metabolite, supports cellular health. In pancreatic beta cells, inflammation and oxidative stress disrupt mitochondrial function, contributing to dysfunction. This study explores how butyrate influences mitochondrial function and redox balance to protect beta cells from interleukin-1beta (IL-1β)-induced stress. Pancreatic mouse islets were treated with IL-1β and/or butyrate for 10 days to model chronic inflammation in type 2 diabetes, and their effects on mitochondrial health and oxidative stress were studied. Butyrate protected against IL-1β-induced impairment of insulin secretion by enhancing mitochondrial function, as evidenced by an increased glucose-stimulated oxygen consumption rate and a higher mitochondrial membrane potential compared to IL-1β treatment alone. IL-1β increased mitochondrial mass, but the mitochondria appeared smaller and rounded, indicating fragmentation. In contrast, butyrate co-treatment promoted mitochondrial hyperfusion, as evidenced by elongated mitochondria, higher levels of fusion proteins Opa1 and Mfn2, and lower levels of fission protein Fis1 compared to IL-1β alone. Furthermore, butyrate reduced IL-1β-induced reactive oxygen species (ROS) production, antioxidant enzyme gene expression, and protein oxidation, indicating protection against oxidative stress. Butyrate co-treatment further enhanced redox balance by increasing reduced glutathione (GSH) levels and the ratio of GSH to oxidized glutathione (GSSG). These findings suggest that butyrate acts as a potent modulator of mitochondrial function and redox balance, counteracting IL-1β-induced dysfunction and providing a potential therapeutic strategy for improving insulin secretion in inflammatory conditions.

Keywords: beta cells; butyrate; cytokine; inflammation; mitochondria; oxidative stress.