Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

Abstract

Islet dysfunction mediated by oxidative and mitochondrial stress contributes to the development of type 1 and 2 diabetes. Acetate and butyrate, produced by gut microbiota via fermentation, have been shown to protect against oxidative and mitochondrial stress in many cell types, but their effect on pancreatic β-cell metabolism has not been studied. Here, human islets and the mouse insulinoma cell line MIN6 were pre-incubated with 1, 2, and 4 mM of acetate or butyrate with and without exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ). Both short-chain fatty acids (SCFAs) enhanced the viability of islets and β-cells, but the beneficial effects were more pronounced in the presence of STZ. Both SCFAs prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) at a concentration of 1 mM but not at higher concentrations. These rescue effects of SCFAs were accompanied by preventing reduction of the mitochondrial fusion genes MFN, MFN2, and OPA1. In addition, elevation of the fission genes DRP1 and FIS1 during STZ exposure was prevented. Acetate showed more efficiency in enhancing metabolism and inhibiting ROS, while butyrate had less effect but was stronger in inhibiting the SCFA receptor GPR41 and NO generation. Our data suggest that SCFAs play an essential role in supporting β-cell metabolism and promoting survival under stressful conditions. It therewith provides a novel mechanism by which enhanced dietary fiber intake contributes to the reduction of Western diseases such as diabetes.

Therapeutic effects of different doses of prebiotic (isolated from Saccharomyces cerevisiae) in comparison to n-3 supplement on glycemic control, lipid profiles and immunological response in diabetic rats

“…Microbial fermentation of prebiotics generates short-chain fatty acids (SCFA), such as acetate and butyrate, that have been shown to protect against oxidative and mitochondrial stress [ 47 ], enhance gut barrier, increase glucangon-like peptide 1 and 2 (GLP-1 and GLP-2) secretion [ 48 ], which delay gastric emptying and induce satiety [ 49 ]. Besides, incretins reduce hepatic expression of inflammatory and oxidative stress markers during obesity and diabetes [ 50 ].…”

“…Besides, SCFA inhibits lipolysis and reduces inflammation, enhancing energy metabolism regulation [ 16 ]. A recent study showed that SCFAs enhanced the viability of islets and β-cells, prevented STZ-induced cell apoptosis, viability reduction, mitochondrial dysfunction, and the overproduction of reactive oxygen species (ROS) and nitric oxide (NO) [ 47 ]. Mechanisms responsible for the efficacy of dietary n-3 PUFAs include reduction in IFN-γ, IL-17, IL-6, and TNF-α corroborating our findings (reduction in TNF-α) [ 53 ].…”

Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes

“…In addition to these rescuing effects, SCFAs prevented the downregulation of the mitochondrial fusion genes Mfn1, Mfn2 and Opa1 and the upregulation of the fission genes Drp1 and Fis1 during STZ exposure. Acetate revealed more efficiency in inhibiting the ROS and increasing the metabolism, while butyrate had a weaker effect but was stronger in inhibiting NO generation and the SCFA receptor GPR41 [101].…”

“…Notably, Mollica et al showed that sodium butyrate reduced ROS production and ameliorated mitochondrial function in the livers of insulin-resistant obese mice [100]. Similarly, Shuxian et al revealed that both acetate and butyrate can prevent mitochondrial dysfunction and reduce oxidative and nitrosative stresses in human islets and β cells after exposure to the apoptosis inducer and metabolic stressor streptozotocin (STZ) [101]. In addition to these rescuing effects, SCFAs prevented the downregulation of the mitochondrial fusion genes Mfn1, Mfn2 and Opa1 and the upregulation of the fission genes Drp1 and Fis1 during STZ exposure.…”

Role and mechanism of action of butyrate in atherosclerotic diseases: a review

“…Some studies have been conducted to examine the relationship between SCFAs, and energy metabolism and immune regulation (D'souza et al 2017;Hu et al 2018). These studies show that, compared to other SCFAs, butyrate has more significant lipid-lowering, antioxidant, and insulin resistance-improving effects, and has been used to prevent a variety of inflammatory diseases (Li et al 2019;Hu et al 2020). In the present article, we discuss the beneficial effects of butyrate on several processes involved in the occurrence and development of AS.…”