Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes

Abstract

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.

Epithelial Barrier Function in Gut-Bone Signaling

“…Recently, in the non-obese diabetic (NOD) mouse model, T1D severity was shown to be inversely correlated with levels of acetate and butyrate, microbial metabolites. When these metabolites were replaced in the diet, NOD mice were protected from the development of T1D [202]. Furthermore, the authors found that acetate supplementation decreased the activation of autoreactive T cells while butyrate supplementation increased the number and function of regulatory T cells, thereby preventing autoimmune development of T1D [202].…”

“…When these metabolites were replaced in the diet, NOD mice were protected from the development of T1D [202]. Furthermore, the authors found that acetate supplementation decreased the activation of autoreactive T cells while butyrate supplementation increased the number and function of regulatory T cells, thereby preventing autoimmune development of T1D [202]. Several studies examining different probiotics have shown that altering the microbiome can influence both the inflammatory state of the intestine as well as prevent the progression of T1D [203].…”

A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity

“…SCFAs exert their effects not only in the gut but also in distant organs by dampening immune responses that are uncontrolled in patients on a low-fiber Western diet (Thorburn et al, 2014). High-fiber diets have been shown to ameliorate metabolic and allergic diseases mainly through their microbiota-dependent fermentation to SCFAs that promote tissue barrier integrity, mucus production, IgA secretion, and regulatory T cell (Treg) differentiation, thereby supporting an anti-inflammatory environment (Mariño et al, 2017; Thorburn et al, 2014). However, little is known about the beneficial effects of a high-fiber diet in autoimmune diseases.…”

Western lifestyle and immunopathology of multiple sclerosis

“…Fatty acids can be classified into short‐ (SCFA, <10 carbon atoms), medium‐ (MCFA, 10–14 carbon atoms), long‐ (LCFA, 16–20 carbon atoms), and very‐long‐chain fatty acids (VLCFA, >20 carbon atoms). SCFAs were recently found to ameliorate EAE, as well as other autoimmune diseases, such as type 1 diabetes, by expanding lamina propria–derived T reg cells through suppression of the JNK1 and p38 pathway 98, 125. In line with these studies, SFCAs also increase the number of colonic T reg cells in an experimental model of inflammatory bowel disease 126, 127.…”