Disruption of the intestinal mucosa contributes to insulin resistance in obesity and Type 2 diabetes. Probiotic supplementation, which restores gut microbiota composition and fortifies intestinal barrier function, has therapeutic potential to treat obesity and metabolic disease. Treatment of mice on a chow diet or high fat diet (HFD) with Palmitic Acid Hydroxystearic Acids (PAHSAs) improves insulin sensitivity. These effects are mediated, at least in part, by changes in the gut microbiome. We used this paradigm to identify new microbes that may have beneficial metabolic effects. Metagenome sequencing of the cecum from mice treated with PAHSAs identified Bacteroides thetaiotaomicron (Bt) to be most strongly associated with insulin sensitivity. Here, we aimed to determine whether Bt supplementation in mice on a HFD diet has beneficial effects on energy balance and/or glucose homeostasis. Daily oral Bt supplementation in female mice fed a HFD resulted in less weight gain, lower adiposity, and improved glucose tolerance compared to vehicle-treated mice. Additionally, Bt supplementation preserved colonic mucus thickness, an indicator of gut health; increased the number of Goblet cells which are the cells that secrete mucin2, the predominant mucus protein that forms the intestinal mucosal barrier; and increased protein levels of mucin2 in the distal gut compared to vehicle-treated controls. These improvements in distal gut barrier architecture were associated with a reduction in circulating levels of pro-inflammatory lipopolysaccharide (LPS) and interleukin-6 (IL-6) . These beneficial effects of Bt were observed in female and not in male HFD-fed mice. These studies indicate that Bt has sex-specific effects to improve host metabolism in the setting of dietary obesity. Bt represents a next-generation probiotic and novel gut-based therapeutic strategy which could improve metabolic health in women.
J.Lee: None. K.Wellenstein: None. B.B.Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; Mellicell, Other Relationship; Alnylam Pharmaceuticals, Inc.
NIH KDK114162; JPB Foundation