Antibiotic Effects on Gut Microbiota, Insulin Signaling and Bile Acid Metabolism is Dependent on Host

Interactions of diet, gut microbiota and host genetics play important roles in development of obesity and insulin resistance. In obesity/diabetes-prone C57BL/6J mice, vancomycin or metronidazole treatment of high fat diet (HFD)-fed animals alters intestinal microbiota, decreases tissue inflammation, improves insulin signaling in the basal and stimulated states, and improves glucose metabolism. Many of these changes can be reproduced by transfer of gut microbiota from antibiotic-treated donors to germ-free mice or mice in which the normal gut flora had been depleted. These physiological changes closely correlate with changes in serum bile acids and levels of the anti-inflammatory bile acid receptor TGR5, and are recapitulated, in part, by treatment with a TGR5 agonist. In contrast, treatment of HFD-fed 129S6/SvEvTac or 129S1/SvImJ mice with antibiotics does not improve metabolism, despite changes in microbiota and bile acids, and these mice also fail to improve glucose tolerance in response to the TGR5 agonist. Thus, antibiotic modification of gut microbiota, acting through changes in bile acid and inflammatory signaling, can improve insulin signaling and glucose metabolism, however, these effects also depend on important interactions with host genetic background and inflammatory potential.