Amelioration of metabolic syndrome by metformin associates with reduced indices of low- grade inflammation independently of the gut microbiota

Metformin beneficially impacts several aspects of metabolic syndrome including dysglycemia, obesity and liver dysfunction, thus making it a widely used front line treatment for early-stage type 2 diabetes, which is associated with these disorders. Several mechanisms of action for metformin have been proposed, including that it acts as anti-inflammatory agent, possibly as a result of its impact on intestinal microbiota. In accord with this possibility, we observed herein that, in mice with diet-induced metabolic syndrome, metformin is impacting the gut microbiota by preventing its encroachment upon the host, a feature of metabolic syndrome in mice and humans. However, the ability of metformin to beneficially impact metabolic syndrome in mice was not impacted by ablation of gut microbiota achieved by use of antibiotics or germfree mice. Rather, while microbiota ablation itself suppressed diet-induced dysglycemia, other features of metabolic syndrome including obesity, hepatic steatosis, and low-grade inflammation were similarly suppressed by metformin in the presence or absence of gut microbiota. These results support a role for metformin's anti-inflammatory activity, irrespective of gut microbiota, in driving some of this drug's beneficial impacts on metabolic syndrome.