Long-term dysbiosis promotes insulin resistance during obesity despite rapid diet-induced changes in the gut microbiome of mice

Abstract The intestinal microbiota and insulin sensitivity are rapidly altered in response to a high fat diet (HFD). It is unclear if gut dysbiosis precedes insulin resistance or vice versa. The initial triggers of diet-induced insulin resistance can differ from mechanisms underlying chronic dysglycemia during prolonged obesity. It is not clear if intestinal dysbiosis contributes to insulin resistance during short-term or long-term HFD-feeding. We found that diet-induced changes in the composition of the fecal microbiome preceded changes in glucose and insulin tolerance at both the onset and removal of a HFD in mice. Dysbiosis occurred after 1-3 days of HFD-feeding, whereas insulin and glucose intolerance manifested by 3-4 days. Antibiotic treatment did not alter glucose tolerance during this short-term HFD period. Conversely, antibiotics improved glucose tolerance in mice with protracted obesity caused by long-term HFD feeding for over 2 months. We also found that microbiota transmissible glucose intolerance only occurred after prolonged diet-induced dysbiosis. Germ-free mice had impaired glucose tolerance when reconstituted with the microbiota from long-term, but not short-term HFD-fed animals. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota.