DC2421 - Microbial D-lactate Contributes To Hyperglycemia During Obesity And Can Be Targeted To Mitigate Disease

Blinded Abstract: Metabolic disorders are associated with changes in the intestinal microbiome which produces metabolites that are substrates for host metabolism. Our group previously showed that D-lactate, the enantiomer of L-lactate, is a key bacterial-derived substrate contributing to liver glycogen and fat. Therefore, we aimed to understand the role of D-lactate in hyperglycemia. We show that D-lactate levels in portal serum are significantly higher in hyperglycemic and normoglycemic obese mice relative to their healthy controls. In systemic serum, D-lactate levels are also significantly higher in hyperglycemic and normoglycemic obese mice, and in diabetic mice. We also show that there is significantly higher serum D-lactate in people with obesity. We conducted an oral lactate tolerance test in chow-fed lean mice versus high fat diet (HFD)-fed obese mice. Administration of 1g/kg of L- or D-lactate resulted in significantly higher blood-glucose in HFD relative to chow-fed mice. Importantly, D-lactate resulted in significantly higher blood-glucose relative to L-lactate in HFD but not in chow mice. Therefore, like L-lactate, D-lactate can be converted to glucose and contribute to hyperglycemia, and D-lactate is a more efficient substrate for glucose production in HFD-fed obese mice. We also found that microbial D-lactate absorption can be restricted using a poly-L-lactide polymer, which acts as a D-lactate trap. This polymer can lower blood-glucose in obese mice and possibly lower liver fat in fatty liver disease.