EngineeredBacillus subtilisas oral probiotics to enhance clearance of blood lactate

Abstract

Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probioticB. subtilisstrains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineeredB. subtilisto the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to “knocking down” metabolites to help understand the roles of metabolites in host physiological and pathological processes.

Dietary Strategies to Improve Exercise Performance by Modulating the Gut Microbiota

“…In order to improve circulatory lactic acid catabolism following administration to the gut, Yang et al modified probiotic Bacillus subtilis strains to produce lactate oxidase. Treatment of mice with engineered B.subtilis administered in the gastrointestinal tract has the potential to reduce serum lactic acid levels without impacting the normal composition of the gut microbiota, inflammatory response, and liver enzymes [132].…”