Engineered Bacillus subtilis as Oral Probiotics To Enhance Clearance\nof Blood Lactate

Elevated lactate concentrations are implicated in various\nacute\nand chronic diseases, such as sepsis and mitochondrial dysfunction,\nrespectively. Conversely, ineffective lactate clearance is associated\nwith poor clinical prognoses and high mortality in these diseases.\nWhile several groups have proposed using small molecule inhibitors\nand enzyme replacement to reduce circulating lactate, there are few\npractical and effective ways to manage this condition. Recent evidence\nsuggests that lactate is exchanged between the systemic circulation\nand the gut, allowing bidirectional modulation between the gut microbiota\nand peripheral tissues. Inspired by these findings, this work seeks\nto engineer spore-forming probiotic Bacillus subtilis strains to enable intestinal delivery of lactate oxidase as a therapeutic\nenzyme. After strain optimization, we showed that oral administration\nof engineered B. subtilis spores to\nthe gut of mice reduced the level of blood lactate in two different\nmouse models involving exogenous challenge or pharmacologic perturbation\nwithout disrupting gut microbiota composition, liver function, or\nimmune homeostasis. Taken together, through the oral delivery of engineered\nprobiotic spores to the gastrointestinal tract, our proof-of-concept\nstudy offers a practical strategy to aid in the management of disease\nstates with elevated blood lactate and provides a new approach to\n“knocking down” circulating metabolites to help understand\ntheir roles in host physiological and pathological processes.