Microbially derived glutathione from Eubacterium rectale alleviates oxidative stress and promotes intestinal epithelial recovery.

BACKGROUND: Certain microbes inhabiting the gut have been implicated in maintaining gut homeostasis and promoting gut damage repair. Lachnospiraceae members were highly detected in dysbiotic IL-10 KO mice that displayed similar physiological outcomes as control mice. Lachnospiraceae is a highly diverse family of microbes that have been shown to display both commensal and pathogenic characteristics in the colon environment. RESULTS: We investigated the impact of genetic variation in five Lachnospiraceae strains on lowering cellular inflammation and reactive oxygen species (ROS) levels. Cell-free spent media (CFSM) from Eubacterium rectale resulted in lowered ROS, and nitric oxide levels in stressed colon cells and colon organoids. CFSM-treated organoids showed reduced ROS accumulation, improved epithelial integrity, and partial recovery of barrier function compared to oxidatively stressed controls. We demonstrated through shotgun metagenomics, metabolomics, host RNA sequencing, and molecular techniques that glutathione (GSH) biosynthesized by E. rectale alleviated host ROS damage. We showed downregulation of cell stress and immune response genes, indicating recovery from ROS stress. Chemical depletion of GSH in CFSM confirmed the role of microbial derived GSH in alleviation of ROS in colon cells. CONCLUSIONS: In this study, we identify E. rectale as a potential probiotic by lowering colon inflammation and ROS damage through production of reduced glutathione. Microbially derived GSH has not been well established in the Lachnospiraceae family which are a large member of the overall gut microbiota. Understanding more about the impacts of microbial functions including GSH on lowering inflammation is needed to develop potential probiotics or therapies for chronic inflammatory conditions. Video Abstract.