Microbial metabolite mitigates arsenic induced oxidative stress, inflammation, and barrier dysfunction in gut epithelia

The intestinal barrier acts as a physical and immunological defense against luminal microorganisms, viruses, food antigens, and environmental factors. Intestinal inflammation and the pathogenesis of inflammatory bowel diseases (IBD) are closely associated with loss of gut barrier integrity and increased immunological responses. Environmental heavy metal toxins like arsenic (iAs3+ ) effectively regulates several cellular processes involved in cellular proliferation and homeostasis. Recently, it was shown that gut microbiota is required for full protection against acute arsenic toxicity using mouse models. In current study, we investigated the potential role of microbial metabolites such as urolithins to provide protection against arsenic-induced gut barrier damage and inflammation. Urolithin A (UroA), a polyphenol derived microbial metabolite has been reported to provide protection against several diseases caused by inflammation and oxidative stress. Previously, our group demonstrated that microbial metabolite reversed the colitis induced defects in epithelial barrier function. In this study, we for the first time reveled the potential of UroA to mitigate arsenite induced toxicity and loss of gut barrier integrity. UroA showed a time- and concentration- dependent protection against iAs3+ -induced apoptosis and oxidative stress. Moreover, UroA treatment protected against iAs3+ -induced gut epithelial tight junction protein disruption/down regulation. Importantly, treatment with microbial metabolite attenuated arsenic induced barrier dysfunction in pre-clinical human 3D small intestinal organoid tissue model. Taken together, our study indicates that beneficial microbial metabolites such as UroA intervention is a putative preventive/therapeutic approach against environmental iAs3+ related adverse activities on gut barrier.