Urolithin A attenuates arsenic-induced gut barrier dysfunction

Environmental chemicals such as inorganic arsenic (iAs) significantly contribute to redox toxicity in the human body by enhancing oxidative stress. Imbalanced oxidative stress rapidly interferes with gut homeostasis and affects variety of cellular processes such as proliferation, apoptosis, and maintenance of intestinal barrier integrity. It has been shown that gut microbiota are essential to protect against iAs³⁺-induced toxicity. However, the effect of microbial metabolites on iAs³⁺-induced toxicity and loss of gut barrier integrity has not been investigated. The objectives of the study are to investigate impact of iAs on gut barrier function and determine benefits of gut microbial metabolite, urolithin A (UroA) against iAs³⁺-induced adversaries on gut epithelium. We have utilized both colon epithelial cells and in a human intestinal 3D organoid model system to investigate iAs³⁺-induced cell toxicity, oxidative stress, and gut barrier dysfunction in the presence or absence of UroA. Here, we report that treatment with UroA attenuated iAs³⁺-induced cell toxicity, apoptosis, and oxidative stress in colon epithelial cells. Moreover, our data suggest that UroA significantly reduces iAs³⁺-induced gut barrier permeability and inflammatory markers in both colon epithelial cells and in a human intestinal 3D organoid model system. Mechanistically, UroA protected against iAs³⁺-induced disruption of tight junctional proteins in intestinal epithelial cells through blockade of oxidative stress and markers of inflammation. Taken together, our studies for the first time suggest that microbial metabolites such as UroA can potentially be used to protect against environmental hazards by reducing intestinal oxidative stress and by enhancing gut barrier function.