There is a fundamental gap in understanding the role of environmental exposure-gut microbiome interactions in affecting human health. The microbiome of the human intestinal tract has a profound effect on human health through its key role in a wide range of host-related functions. Exposure to inorganic arsenic (iAs) is a significant public health issue worldwide and has been linked to a number of diseases, including cancers, metabolic disorders, cardiovascular diseases and impaired immune functions. Mounting evidence indicates that dysregulated gut microflora contribute significantly to many of these diseases, underscoring a potentially important role of the gut microbiome in arsenic-induced diseases. However, functional interaction between the gut microbiome and arsenic exposure is largely unexplored, except for the investigators' recent studies. Their central hypothesis is that the gut microbiome-arsenic interaction influences iAs toxicity. This hypothesis has been formulated on the basis of exciting preliminary data produced in the Principal Investigator's laboratory and will be tested by pursuing three specific aims, with the goal of defining the effects of iAs on the gut microbiome and its function and elucidating the role of gut microbiome community structures in mediating arsenic toxicity. The significance of this grant application lies in the fact that gut microbiome-exposure interaction is still largely unexplored despite the diverse and profound roles of the microbiome in human health. The investigators' proposed studies are also highly innovative and represent a paradigm shift in toxicology because they focus on gut microbiome perturbations as a novel mechanism of exposure-induced diseases and an unexplored risk factor responsible for individual susceptibility. The innovation of this grant application also stems from the novel application of integrated bioanalytical and computational tools to a systems-level study of a significant gut microbiome-exposure interaction. Findings from this study are expected to lay a foundation for future studies aiming at expanding our understanding of new mechanisms by which exposure to iAs leads to or exacerbates human disease: the role of the microbiome.