Chronic exposure to inorganic arsenic (iAs) from drinking water has been associated with increased risks of preclinical and clinical endpoints of cardiovascular disease (CVD). Methylation of InAs, first generates monomethylarsonic acid (MMAV), which is metabolized to MMAIII, and secondly dimethylarsinic acid (DMAV). A growing number of mechanistic studies have shown that MMAIII is more toxic than iAs or any of the pentavalent metabolites. Incomplete methylation, indicated by a high urinary MMA%, due to high MMAIII%, has been consistently related to the risk of skin and internal cancers and more recently incidence of cardiovascular disease (CVD) and carotid intima-media thickness (cIMT), a surrogate marker of atherosclerosis. Emerging experimental data indicate that gut microbes could convert AsV to AsIII and form MMAV and MMAIII. However, no epidemiologic studies have been conducted to identify the specific gut bacterial taxa that may influence As methylation capacity and for the role of gut bacterial taxa in As toxicology. The principal investigators have established the Health Effects of Arsenic Longitudinal Study (HEALS), a well characterized cohort in Bangladesh with 30,040 participants recruited since year 2000, with extensive experience of the collection, processing, storage, and transport of biological samples, including serum, whole blood, and spot urine samples collected from > 95% study participants. In the proposed study, they will collect fecal samples from a random 600 participants of HEALS to assess the association between gut microbiome, urinary As metabolites profile, and cIMT. Gut microbiome composition in fecal samples will be characterized as relative abundance of bacterial taxa using 16S rRNA pyrosequencing. The 600 participants will be randomly selected from an ongoing study of 3K subjects for whom measurements of cIMT and urinary As metabolites are being conducted as part of the parent study (2P42ES010349-11). The proposed study is highly relevant to the goal of RFA and will be the first epidemiologic study to address 1) whether gut microbiome may have a significant impact on the ultimate As methylation capacity, and 2) whether differences in gut microbiome composition could contribute to population variation in susceptibility to cardiovascular effects of As exposure. Microbiome-focused studies are leading new research efforts with innovative approaches to identify emerging bacterial risk factors of human disease. Since bacterial profiles are modifiable, the study could generate knowledge that may lead to interventions. ExpandCollapse Abstract