Arsenic Removal from the Body Through Mechanism-Guided Gut Microbiome Modulation

Abstract Environmental exposure to inorganic arsenic (iAs), a toxic heavy metal, is a significant public health risk, estimated to affect hundreds of millions of people globally. The objective of this project is to develop novel microbiome-based solutions to reduce exposure to iAs, which is ubiquitously found in groundwater, food, soil, air, and other sources. Chronic iAs exposure is associated with a range of serious health issues such as cardiovascular disease, neurological disorders, diabetes, and various types of cancers. Current water filtration methods inadequately address iAs exposure due to limitations in efficacy, cost and performance, and they do not target other exposure routes, such as diet. In fact, rice consumption alone is estimated to account for as much iAs exposure as drinking water in some U.S. populations. Given the widespread nature of iAs exposure from multiple sources and the shortcomings of existing methods to remove iAs from water, there is a critical need for innovative strategies to reduce arsenic exposure in the body. Our innovative approach leverages the gut microbiome's role in arsenic metabolism. We propose a mechanism-guided strategy to engineer custom microbiomes that enhance iAs uptake, methylation, and efflux. Preliminary studies have identified six bacterial strains that significantly reduce iAs body burden and tissue accumulation in mice. This Phase I project aims to optimize human gut bacterial strains and evaluate their efficacy and safety in in vivo models, positioning us for further development of microbiome-based products to mitigate iAs toxicity. Two Specific Aims will be pursued: Aim 1 is to screen top bacterial strains for arsenic metabolism in vitro, identifying ≥10 candidates with substantial arsenic reduction/methylation capabilities; Aim 2 is to evaluate the efficacy of these strains in germ-free and conventionally raised humanized mice, aiming for bacterial formulations that lead to significant reductions in urinary arsenic, liver bioaccumulation, and increased arsenic methylation, without adverse effects on health. Successful completion of this project will yield a first-generation bacterial treatment to reduce iAs exposure, paving the way for Phase II development and broader application to other environmental toxicants.