Thursday, November 21, 2024
11/21/2024
Project Summary The proposed project addresses the role of the human microbiome in the detoxifying arsenic following ingestion. Arsenic poisoning is a significant worldwide threat to public health that leads to a variety of human diseases, including cancer. Polymorphisms in genes involved with arsenic metabolism and transport have been epidemiologically linked to increased risk of lung, skin, bladder, and liver cancer, but there is large inter-individual variability in cancers among similarly exposed individuals, indicating other important factors are involved in disease penetrance. We showed the gut microbiome is an important determinant in arsenicosis and this project continues to evaluate which microbiome-arsenic interactions provide the most benefits during exposure. This includes engineering bacteria to evaluate specific microbiome-driven arsenical metabolisms in the gut of gnotobiotic mice, focusing specifically on reduction, methylation, and thiolation pathways (Aim 1). We also found antibiotic perturbation of the murine microbiome significantly increases the toxicity of inorganic arsenic and leads to inter-individual differences in lethality. At least some of these differences appear to result from sepsis or sepsis-like disease also observed in human arsenic poisoning. We will quantify the impact of commonly prescribed antibiotics on arsenic toxicity and test whether microbiome manipulation can be used to rescue arsenic-attributable sepsis (Aim 2). This information is important given the large number of individuals treated with antibiotics in the US and countries around world. PD/PI's Walk and McDermott have had success leading this multidisciplinary research program since 2017. The research new team members and collaborators with years of training and technical expertise in murine models of the gut microbiome, microbial ecology, molecular biology, arsenical speciation, clinical pharmacology, and immunology. Collectively, the assembled team will ensure the continued success of a highly productive research effort into microbiome-arsenic-host interactions.
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