THE FUNCTIONAL INTERACTIONS OF ARSENIC EXPOSURE, GUT MICROBIOTA, AND HOST

The interactions between gut microbiota and xenobiotics play a significant role in host health. Gut microbiota has powerful capabilities to conduct xenobiotic metabolism, which can profoundly alter the toxicity of xenobiotics. In turn, xenobiotics can perturb the gut microbiota to affect host health. Arsenic is a ubiquitous contaminant affecting millions of people in the world. There are complex interactions between the gut microbiota and arsenic exposure. However, the specific role of the gut microbiota in arsenic metabolism and how arsenic alters gut microbiota to influence host health are still unclear. The objectives of this project are to investigate the functional interactions between arsenic exposure and the gut microbiota and evaluate the impact of these cross-talks on the host. To accomplish this goal, three specific objectives were pursued: (i) to determine the roles of the gut microbiota in arsenic bioavailability and biotransformation in physiological conditions; (ii) to characterize the chronic arsenic exposure-caused perturbation of key functional genes and metabolites in the gut microbiota; (iii) to determine the roles of arsenic-perturbed gut microbiota in arsenic-induced adverse health effects. First, by comparing different arsenic metabolic fates in conventional mice and microbiota-depleted mice, we found that the presence of gut microbiota could significantly reduce arsenic bioavailability and promote arsenic methylation by improving the efficiency of one-carbon metabolism in host livers. We demonstrated the protective role of normal gut microbiota on arsenic metabolism. Second, by combining metagenomic sequencing and metabolomics, we characterized the specific effects of chronic low-level arsenic exposure on the metagenome and metabolome of the gut microbiota. Arsenic exposure significantly perturbed multiple functional genes and metabolites in the gut microbiota, such as SCFAs and bile acids. Third, we compared the arsenic toxic effects in conventional mice and gut bacteria-depleted mice and found that arsenic-induced LXR signaling inhibition depended on the gut microbiota status. We also demonstrated that arsenic-perturbed gut microbiota could impair host glucose tolerance by gut microbiota transplantation. These findings improve our understanding of the mechanistic cross-talks of arsenic exposure, gut microbiota, and host health, and may provide new specific targets for the development of microbiota-based therapeutic approaches or intervention to treat or reduce arsenic-associated diseases.Doctor of Philosoph