Microbial Mechanisms of Methylmercury Metabolism in Humans

The overall objective of this study is to investigate the role of gut microbes in mediating how humans metabolize and excrete the environmental neurotoxicant methylmercury (MeHg). Exposure to MeHg through consumption of fish continues to pose a health risk for many populations globally. There remains considerable uncertainty in advising the public on mercury risks associated with fish consumption. A great deal of uncertainty stems from the fact that the MeHg metabolism and elimination rate is known to vary widely from individual to individual. This translates into the possibility that two individuals consuming the same amount of fish with the same frequency could, unknowingly, experience as much as 4-fold difference in accumulation of MeHg in their bodies. Thus, there is a need for greater understanding of the mechanisms of MeHg metabolism and elimination, as well as for development of tools to assess these characteristics in people. Our scientific premise is that symbiotic microbes in the human gut are required for the efficient biotransformation (demethylation) and excretion of toxic MeHg. In this prospective intervention study we will examine the variation in the rate at which MeHg is excreted, both between human subjects and within subjects over time, and relate it to the MeHg demethylation activity that is harbored in their respective gut microbes. Furthermore, through intervention with a prebiotic dietary supplement, we will induce a change in the gut microbial composition within the same individual and evaluate if slower of faster MeHg metabolism ensues. With these approaches we will obtain gut microbiome samples that correlate with faster or slower MeHg elimination kinetics. We then aim to identify specific genera and species of bacteria in the human gut responsible for MeHg metabolism. We will do this by feeding volunteers fish meals with documented trace levels of MeHg that are below any harmful level of exposure. We will subsequently measure kinetic rates of MeHg elimination via mass-spectrometry analysis of hair strands. We will also sample feces from the subjects as a source of the gut microbiota and as a medium to analyze the extent of MeHg metabolism (demethylation) that parallels its elimination. Study team members at Montana State University will directly examine the ability of the human gut microbiota to induce MeHg metabolizing activity in germ-free mice at rates that correspond with that seen in the human subject it was derived from. In parallel, we will use metagenomic sequence-informed strategies to bring isolated strains of the human gut bacteria to culture and subsequently interrogate their MeHg demethylating activity. We anticipate our results will lead to a clearer understanding of the microbial basis of human MeHg metabolism.