Defining the impact of developmental herbicide exposures on gut microbiome physiology and interactions with health

This project will define how interactions between herbicide exposure, the microbiome, and the host promote adiposity. Billions worldwide are overweight or obese. The gut microbiota regulate host energy metabolism, and imbalance in these communities correlates with increased body mass, adiposity, and altered lipid metabolism. Common herbicides are known potent disruptors of gut microbial communities and the patterns of microbial community disruption induced by herbicides are consistent with those that manifest in obese individuals. Moreover, disruption of the gut microbiota during key developmental windows has been linked with increased risk of obesity. However, it remains unclear if herbicide induced disruptions of gut microbiomes or their functioning yields obesogenic effects. We hypothesize that early life exposure to environmentally relevant concentrations of three widely used herbicides (glyphosate, atrazine, and 2,4-D) induces disruption of the microbiome favoring the assembly of a microbiota that contributes to elevated adipogenesis. We propose a series of innovative experiments that integrate multiomic microbiome data with measures of host physiology to identify herbicide disrupted microbial pathways that correlate with adiposity. Germ-free animals, microbiome transplants, and in vitro assays will allow us to resolve causal relationships between microbiota and obesity. Additionally, this project will define the role of the gut microbiome in mediating the acute toxicological effects of herbicide exposure, identify the molecular pathways that mediate this functioning, and isolate and characterize the microbes responsible for its execution. Consequently, the proposed work will clarify herbicide exposure hazards by defining concentrations that sufficiently disrupt microbiota to contribute to obesity, define mechanistic links between herbicide associated microbiome disruption and adiposity, and propel subsequent research in mammals towards generating microbiome targeting or mimicking therapeutics capable of preventing or treating obesity.