Diabetes is a pandemic, causing grave social and economic burdens. This complex disease is caused by an interactionamonggenetic,metabolic,behavioral,andenvironmentalfactors. Epidemiologystudiesandanimal experiments demonstrate that developmental exposure to the persistent environmental toxicants polybrominated diphenyl ethers (PBDEs) is associated with increased diabetes prevalence and persistent diabetic phenotype in adulthood. However, mechanisms governing early life PDBE exposure and the diabetogenic phenotype remain unknown. Current literature supports the mechanistic link between gut microbiome and metabolic syndrome inhumans and animal models. We showedthat oral exposure toPBDEs in adult mice results in dysbiosis with profound changes inbacteria known tobe associated with inflammation and obesity,as well as reduced tryptophan microbial metabolites including indoles, which arenovel activators of the host pregane X receptor (PXR) which is known to contribute to obesity and diabetes. Building on our findings that there is a gene-environment interaction between PXR and PBDEs through gut microbiome and indole metabolites, we seek to establish a causal relationship between developmental PBDE exposure, a change inthe gut microbiome,and diabetes later in lifeusinghumanizedPXR transgenic (hPXR-TG) mice in conventional (CV) and germ-free (GF) background. We hypothesize that developmental PBDE exposure causes acute and persistent dysbiosis, which contributes to diabetes through suppression of microbial tryptophan metabolism and selective PXR modulation (sPXRm) in early life and beyond. To test our hypothesis, in Aim 1 we will determine if developmental PBDE exposure perturbs the gut microbiome and microbial metabolism of tryptophan, leading to sPXRm in early life and beyond.
In Aim 2 we will determine whether microbial metabolites, mainly including indoles and indole-derivatives, can reduce inflammationand rescue the diabetic phenotype following developmental PBDE exposure.
In Aim 3 we will determine that reprogramming thegut microbiome using fecaltransplant mechanistically contributes todevelopmentalPBDE exposure mediated disruption of PXR signaling and delayed onset of diabetes. The expected outcome of the proposed research is a new research paradigm demonstrating that dysbiosis of the gut microbiome mechanistically contributesto early lifePBDEexposure-induceddiabetes and metabolic syndrome later in life, and more importantly, enables a toxico-metagenomics approach targeting metabolic disorders resulted from exposuretoPBDEsandpotentiallyotherpersistentorganicpollutants.
S Diabetes is a complex disease is caused by an interaction among genetic, behavioral, and environmental factors. The persistent environmental chemicals polybrominated diphenyl ethers (PBDEs) are linked to diabetes in humans and animal models. The proposed study will use humanized mouse models to mechanistically investigate how early life PBDE exposure mediated dysbiosis modulates host receptor signaling and contributes to delayed onset of diabetes phenotype in adulthood, paving the path for identifying novel ?druggable? targets within the gut microbiome to reduce PBDE-induced persistent adverse health effects in humans.