PROJECT SUMMARY Obesity and type-II diabetes are a pandemic, causing grave social and economic burdens in the United States. Epidemiological and animal studies showed that the flame retardants polybrominated diphenyl ethers (PBDEs) and a most widely used current PBDE-alternative – tetrabromobisphenol A (TBBPA) are linked to obesity and diabetes. However, mechanisms governing early life exposure to flame retardants and obesity/diabetes remains unknown; no studies have compared the effect of PBDEs vs. TBBPA, and little is known regarding how early life flame retardant plus additional risk factors (e.g. dietary factors) later in life modulate obesity. The liver- and intestine-enriched pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are novel regulators for obesity. Intestinal inflammation, as triggered by dysbiosis of the gut microbiota, is an early mediator of obesity and type-II diabetes. In the previous grant cycle, we have demonstrated that: 1) early life exposure to the PBDEs and TBBPA produces a pro-inflammatory/pro-obese microbial signature later in life; 2) PXR and CAR are necessary in maintaining the basal healthy gut flora to prevent the blooming of pro-inflammatory microbes; 3) the presence of gut microbiome promotes immunotolerance in the liver, whereas early life exposure to PBDEs produced gut dysbiosis associated with enhanced immune cell hepatic mobilization, reduced PXR/CAR signaling, and predicted liver injuries in adulthood; Early life exposure to an industrial PBDE mixture persistently disrupted the microbial tryptophan metabolism. We also showed that the microbial tryptophan metabolite indole-3- propionic acid (IPA) mimicry FKK6 compound protected against intestinal inflammation associated with increased anti-inflammatory short-chain fatty acids (SCFAs) and the SCFA-producing microbes. Building on our findings, the objective of the renewal is to determine how the host nuclear receptors, gut microbiome, and early life flame retardant exposure interact to modulate the adult onset of obesity and type-II diabetes. Our central hypothesis is: early life flame retardant exposures upset the physiological functions of PXR/CAR, leading to pro- inflammation and pro-obesity microbial metabolites and elevated AhR signaling, which augmented obesity following a 2nd hit (e.g. a high fat diet [HFD]) later in life; whereas the microbial mimicry is a novel remediation strategy. We will test this hypothesis in 3 Aims: Aim 1 will determine to what extent PXR and CAR modulate the inflammation- and obesity-related host and microbial signatures following early life exposure to PBDEs and TBBPA. Aim 2 will determine how early life flame retardant exposure and PXR/CAR interact to modulate the high fat diet-induced obesity later in life. Aim 3 will determine how gut microbiome mechanistically contributes to the divergent roles of PXR and CAR in obesity following the “two-hit” exposure paradigm. The overall impact of this research is tha...