Impact of developmental exposure to PFAS on the microbiota-gut-brain axis

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ABSTRACT Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, and neurogenesis all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection, or environmental chemicals during neonatal life could detrimentally impact the developing microbiota, gut, and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including inflammatory bowel disease (IBD), autism spectrum disorder, major depressive disorder, and obesity. Environmental exposures to chemicals can result in accumulation over time and can impair health in affected individuals. Early neonatal life is a particularly sensitive period for exposures, potentially impairing rapid growth and development associated with this period. Per- and polyfluoroalkyl substances (PFAS) are a group of man-made chemicals manufactured and used in a variety of industries worldwide since the 1940s. They are very persistent in the environment and in the human body, leading to accumulation over time. Increasing evidence suggests that exposure to PFAS, particularly perfluorooctanoic acid (PFOA), can lead to adverse human health effects, specifically development of IBD, in the elderly. In this proposal, we hypothesize that neonatal PFOA exposure will have a long-lasting impact on the MGB axis, including GI pathophysiology, and altered behavior, leading to increased severity of colitis in late adulthood. This hypothesis will be tested by the following Specific Aims: SA1. Determine whether neonatal oral PFOA exposure leads to long-term MGB axis deficits and SA2. Determine whether neonatal oral PFOA exposure increases severity of IBD in adulthood. Taken together, these proposed studies will demonstrate whether neonatal dysbiosis following exposure to PFOA disrupts the developing MGB axis, impacting the microbiota composition, impairing GI physiology, and causing behavioral deficits in adulthood. Furthermore, we will determine whether neonatal PFOA exposure increases the susceptibility to development of colitis. Finally, our results may identify PFOA as a novel environmental risk factor for gut-brain deficits in IBD.