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

摘要 宿主-微生物的相互作用对维持人类宿主的正常生理至关重要，包括 大脑和行为。胃肠道细菌定植、胃肠道粘膜屏障的形成 功能和神经发生都发生在生命早期的关键发育窗口期。因此，接触到 新生儿生命中的创伤，如压力、感染或环境化学物质，可能有害地影响 发展微生物区系、肠道和脑(MGB)轴。破坏MGB轴信号，包括生物失调，粘膜 屏障缺陷和/或行为改变，发生在多种疾病中，包括炎症性肠病 (IBD)、自闭症谱系障碍、严重抑郁障碍和肥胖。 在环境中暴露于化学品会导致随着时间的推移而积累，并可能损害健康 受影响的个体。新生儿早期生活是暴露的一个特别敏感的时期，潜在地损害 与这一时期相关的快速增长和发展。全氟和多氟烷基物质(PFA)是一种 自20世纪80年代以来在世界各地的各种工业中制造和使用的人造化学品集团 20世纪40年代。它们在环境和人体内非常持久，导致随着时间的推移而积累。 越来越多的证据表明，暴露于全氟辛酸，特别是全氟辛酸，可导致 对人类健康的不利影响，特别是对老年人的IBD的发展。 在这项提案中，我们假设新生儿接触全氟辛烷磺酸将对MGB产生长期影响 AXIS，包括胃肠道病理生理学，和行为改变，导致晚期结肠炎严重程度增加 成人期。这一假设将通过以下具体目标进行检验：SA1。确定新生儿是否 口服全氟辛酸暴露会导致长期的MGB轴缺陷和SA2。确定新生儿是否口服 全氟辛酸暴露会增加成人IBD的严重程度。 综上所述，这些拟议的研究将证明暴露于 全氟辛酸破坏发育中的MGB轴，影响微生物区系组成，损害胃肠道生理，以及 导致成年后的行为缺陷。此外，我们将确定新生儿接触全氟辛烷磺酸是否 增加患结肠炎的易感性。最后，我们的结果可能会将全氟辛酸确定为一种新的 IBD肠脑缺陷的环境危险因素。

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.