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

发育阶段接触 PFAS 对微生物群-肠-脑轴的影响

• 批准号: 10740775
• 负责人: Melanie G Gareau
• 金额: $ 42.37万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-22 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740775
• 关键词: 16S ribosomal RNA sequencing; Acute; Adult; Affect; American; Behavior; Behavioral; Brain; Cell Differentiation process; Cell Maturation; Chemicals; Chronic; Cognitive deficits; Colitis; Colon; Colonic inflammation; Communication; Communication impairment; Crohn' s disease; Defect; Development; Disease; Disease model; Disease remission; Disease susceptibility; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Epithelial Cells; Etiology; Exposure to; Flow Cytometry; Functional disorder; Gastrointestinal Physiology; Goals; Growth and Development function; Health; Histology; Human; Human body; Immune response; Impaired health; Impairment; Individual; Industry; Infection; Inflammatory; Inflammatory Bowel Diseases; Ion Transport; Knockout Mice; Knowledge; Life; Major Depressive Disorder; Mass Spectrum Analysis; Metagenomics; Mucous Membrane; Mus; Neonatal; Obesity; Onset of illness; Oral; Organoids; Patients; Permeability; Physiology; Play; Poly-fluoroalkyl substances; Predisposition; Prevalence; Property; Relapse; Risk; Role; Sampling; Serum; Severities; Severity of illness; Shotguns; Signal Transduction; Stress; Testing; Time; Toxic Environmental Substances; Ulcerative Colitis; anxiety-like behavior; autism spectrum disorder; bacterial community; behavior test; bioaccumulation; contaminated drinking water; disorder risk; dysbiosis; environmental chemical; fecal transplantation; gastrointestinal; genetic risk factor; gut colonization; gut dysbiosis; gut microbiota; host-microbe interactions; ileum; intestinal epithelium; manufacture; men' s group; microbiome; microbiota; microbiota-gut-brain axis; mouse model; neonatal exposure; neurodevelopment; neurogenesis; novel; perfluorooctanoic acid; proctolin; rapid growth; surfactant; trauma exposure

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.

抽象的 宿主与微生物的相互作用对于维持人类宿主的正常生理机能至关重要，包括 大脑和行为。胃肠道（GI）的细菌定植，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，暴露于 新生儿生活期间的压力、感染或环境化学物质等创伤可能会对新生儿产生不利影响。 微生物群、肠道和大脑 (MGB) 轴的发育。 MGB 轴信号传导中断，包括生态失调、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、重度抑郁症和肥胖。 环境中化学品的暴露会随着时间的推移而积累，并可能损害健康 受影响的个人。新生儿早期是接触特别敏感的时期，可能会损害 与这一时期相关的快速成长和发展。全氟烷基物质和多氟烷基物质 (PFAS) 是 自诞生以来在全球各行各业制造和使用的一系列人造化学品 20 世纪 40 年代。它们在环境和人体中非常持久，会随着时间的推移而积累。 越来越多的证据表明，接触 PFAS，特别是全氟辛酸 (PFOA)，可能会导致 对人类健康产生不利影响，特别是对老年人的炎症性肠病（IBD）的发展。 在本提案中，我们假设新生儿 PFOA 暴露将对 MGB 产生长期影响 轴，包括胃肠道病理生理学和行为改变，导致晚期结肠炎的严重程度增加 成年期。该假设将通过以下具体目标进行检验：SA1。判断是否是新生儿 口服 PFOA 暴露会导致长期 MGB 轴缺陷和 SA2。判断新生儿是否经口 PFOA 暴露会增加成年 IBD 的严重程度。 总而言之，这些拟议的研究将证明新生儿暴露后是否会出现菌群失调 PFOA 会破坏正在发育的 MGB 轴，影响微生物群组成，损害胃肠道生理机能，并 导致成年后的行为缺陷。此外，我们将确定新生儿是否接触 PFOA 增加患结肠炎的易感性。最后，我们的结果可能会将 PFOA 视为一种新颖的 IBD 肠脑缺陷的环境危险因素。