Environmental Ah Receptor Ligand Impact on the Host-Microbiome Metabolic Axis

项目摘要/摘要 科学界越来越认识到芳烃受体(AHR)的重要作用。 在调节宿主-微生物组的代谢轴方面发挥作用。有趣的是，内脏和内脏 微生物区系与非酒精性脂肪性肝病(NAFLD)的发展和/或恶化，所有这些 通过激活或抑制AHR来调节。然而，目前AHR之间的直接联系 激活，肠道微生物区系组成的变化，神经酰胺的合成和NAFLD的发展 已经成立了。此外，环境污染物介导的破坏和/或调节环境污染的概念 AHR-肠道微生物区系代谢轴导致NAFLD的发展尚未得到解决。我们的 已发表的2，3，7，8-四氯二苯并呋喃(TCDF)的初步数据表明AHR激活 从质和量上深刻改变肠道微生物区系，增加肝脏脂肪生成， 并通过直接AHR活性显著改变肝脏神经酰胺的合成(被认为是NAFLD的驱动因素)。 这些结果使我们得出了新的中心假设：从饮食中暴露于强有力的环境AHR 配体导致肠道微生物区系功能上的显著变化，从而加剧了NAFLD。 依赖于时间和AHR的方式。 通过创新使用尖端技术(元基因组学和代谢组学)和独特的小鼠 模型(AhR的组织特异性敲除、灵知生菌小鼠和粪便转移实验)，我们计划识别 饮食暴露于有效的AHR配体后对肠道微生物区系的功能变化 TCDF，并评价神经酰胺在NAFLD发生和发展中的AhR依赖作用。 这种方法的结合将使我们能够准确地评估细菌门的动态及其相互作用。 对宿主的影响，以及这些变化是否导致对NAFLD的易感性增加。我们是 尤其感兴趣的是暴露的时机(断奶和成年期)如何影响疾病结果。 这项研究将提供宝贵的洞察力，了解暴露对许多与环境相关的 持久性AHR配体，如2，3，7，8-四氯二苯并-对二恶英(TCDD)和共面多氯联苯，并提供 为未来人类种群研究提供有价值的终点。

PROJECT SUMMARY/ABSTRACT The scientific community is increasingly appreciative of the important role the aryl hydrocarbon receptor (AHR) plays in modulating the host-microbiome metabolic axis. Interestingly, there are strong links between the gut microbiota and the development and/or exacerbation of nonalcoholic fatty liver disease (NAFLD), all of which are modulated by activation or repression of the AHR. At present, however, a direct connection between AHR activation, changes in gut microbiota composition, ceramide synthesis, and NAFLD development has not been established. Further the concept that environmental pollutant-mediated disruption and/or modulation of the AHR-gut microbiota metabolic axis leads to the development of NAFLD has not been addressed. Our published and preliminary data with 2,3,7,8-tetrachlorodibenzofuran (TCDF) indicates AHR activation profoundly alters the gut microbiota in a qualitative and quantitative manner, increases hepatic lipogenesis, and significantly alters hepatic ceramide synthesis through direct AHR activity (a proposed driver of NAFLD). These results have led us to the novel central hypothesis: Dietary exposure to potent environmental AHR ligands leads to functionally significant changes in the gut microbiota that exacerbate NAFLD in a time- and Ahr-dependent manner. Through the innovative use of cutting-edge techniques (metagenomics and metabolomics) and unique mouse models (tissue specific knockouts of Ahr, gnotobiotic mice, and fecal transfer experiments), we plan to identify the functional changes imparted to the gut microbiota following dietary exposure to potent AHR ligands such as TCDF and to evaluate the Ahr-dependent role of ceramides in driving NAFLD pathogenesis and progression. This combination of approaches will allow us to accurately assess bacterial phyla dynamics and its interaction with and impact on the host, and whether these changes result in increased susceptibility to NAFLD. We are particularly interested in how the timing (weaning and adulthood) of the exposure influences disease outcome. This study will provide invaluable insight into the effects of exposure on a number of environmentally relevant persistent AHR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and co-planar PCBs and provide valuable endpoints for future studies in human populations.