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

摘要 芳烃受体(AHR)调节宿主-微生物组的代谢轴。有很强的联系 肠道微生物区系与非酒精性脂肪性肝病的发生和/或加重之间的关系 (NAFLD)，所有这些都通过激活或抑制AHR来调节。机械连接 在AHR激活、肠道微生物区系组成/功能改变和NAFLD发展之间没有 已经建立了。此外，环境污染物介导的干扰和/或调节的概念 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 发表的4-7和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， 通过直接AHR活性显著改变肝脏神经酰胺的合成(NAFLD的一个拟议驱动因素)，以及 增加全身炎症。这些结果导致了新的中心假说：饮食暴露于 强有力的环境AHR配体导致肠道微生物区系功能上的重大变化， 以时间和时间依赖的方式加重非酒精性脂肪肝。 通过创新地使用尖端技术(16S rRNA基因测序、元基因组学和 代谢组学)和独特的小鼠模型(AhR、诺生菌小鼠和粪便的组织特异性敲除 转移实验)，我们计划确定以下给肠道微生物区系带来的功能变化 膳食暴露于TCDF等强有力的AHR配体，并评估神经酰胺对AHR的依赖作用 在推动非酒精性脂肪性肝病的发病和进展中起重要作用。这种方法的组合将使我们能够准确地 评估细菌群落动态及其与宿主的相互作用和影响，以及这些 这些变化导致对NAFLD的易感性增加。我们特别感兴趣的是时间(断奶， 成年期)的暴露会影响疾病的结局。这项研究将为我们提供新的视角来了解 暴露于一些与环境有关的持久性AHR配体，如2，3，7，8-四氯二苯并-2，3，7，8-四氯二苯并 P-二恶英(TCDD)和共面多氯联苯(PCB-126)，并为未来的人类研究提供有价值的终点 人口。

ABSTRACT The aryl hydrocarbon receptor (AHR) modulates the host-microbiome metabolic axis. 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. A mechanistic connection between AHR activation, changes in gut microbiota composition/function, 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 published4-7 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, significantly alters hepatic ceramide synthesis through direct AHR activity (a proposed driver of NAFLD), and increases systemic inflammation. These results have led 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 (16S rRNA gene sequencing, 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 community 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, adulthood) of the exposure influences disease outcome. This study will provide new 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 (PCB-126) and provide valuable endpoints for future studies in human populations.