NF-kB Mediated Inflammatory Changes inthe Gut and Microbiome by PCB 153

项目总结/摘要 多氯联苯（PCBs）是一种普遍存在的持久性有机污染物，对人类健康具有严重的危害 健康虽然多氯联苯的工业生产已经停止，但它们仍然是一个紧迫的环境问题。 这是由于它们的生物降解缓慢和高亲脂性造成的问题。这些特性使多氯联苯能够在生物体内积累 在食物链中，导致对人类消费很重要的有机体中的组织水平较高。一旦进入体内， 多氯联苯在各种器官中积累，导致炎症和转录因子NF-κ B的激活。 NF-B是炎症的驱动因子，并与多种疾病有关，如炎症性肠病 疾病、癌症和糖尿病。尽管饮食接触是接触多氯联苯的主要途径， 在研究多氯联苯的促炎作用时，胃肠道被广泛忽视。这是一 考虑到肠上皮细胞（IEC）同时暴露于 炎症影响肠道微生物群，这也受到多氯联苯的影响。的功能性后果 多氯联苯对微生物组的影响也有待研究。这是一个重要的信息，因为广泛的 微生物的影响。拟议的研究将调查多氯联苯、独立选举委员会和 微生物群，特别关注的机制，多氯联苯153（最普遍的多氯联苯在 环境）发挥其作用。暴露于PCB 153已被证明会导致肠道 随着总肠道炎症和微生物组变化的迹象，渗透性沿着降低。我假设 PCB 153通过基因毒性激活导致肠道炎症并增加肠道通透性， NF-κ B和促炎肠道微生物组的产生。为了探究这一点，具体目标1将着眼于 PCB 153在体外和体内对IEC的特异性影响。肠细胞系沿着与gnotobiotic 小鼠，完全缺乏微生物组的小鼠，将用于确定NF-B激活的程度和机制 在没有微生物组的情况下，PCB 153。拟议机制的特异性将通过使用 NF-κ B B的化学抑制剂。具体目标2将确定多氯联苯153对生物体的影响对生物体的功能影响。 微生物组将暴露于PCB的微生物组移植到gnotobiotic小鼠中，然后用 一种促炎剂他们的炎症水平将与移植了 未接触过PCB的微生物组揭示了暴露于PCB的微生物组对 主持人这些研究将确定NF-B在炎症和通透性变化中的重要性 我的PCB 153重要的是，他们将能够得出明确的结论， 微生物群和IEC。这些知识将为人类描绘新的研究路线和潜在的治疗方法 以及其他暴露于有机污染物的生物。

Project Summary/Abstract Polychlorinated biphenyls (PCBs) are ubiquitous and persistent organic pollutants that adversely affect human health. Although industrial production of PCBs has been discontinued, they remain a pressing environmental problem due to their slow biodegradation and high lipophilicity. These properties enable PCBs to bio-accumulate in food chains leading to high tissue levels in organism important for human consumption. Once in the body, PCBs accumulates in various organs leading to inflammation and activation of the transcription factor NF-кB. NF-кB is a driver of inflammation and has been linked to a multitude of diseases such as inflammatory bowel disease, cancer and diabetes. Despite dietary exposure being the main route of exposure to PCBs, the human gastrointestinal tract has been widely ignored when studying the pro-inflammatory effects of PCBs. This is a significant oversight given that the intestinal epithelial cells (IECs) are simultaneously exposed to the inflammatory effects the gut microbiota, which are also affected by the PCBs. The functional consequences of PCBs effects on the microbiome have also yet to be studied. This is vital information given the widespread influence of the microbiome. The proposed studies will interrogate interaction between PCBs, IECs, and the microbiota with particular focus on the mechanism by which PCB153 (the most prevalent PCB in the environment) exerts its effects. Exposure to PCB153 has been shown to lead to an increased intestinal permeability along with signs of gross intestinal inflammation and changes in the microbiome. I hypothesize that PCB153 causes intestinal inflammation and increases gut permeability via genotoxic activation of NF-кB and the creation of a pro-inflammatory gut microbiome. To interrogate this, specific aim 1 will look at the effects of PCB153 specifically on the IECs, both in vitro and in vivo. Intestinal cell lines along with gnotobiotic mice, mice entirely lacking a microbiome, will be used to determine the extent and mechanism of NF-кB activation by PCB153 in the absence of the microbiome. Specificity to the proposed mechanism will be established using a chemical inhibitor of NF-кB. Specific aim 2 will determine the functional consequences of PCB153's effect on the microbiome. PCB-exposed microbiomes will be transplanted into gnotobiotic mice and then challenged with a pro-inflammatory agent. Their levels of inflammation will be compared with those of mice transplanted with PCB-naïve microbiomes shedding light on the pro-inflammatory effects of the PCB-exposed microbiome on the host. These studies will establish the importance of NF-кB in the inflammatory and permeability changes caused my PCB153 in the gut. Importantly, they will be able to draw clear conclusions about the distinct roles of the microbiota and IECs. This knowledge, will depict new routes of investigation and potential therapies for humans and other organisms exposed to organic pollutants.