Novel effects of xenoestrogens and gut microbiota derived estrogenic compounds in colonic inflammation

摘要 拟议工作的总体目标是研究异种雌激素（XEs）对肠道健康的影响。 Xe，包括双酚A（BPA），是具有生物活性的环境污染物的重要分类。 可能影响胃肠道健康。雌激素类化合物对结肠功能的影响 炎症是复杂的，但临床和实验数据表明，XEs加剧症状， 溃疡性结肠炎（UC）的标志物，这是一种高度流行的疾病状态，需要医疗干预 在生活中。此外，数据表明，雌激素化合物可以作为一个子集的促进剂， 炎症相关的结肠肿瘤。虽然一些雌激素化合物（即BPA）对 已经开始探索肠上皮，微生物群在多大程度上影响它们的作用， 炎症仍然是一个未解决的问题。确定微生物群的作用并发现新的 微生物群来源的雌激素受体（ER）配体将为肠道激素受体的积极作用提供新的证据。 在通过ER β（ERβ）介导XE的作用中，微生物群起着重要作用。核心假设是， 肠道微生物群在介导XE对肠道健康的影响中起着关键作用， ER配体的产生和/或修饰。使用野生型和ERβ肠特异性敲除小鼠， 结合体外培养和最先进的代谢组学工具，研究人员将检查 XEs对肠道健康的微生物群依赖性和独立性影响。具体目标是：（一）调查 微生物群在XE暴露后产生ER配体中的作用;（ii）确定ER介导的 XE和微生物衍生的代谢物（MDM）对结肠上皮功能的影响;和（iii） 研究XEs和微生物源性雌激素在加重肠道炎症中的作用 以及随后通过ER的结肠肿瘤进展。

ABSTRACT The overall goal of the proposed work is to investigate the effects of xenoestrogens (XEs) on intestinal health. XEs, including bisphenol A (BPA), are an important classification of environmental contaminants that have the potential to influence gastrointestinal health. The role of estrogenic compounds on influencing colonic inflammation is complicated, but clinical and experimental data suggest that XEs exacerbate symptoms and markers of ulcerative colitis (UC), which is a highly prevalent disease state that requires medical intervention throughout life. Furthermore, data suggests that estrogenic compounds may serve as promoters of a subset of inflammation-associated colon tumors. While the effects of some estrogenic compounds (i.e. BPA) on the intestinal epithelium have begun to be explored, the extent to which microbiota influence their effects during inflammation remains an unresolved question. Identifying the role for the microbiota and discovering novel microbiota-derived estrogen receptor (ER) ligands would provide new evidence for an active role of the intestinal microbiota in mediating the effects of XEs through the ER beta (ERβ). The central hypothesis is that the intestinal microbiota plays a critical role in mediating the effects of XEs on intestinal health through de novo production and/or modification of ER ligands. Using wild type and ERβ intestinal specific knockout mice in conjunction with in vitro cultures and state-of-the-art metabolomics tools, the investigators will examine the microbiota-dependent and independent effects of XEs on intestinal health. The Specific Aims are: (i) Investigate the microbiota’s role in generating ER ligands following XE exposure; (ii) Determine the ER-mediated effects of XEs and microbiota-derived metabolites (MDMs) on colonic epithelial function; and (iii) Investigate the effect of XEs and microbiota-derived estrogens in exacerbating intestinal inflammation and subsequent colon tumor progression through the ER.