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

异种雌激素和肠道微生物衍生的雌激素化合物在结肠炎症中的新作用

• 批准号: 10662075
• 负责人: Clinton D Allred
• 金额: $ 37.5万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662075
• 关键词: Acids; Acute; Amino Acids; Apoptosis; Area; Aryl Hydrocarbon Receptor; Attenuated; Cell Cycle Progression; Cell Proliferation; Cells; Chemicals; Chronic; Classification; Clinical; Colonic Neoplasms; Colonic inflammation; Computing Methodologies; Cytokine Gene; Data; Disease; Environmental Pollution; Enzymes; Epidemiology; Epithelial; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exposure to; Gene Expression; Goals; Health; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Intervention; Intestinal Neoplasms; Intestines; Knockout Mice; Life; Ligands; Mediating; Medical; Metabolic; Metabolic Biotransformation; Metabolism; Modeling; Modification; Monitor; Mucous Membrane; Mus; Phenotype; Physiological; Play; Production; Receptor Gene; Receptor Signaling; Research Personnel; Role; Route; Shapes; Signal Transduction; Symptoms; Testing; Tight Junctions; Tissues; Ulcerative Colitis; Work; aryl hydrocarbon receptor ligand; base; bisphenol A; chemical synthesis; colon growth; cytokine; environmental chemical; estrogenic; experimental study; gastrointestinal; gut inflammation; gut microbiota; host microbiota; in vitro Model; in vivo; intestinal epithelium; liver metabolism; metabolomics; microbial; microbiome; microbiome analysis; microbiota; microbiota metabolites; novel; promoter; receptor expression; response; tool; tumor progression; xenoestrogen

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.

抽象的 拟议工作的总体目标是研究异雌激素（XE）对肠道健康的影响。 XE，包括双酚 A (BPA)，是环境污染物的一个重要分类，具有 潜在影响胃肠道健康的雌激素化合物对结肠的影响。 炎症很复杂，但临床和实验数据表明 XE 会恶化症状并 溃疡性结肠炎 (UC) 的标志物，这是一种非常普遍的疾病状态，需要医疗干预 此外，数据表明雌激素化合物可以作为一部分的促进剂。 某些雌激素化合物（即 BPA）对炎症相关的结肠肿瘤的影响。 人们已经开始探索肠道上皮，微生物群在多大程度上影响其作用 炎症仍然是一个悬而未决的问题。确定微生物群的作用并发现新的机制。 微生物群衍生的雌激素受体（ER）配体将为肠道的积极作用提供新证据 微生物群通过 ER β (ERβ) 介导 XE 的作用。 肠道微生物群在通过从头调节 XE 对肠道健康的影响中发挥着关键作用 使用野生型和 ERβ 肠道特异性敲除小鼠生产和/或修饰 ER 配体。 结合体外培养和最先进的代谢组学工具，研究人员将检查 XE 对肠道健康的微生物群依赖性和独立性影响具体目标是： (i) 研究。 XE 暴露后微生物群在生成 ER 配体中的作用 (ii) 确定 ER 介导的作用； XE 和微生物群衍生代谢物 (MDM) 对结肠上皮功能的影响；以及 (iii) 研究 XE 和微生物源性雌激素对加剧肠道炎症的影响 以及随后结肠肿瘤通过 ER 的进展。