Gut Microbiome and Steroid Hormones

肠道微生物组和类固醇激素

• 批准号: 10054472
• 负责人: Serdar E. Bulun
• 金额: $ 20.45万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054472
• 关键词: Adrenal Glands; Affect; Anaerobic Bacteria; Androgens; Androstenedione; Antibiotics; Back; Bacteria; Bile fluid; Biological Availability; Blood specimen; Breast Cancer Patient; Breast Cancer Risk Factor; Cancer Control; Candidate Disease Gene; Chemicals; Clinical; Cloning; Data; Databases; Deposition; Development; Dietary intake; Disease; Effectiveness; Enterohepatic Circulation; Estradiol; Estrogens; Excretory function; Exposure to; Feces; Food; Gastrointestinal tract structure; Gene Proteins; Genes; Goals; Growth; Gut Mucosa; Health; Hormones; Human; Incubated; Individual; Intake; Intestines; Knowledge; Liver; Malignant Neoplasms; Measures; Metabolic; Metagenomics; Modeling; Newly Diagnosed; Oral; Oral Contraceptives; Organism; Patients; Persons; Pharmaceutical Preparations; Physiological; Play; Postmenopause; Progesterone; Progestins; Proteins; Recombinant DNA; Reporting; Role; Sampling; Series; Sewage; Shotguns; Steroids; Testosterone; Time; Validation; Variant; Woman; bacterial community; base; chemical group; cohort; design; endometriosis; experimental study; follow-up; gut bacteria; gut microbiome; gut microbiota; malignant breast neoplasm; metagenome; metagenomic sequencing; metatranscriptome; metatranscriptomics; microbiome; microbiota; novel; precision medicine; sex; steroid hormone; steroid hormone metabolism; steroid metabolism

ABSTRACT GI tract microbiome is highly metabolically active, comparable to the host's liver. It has a significant role in the bioavailability and the physiological effects of chemicals within foods and medications, esp. those that undergo enterohepatic circulation (with excretion from the liver into the bile and the reabsorption back from the intestines). One group of chemicals that are extensively metabolized in the GI tract and/or undergo enterohepatic circulation are steroid hormones (such as estrogens, progestogens, androgens). The overall goal of this translational R21 proposal is to identify bacterial taxa and their candidate genes that contribute to the metabolism of steroid hormones within the GI tract. Thereby, this proposal lays the groundwork for individualized microbiome-based precision medicine therapies that can target steroid hormone metabolism in the GI tract. One specific example in which steroid hormones are related to a disease is breast cancer (BC): Exposure to high levels of estrogens is a well-known risk factor for BC. Although many hypotheses have been put forth that the GI tract microbiota play a role in BC primarily in terms of the enterohepatic circulation of estrogens, alterations in bacterial taxa in BC are not known. We undertook the first study to look at bacterial taxa in the gut mucosa of breast cancer patients and our data support our model for a role for bacterial taxa in breast cancer. We also identified two novel associations between steroid hormones and bacterial genera. This preliminary data suggests that a person's own gut microbiota may contribute to the development of BC by directly affecting the availability of steroid hormones. Importantly however, the majority of the bacterial taxa and their genes responsible for steroid hormone metabolism in the gut are still unknown. We hypothesize that the GI tract microbiome is different in BC; and that there are GI tract bacteria and their genes/proteins that are yet to be identified that directly metabolize steroid hormones. Hence, we propose the following Specific Aims: Aim 1. Characterize fecal bacterial taxa and steroid hormone levels in BC patients and controls with metagenomic sequencing and also with a second sample set. Aim 2. Identify bacterial taxa and their candidate genes that metabolize steroid hormones. We will perform metagenomics sequencing in patient and control samples. We will also determine the ability of whole bacterial communities from feces of BC patients and controls and two specific bacterial taxa in metabolizing steroid hormones. Sample will be examined with 16S rDNA sequencing, shot-gun metagenomics and metatranscriptomics to identify bacterial communities and their metabolic genes that are enhanced with steroid hormone exposure. Understanding which bacterial taxa may play a role in the metabolism of steroid hormones in the GI tract and identification of bacterial taxa and genes that are involved in steroid metabolism can potentially be used to design individualized microbiome-based therapies directed at these organisms.

摘要 胃肠道微生物组具有高度代谢活性，与宿主的肝脏相当。它在以下方面发挥着重要作用： 食品和药物中化学物质的生物利用度和生理效应，特别是那些经过 肠肝循环（从肝脏排泄到胆汁中，从肝脏再吸收回来） 肠）。一组在胃肠道中广泛代谢和/或经历 肠肝循环中的激素是类固醇激素（如雌激素、孕激素、雄激素）。整体 这个翻译R21建议的目标是鉴定细菌分类群及其候选基因， 有助于类固醇激素在胃肠道内的代谢。因此，这项建议奠定了 为基于微生物组的个体化精准医学疗法奠定基础， 胃肠道的激素代谢。一个具体的例子，其中类固醇激素与一个 乳腺癌（BC）：暴露于高水平的雌激素是BC的一个众所周知的风险因素。 尽管已经提出了许多假设，即胃肠道微生物群主要在以下方面在BC中起作用： 在雌激素的肝肠循环中，BC中细菌分类群的改变尚不清楚。我们进行 这是第一项研究乳腺癌患者肠道粘膜中的细菌分类群的研究，我们的数据支持我们的观点。 细菌分类群在乳腺癌中的作用的模型。我们还发现了两个新的关联类固醇 激素和细菌属。这些初步数据表明，一个人自己的肠道微生物群可能 通过直接影响类固醇激素的可用性而促进BC的发展。 然而，重要的是，大多数细菌分类群及其负责类固醇激素的基因 在肠道中的代谢仍然是未知的。我们假设BC中的胃肠道微生物组不同;并且 有胃肠道细菌和它们的基因/蛋白质尚未被确定， 类固醇激素因此，我们提出以下具体目标：目标1。表征粪便细菌分类群 和类固醇激素水平在BC患者和对照组中的宏基因组测序， 第二个样本集。目标二。确定代谢类固醇的细菌分类群及其候选基因 荷尔蒙我们将在患者和对照样本中进行宏基因组测序。我们还将确定 来自BC患者和对照的粪便的整个细菌群落和两个特定细菌分类群的能力 类固醇激素的代谢。样品将用16 S rDNA测序法进行检查，鸟枪法 宏基因组学和元转录组学，以确定细菌群落及其代谢基因， 类固醇激素的作用会增强了解哪些细菌分类群可能在 类固醇激素在胃肠道中的代谢以及相关细菌分类群和基因的鉴定 在类固醇代谢中的应用可能被用于设计个体化的基于微生物组的治疗， 这些有机体。