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.

抽象的 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，尤其是。那些经历过 肠肝循环（从肝脏排泄到胆汁中，然后从胆汁中重吸收） 肠）。一组在胃肠道中广泛代谢和/或经历的化学物质 肠肝循环中有类固醇激素（如雌激素、孕激素、雄激素）。整体 该翻译 R21 提案的目标是识别细菌分类群及其候选基因 有助于胃肠道内类固醇激素的代谢。因此，本提案规定 为针对类固醇的基于微生物组的个性化精准医学疗法奠定了基础 胃肠道中的激素代谢。类固醇激素与以下物质有关的一个具体例子 疾病是乳腺癌 (BC)：众所周知，接触高水平的雌激素是乳腺癌的危险因素。 尽管已经提出了许多假设，认为胃肠道微生物群主要在 BC 中发挥作用 关于雌激素的肠肝循环，BC 细菌分类群的改变尚不清楚。我们承担了 第一项研究乳腺癌患者肠道粘膜中的细菌分类群，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模型。我们还发现了类固醇之间的两种新关联 激素和细菌属。这一初步数据表明，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来促进 BC 的发展。 然而重要的是，大多数细菌类群及其负责类固醇激素的基因 肠道内的代谢尚不清楚。我们假设 BC 地区的胃肠道微生物组有所不同；和 存在胃肠道细菌及其尚未确定的直接代谢的基因/蛋白质 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 通过宏基因组测序以及 BC 患者和对照的类固醇激素水平 第二个样本集。目标 2. 鉴定细菌类群及其代谢类固醇的候选基因 荷尔蒙。我们将对患者和对照样本进行宏基因组测序。我们还将确定 BC 患者和对照粪便中的整个细菌群落以及两个特定细菌类群的能力 在类固醇激素的代谢中。样本将通过 16S rDNA 测序、鸟枪法进行检查 宏基因组学和宏转录组学，用于识别细菌群落及其代谢基因 类固醇激素暴露增强。了解哪些细菌类群可能在 胃肠道中类固醇激素的代谢以及相关细菌分类群和基因的鉴定 类固醇代谢中的研究有可能用于设计基于微生物组的个体化疗法 这些生物体。