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代谢活性，与宿主的肝脏相当。它在 食品和药物中化学物质的生物利用度以及化学物质的生理影响，尤其是。那些经历的 肠肝循环（从肝脏排泄到胆汁，然后从 肠）。一组在胃肠道中广泛代谢和/或经历的化学物质 肠肝循环是类固醇激素（例如雌激素，孕激素，雄激素）。总体 该翻译R21提案的目标是确定细菌分类单元及其候选基因 有助于胃肠道内类固醇激素的代谢。因此，该提议奠定了 基于微生物组的精确药物疗法的基础，可以靶向类固醇 胃肠道中的激素代谢。类固醇激素与A相关的一个具体示例 疾病是乳腺癌（BC）：暴露于高水平的雌激素是卑诗省众所周知的危险因素。 尽管已经提出了许多假设，即胃肠道菌群主要在卑诗省发挥作用 在雌激素的肠肝循环中，不知道卑诗省细菌分类群的改变。我们进行了 首次研究乳腺癌患者肠道粘膜中细菌分类群的研究，我们的数据支持我们 细菌分类群在乳腺癌中的作用的模型。我们还确定了类固醇之间的两个新型关联 激素和细菌属。此初步数据表明，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。 但是，重要的是，大多数细菌分类群及其基因负责类固醇激素 肠道中的代谢仍然未知。我们假设在BC中，GI道微生物组不同。和 有胃肠道细菌及其基因/蛋白质尚未鉴定出直接代谢 类固醇激素。因此，我们提出以下特定目的：目标1。表征粪便细菌类群 卑诗省患者的类固醇激素水平以及具有元基因组测序的对照以及 第二个样本集。目标2。确定代谢类固醇的细菌类群及其候选基因 激素。我们将在患者和对照样品中进行核类测序。我们还将确定 来自卑诗省患者和对照组的粪便以及两个特定细菌分类单元的整个细菌群落的能力 在代谢类固醇激素中。样品将通过16S rDNA测序进行检查 宏基因组学和元转录组学鉴定细菌群落及其代谢基因 通过类固醇激素暴露增强。了解哪种细菌类群可能在 类固醇激素在胃肠道中的代谢以及涉及细菌类群和基因的鉴定 在类固醇中，代谢可能有可能用于设计针对的基于微生物组的个性化疗法 这些生物。