Gut Microbiome and Steroid Hormones

摘要 胃肠道微生物群具有高度的代谢活性，可与宿主肝脏相媲美。它在世界上扮演着重要的角色 食品和药物中化学物质的生物利用度和生理效应，特别是。那些经历了 肠-肝循环(从肝脏排泄到胆汁中，并从肝脏重新吸收 肠道)。在胃肠道中广泛代谢和/或经历的一组化学物质 肠肝循环是类固醇激素(如雌激素、孕激素、雄激素)。整体而言 这一翻译R21提案的目标是识别细菌分类及其候选基因， 有助于胃肠道内类固醇激素的代谢。因此，这项建议为 针对类固醇的基于微生物组的个体化精准药物治疗的基础 胃肠道中的激素代谢。类固醇激素与一种 疾病是乳腺癌(BC)：暴露于高水平的雌激素是BC的众所周知的危险因素。 尽管已经提出了许多假设，即胃肠道微生物区系在BC中起作用的主要是 在雌激素的肠-肝循环中，不列颠哥伦比亚省的细菌分类群的变化尚不清楚。我们承诺 第一项关于乳腺癌患者肠道粘膜细菌分类的研究和我们的数据支持我们的 细菌分类群在乳腺癌中的作用模型。我们还发现了类固醇与两种新的 荷尔蒙和细菌属。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获得性，促进BC的发展。 然而，重要的是，大多数与类固醇激素有关的细菌分类群及其基因 肠道内的新陈代谢尚不清楚。我们假设不列颠哥伦比亚省的胃肠道微生物群不同； 有胃肠道细菌及其基因/蛋白尚未被鉴定为直接代谢 类固醇激素。因此，我们提出了以下具体目标：目标1.粪便细菌分类群的特征 和类固醇激素水平在BC患者和对照组中的变化 第二个样本集。目的2.鉴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 慢性结肠炎患者和对照组粪便细菌群落的能力及两个特异性细菌类群 在代谢类固醇激素方面。样本将用16S rDNA测序，猎枪 元基因组学和元转录组学，以确定细菌群落及其代谢基因 随着类固醇激素的暴露而增强。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及其相关细菌类群和基因的鉴定 在类固醇代谢方面，可以潜在地用于设计针对以下目标的个性化微生物组疗法 这些有机体。

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.