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 激素和细菌属：嗜胃肠杆菌与孕酮水平和 链杆菌与雄烯二酮呈正相关。这一初步数据表明，一个人的 自己的肠道微生物区系可能通过直接影响可获得性而促进BC的发展 类固醇激素。然而，重要的是，大多数细菌分类群及其基因对 类固醇激素在肠道中的代谢仍不清楚。我们假设胃肠道微生物群是 BC不同；还有胃肠道细菌及其基因/蛋白尚未鉴定 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.特征 BC患者和对照组的粪便细菌分类群和类固醇激素水平 测序和第二个样本组。目的2.鉴定细菌分类群及其候选基因 代谢类固醇激素的物质。和2a。确定整个细菌群落的能力 BC患者和正常对照粪便中类固醇激素的代谢。高增长水平的样本 即高类固醇代谢将进一步用16S rDNA测序，枪炮元基因组学和 后转录组学用于鉴定类固醇增强的细菌群落及其代谢基因 荷尔蒙暴露。了解哪些细菌分类群可能在类固醇激素的代谢中发挥作用 在胃肠道中，并鉴定参与类固醇代谢的细菌分类群和基因可以 有可能被用来设计针对这些微生物的个性化微生物组疗法。

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: Peptoniphilus was negatively correlated with progesterone levels and Catenibacterium positively correlated with androstenedione. 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. And 2a. Determine the ability of whole bacterial communities from feces of BC patients and controls in metabolizing steroid hormones. Samples with high levels of growth i.e. high-steroid-metabolism will be further 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.