Gut Microbiome and Steroid Hormones

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：嗜胨菌与孕酮水平呈负相关， 链杆菌与雄烯二酮呈正相关。初步数据表明， 自身肠道微生物群可能通过直接影响 类固醇激素然而，重要的是，大多数细菌分类群及其基因负责 类固醇激素在肠道中的代谢仍然是未知的。我们假设胃肠道微生物组是 BC中的不同;还有胃肠道细菌及其基因/蛋白质尚未被识别， 直接代谢类固醇激素。因此，我们提出以下具体目标：目标1。表征 BC患者和对照者的粪便细菌分类群和类固醇激素水平 测序以及第二样品组。目标2.鉴定细菌分类群及其候选基因 代谢类固醇激素。和2a。确定整个细菌群落从 BC患者和对照的粪便中代谢类固醇激素。高水平生长的样本 即高类固醇代谢将进一步研究与16 S rDNA测序，猎枪宏基因组学， 元转录组学用于鉴定细菌群落及其代谢基因，其通过类固醇增强 荷尔蒙暴露了解哪些细菌分类群可能在类固醇激素代谢中发挥作用 在胃肠道和细菌分类群的鉴定和基因参与类固醇代谢， 可能用于设计针对这些生物体的基于微生物组的个体化疗法。

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.