The Impact of Gut Bile Acid Deconjugation on Host Fertility

最近的研究表明，肠道微生物群可以通过改变胆汁酸来影响生育力和下丘脑-垂体-性腺轴(HPG)。这项研究的总体目标是确定肠道微生物群对胆汁酸的调节是否影响生殖功能和生育能力。为了更好地从机制上了解细菌胆汁酸修饰如何影响生殖健康，迫切需要一种工具，将特定的细菌生物转化引入肠道微生物组，并研究它们对宿主HPG轴的影响。这一提议的一个创新是一种新的战略，它允许我们通过设计宿主的本地细菌来诱导生理变化，以持续、永久的方式快速有效地注入有益的功能。候选人将使用这一工具来解决她的核心假设，即胆汁酸是HPG轴和生育能力的关键调节器。在接下来的三年里，候选人将带着三个具体目标来追求该提案的核心假设。第一个目标将确定肠道微生物群中的细菌胆汁酸生物转化如何影响雄性和雌性小鼠的生育能力。通过使用工程化的本地细菌来增加胆汁酸的去结合作用，候选人将确定改变胆汁酸成分对血清性激素和其他指标宿主生育能力的影响。总体而言，这一目标将决定胆汁酸的微生物群调控是否存在性别二型性，并与宿主生殖健康有关。在第二个目标中，候选人将评估胆汁信号调节和血清雄激素水平降低对一组雄性小鼠繁殖力的影响，我的初步结果显示了这一点。这将决定胆汁酸的生物转化是否会对生殖轴产生足够强的影响，从而降低男性的繁殖力。第三个目的将确定核胆汁酸受体法尼醇X受体(FXR)是否对于细菌胆汁酸生物转化对睾酮水平的影响是必要的。最终，这一目标将决定该受体是否是控制生育和繁殖力的新的治疗靶点。这些研究的预期结果是进一步明确胆汁酸信号与生殖健康之间的关系。积极的翻译影响包括确定肠道微生物组是否可以用来更好地理解和潜在地治疗男性和女性的不育症。候选人是一位杰出的科学家，他的目标是成为一名独立科学家，研究肠道微生物群与宿主生殖健康之间的关系。她的培训目标包括发展生殖生理学方面的专业知识，设计微生物组实验，开发疾病动物模型方面的专业知识，学习成为独立研究人员所需的技能，以及建立她的专业网络。为了实现这些培训目标，候选人在由Amir Zarrinpar博士和Pamela Mellon博士领导的指导委员会的指导下，概述了一项包括实践板凳研究、课程、研讨会、全国会议和其他职业发展机会的计划。

Recent studies suggest that the gut microbiome can influence fertility and the hypothalamic-pituitary-gonadal (HPG) axis through modifications of bile acids. The overall goal of this study is to determine whether the gut microbiome’s modulation of bile acids affects reproductive function and fertility. To have a better mechanistic understanding of how bacterial bile acid modifications affect reproductive health, there is a critical need for a tool that will introduce specific bacterial biotransformations into the gut microbiome and investigate their effects on the host HPG axis. An innovation of this proposal is a new strategy that allows us to quickly and effectively knock- in a beneficial function in a sustained manner, for perpetuity, by engineering the host’s native bacteria to induce a physiological change. The candidate will use this tool to address her central hypothesis, that bile acids are key modulators of the HPG axis and fertility. In the next three years, the candidate will pursue the proposal’s central hypothesis with three specific aims. The first aim will determine how bacterial bile acid biotransformations in the gut microbiome affect fertility in both male and female mice. By using engineered native bacteria to increase bile acid deconjugation, the candidate will determine the effect of altered bile acid composition on serum sex hormones and other markers host fertility. Overall, this aim will determine if there is sexual dimorphism in microbiome modulation of bile acids and host reproductive health. In the second aim, the candidate will evaluate the effect of bile signaling modulation and reduced serum androgen levels, shown in my preliminary results, on fecundity in a cohort of male mice. This will determine whether bile acid biotransformations elicit a strong enough effect on the reproductive axis to reduce fecundity in males. The third aim will determine whether the nuclear bile acid receptor, farnesoid X receptor (FXR), is necessary for the effect of bacterial bile acid biotransformations on testosterone levels. Ultimately, this aim will determine whether this receptor is a novel therapeutic target to manipulate fertility and fecundity. The expected outcome of these studies is further clarity about the relationship between bile acid signaling and reproductive health. The positive translational impact includes the determination of whether the gut microbiome can be used to better understand, and potentially treat, male and female subfertility. The candidate is an exceptional scientist whose goal is to become an independent scientist investigating the relationship between the gut microbiome and host reproductive health. Her training goals include developing expertise in reproductive physiology, designing microbiome experiments, developing expertise in animal models of disease, learning the skills necessary to become an independent researcher, and building her professional network. To accomplish these training goals, the candidate has outlined a plan with hands-on bench research, coursework, seminars, national meetings, and other career development opportunities under the guidance of mentorship committee led by Drs. Amir Zarrinpar and Pamela Mellon.