The Impact of Gut Bile Acid Deconjugation on Host Fertility

最近的研究表明，肠道微生物组可以通过改变胆汁酸来影响生育能力和下丘脑-垂体-性腺（HPG）轴。本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会影响生殖功能和生育能力。为了更好地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群，并研究它们对宿主HPG轴的影响。这项提议的创新之处在于，它是一种新的策略，通过设计宿主的原生细菌来诱导生理变化，使我们能够快速有效地以持续的方式永久地敲入有益的功能。候选人将使用这个工具来解决她的中心假设，即胆汁酸是HPG轴和生育能力的关键调节剂。在接下来的三年里，候选人将以三个具体目标来追求提案的中心假设。第一个目标是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。通过使用工程原生细菌增加胆汁酸解结，候选人将确定改变胆汁酸组成对血清性激素和其他标志物宿主生育能力的影响。总的来说，这个目的将确定是否存在性别二态性在微生物组调节胆汁酸和宿主生殖健康。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的影响，在我的初步结果中显示，对雄性小鼠的生育能力。这将决定胆汁酸生物转化是否会对生殖轴产生足够强的影响，从而降低雄性的繁殖力。第三个目标将确定核胆汁酸受体，法尼索酮X受体（FXR）是否对细菌胆汁酸生物转化对睾酮水平的影响是必要的。最终，这一目标将确定该受体是否是操纵生育和繁殖力的新治疗靶点。这些研究的预期结果是进一步明确胆汁酸信号传导与生殖健康之间的关系。积极的转化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生育能力低下。该候选人是一位杰出的科学家，其目标是成为一名独立的科学家，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，发展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，并建立她的专业网络。为了实现这些培训目标，候选人在博士领导的指导委员会的指导下，概述了一个实践实验、课程、研讨会、全国会议和其他职业发展机会的计划。Amir Zarrinpar和Pamela Mellon。

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.