The Impact of Gut Bile Acid Deconjugation on Host Fertility

肠道胆汁酸解离对宿主生育力的影响

• 批准号: 10579823
• 负责人: Erica Maissy
• 金额: $ 4.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579823
• 关键词: Address; Affect; Androgen Receptor; Androgens; Animal Disease Models; Back; Bacteria; Bile Acids; Bile fluid; Circulation; Data; Development Plans; Embryonic Development; Engineering; Engraftment; Environment; Escherichia coli; Female; Fertility; Frequencies; Goals; Gonadal Steroid Hormones; Gonadal structure; Homeostasis; Hypothalamic structure; In Vitro; Infertility; Inflammation; Knock-in; Learning Skill; Measures; Mediating; Mentors; Mentorship; Metabolic Biotransformation; Metabolism; Methods; Modification; Mus; Nature; Nuclear; Nuclear Receptors; Outcome Study; Pathway interactions; Physiological; Physiology; Public Health; Receptor Signaling; Reproduction; Reproductive Health; Reproductive Physiology; Research; Research Personnel; Role; Sample Size; Scientist; Serum; Signal Transduction; Signaling Molecule; Source; Supplementation; System; Testing; Testis; Testosterone; Time; Tissues; Training; Weaning; Wild Type Mouse; Work; absorption; career development; career networking; cohort; design; experimental study; fitness; gut microbes; gut microbiome; host-microbe interactions; hypothalamic pituitary gonadal axis; improved; innovation; insight; interest; male; meetings; microbial; microbiome; microbiome research; microorganism; new therapeutic target; novel; novel strategies; pup; receptor; reproductive; reproductive axis; reproductive function; research and development; secondary metabolite; sexual dimorphism; skills; subfertility; therapeutic target; tool; translational impact; vector

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.

最近的研究表明，肠道微生物组可以通过胆汁酸的修饰来影响生育能力和下丘脑 - 垂体 - 基达（HPG）轴。这项研究的总体目标是确定肠道微生物组的调节是否会影响生殖功能和生育能力。为了更好地理解细菌胆汁酸如何改变复制性健康，对工具的迫切需要将特定的细菌生物转化引入肠道微生物组，并研究其对宿主HPG轴的影响。该提案的创新是一种新策略，它使我们能够以持续的方式快速有效地敲击，以永久性，通过工程宿主的原生细菌来诱导身体变化。候选人将使用此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。在接下来的三年中，候选人将以三个特定的目标追求该提案的中心假设。第一个目的将决定肠道微生物组中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。通过使用工程化的天然细菌来增加胆汁酸解轭，候选者将确定胆汁酸成分对血清性恐怖症和其他标记物的影响。总体而言，这个目标将确定胆汁酸和宿主生殖健康的微生物组调节中是否存在性二态性。在第二个目标中，候选人将评估胆汁信号调节和降低的血清雄激素水平的影响，这在我的初步结果中，对雄性小鼠队列中的繁殖力。这将确定胆汁酸生物转化是否会对生殖轴产生足够的影响，以减少雄性的繁殖力。第三个目标将确定核胆汁酸受体Farnesoid X受体（FXR）是否对于细菌胆汁酸生物转化对睾丸激素水平的影响是必需的。最终，这个目标将决定该受体是否是操纵生育和繁殖力的新型治疗靶点。这些研究的预期结果进一步清楚了胆汁酸信号传导与生殖健康之间的关系。积极的翻译影响包括确定是否可以使用肠道微生物组来更好地理解和治疗男性和女性的属性。候选人是一位杰出的科学家，其目标是成为一名独立科学家，研究肠道微生物组与宿主复制健康之间的关系。她的培训目标包括开发生殖生理学专业知识，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以及建立她的专业网络。为了实现这些培训目标，候选人概述了一项计划，并在由DRS领导的Mentalship委员会的指导下，动手替补席研究，课程，半少数会议，国家会议和其他职业发展机会。 Amir Zarrinpar和Pamela Mellon。