Menopause and hormonal influences on the gut microbiome for CVD risk in HIV

项目摘要/摘要 携带艾滋病毒的女性比未感染的女性面临更高的心血管疾病(CVD)风险，潜在地 这与艾滋病毒携带者的卵巢储备和性类固醇激素水平较低有关。我们的初步调查结果 艾滋病毒携带者的研究表明，更年期会改变肠道微生物群和微生物易位，这可能会 增加心血管疾病的风险。然而，还没有研究调查更年期和性激素与 肠道微生物群组成和微生物易位，也没有考虑对心血管疾病风险的影响。这是 尤其与艾滋病毒感染有关，在这种情况下，肠道微生物群和微生物易位 被认为会导致持续的免疫失调，增加患心血管疾病和其他慢性病的风险。 在这里，我们探索了一个新的假设，即更年期和性激素通过调节 肠道微生物区系和微生物易位，特别是在艾滋病毒感染中。利用正在进行的肠道微生物群 和心血管疾病项目在妇女机构间艾滋病毒研究(WIHS)中，该项目将：1)纵向调查 HIV携带者和非HIV携带者的绝经状态对肠道微生物群的影响；2)检查关系 性类固醇激素与肠道微生物群和微生物生物标志物可溶性CD14(SCD14)的关系 易位；以及3)检查更年期和性激素相关的肠道之间的关系 微生物组/微生物易位特征与亚临床心血管疾病。这些目标将利用预先存在的数据， 包括WIHS队列收集的全面的人口学和临床数据，16S rRNA基因 来自粪便样本、血清sCD14以及颈动脉斑块和内膜的测序和鸟枪式测序数据- 来自B超的中层厚度数据。此外，我们还提出了14种性激素的新测量方法 血清中的激素，包括肾上腺前体、雄激素和雌激素，使用黄金标准质量 对200名绝经后妇女进行光谱分析。为了促进我的职业发展，我还将继续 在以下领域进行培训：1)艾滋病毒和心血管疾病科学；2)生殖内分泌学；3)生物信息学和 统计方法；4)临床研究操作；5)授予发展技能。拟议的研究将 在更年期、性激素和亚临床心血管疾病之间发现新的微生物组相关联系 感染和未感染艾滋病毒的妇女。该奖项建议的培训和研究将直接为 在WIHS中进行更大规模的研究，以更全面地评估肠道微生物群、微生物的纵向变化 在绝经过渡期间易位和其他心血管风险生物标志物，并与纵向相关 HIV感染和心血管疾病进展的轨迹和微生物组-生物标记物的相互作用；以及支持 未来在其他人群(例如，艾滋病毒携带者、非艾滋病毒人群)和临床试验中的研究。归根结底，这 研究可能导致针对肠道微生物组的治疗干预的新途径，以降低心血管疾病的风险 无论是否患有艾滋病毒的绝经后妇女。

PROJECT SUMMARY/ABSTRACT Women with HIV face particularly higher risk of cardiovascular disease (CVD) than uninfected women, potentially related to lower levels of ovarian reserve and sex steroid hormones in women with HIV. Our preliminary findings in women with HIV suggest that menopause alters the gut microbiome and microbial translocation, which may contribute to CVD risk. Yet, no studies have investigated the association of menopause and sex hormones with gut microbiome composition and microbial translocation, nor considered the impact on CVD risk. This is particularly relevant in the context of HIV infection, where a dysbiotic gut microbiome and microbial translocation are thought to lead to persistent immune dysregulation and increased risk of CVD and other chronic diseases. Here, we explore the novel hypothesis that menopause and sex hormones influence CVD risk via modulation of the gut microbiota and microbial translocation, particularly in HIV infection. Leveraging ongoing gut microbiome and CVD projects in the Women's Interagency HIV Study (WIHS), this project will: 1) investigate longitudinal changes in the gut microbiome by menopausal status in women with and without HIV; 2) examine relationships of sex steroid hormones with the gut microbiome and soluble CD14 (sCD14), a biomarker of microbial translocation; and 3) examine the associations of menopause- and sex hormone-related gut microbiome/microbial translocation features and subclinical CVD. These aims will utilize pre-existing data, including comprehensive demographic and clinical data collected by the WIHS cohort, 16S rRNA gene sequencing and shotgun sequencing data from stool samples, serum sCD14, and carotid plaque and intima- media thickness data from B mode ultrasound. We additionally propose new measurement of 14 sex steroid hormones in serum, including adrenal precursors, androgens, and estrogens, using gold standard mass spectrometry assays, in 200 post-menopausal women. To facilitate my career development, I will also pursue training in the following areas: 1) HIV and CVD science; 2) Reproductive endocrinology; 3) Bioinformatic and statistical methods; 4) Clinical research operations; and 5) Grant development skills. The proposed study will uncover novel microbiome-related connections between menopause, sex hormones, and subclinical CVD in women with and without HIV. The training and research proposed in this award will directly set the stage for a larger study in the WIHS, to more comprehensively assess longitudinal changes in the gut microbiome, microbial translocation, and other cardiovascular risk biomarkers during the menopausal transition, and relate longitudinal trajectories and microbiome-biomarker interactions to HIV infection and CVD progression; as well as support future studies in other populations (e.g. men with HIV, non-HIV cohorts) and in clinical trials. Ultimately, this research may lead to new avenues of therapeutic intervention targeting the gut microbiome, to lower CVD risk in post-menopausal women with or without HIV.