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

更年期和激素对肠道微生物群的影响对 HIV 心血管疾病风险的影响

• 批准号: 10319314
• 负责人: Brandilyn A Peters
• 金额: $ 17.25万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319314
• 关键词: 16S ribosomal RNA sequencing; Adrenal Glands; Age; Androgens; Area; Award; Bacteria; Bioinformatics; Biological Assay; Biological Markers; CD14 gene; Cardiovascular Diseases; Carotid Artery Plaques; Chronic; Chronic Disease; Clinical Data; Clinical Research; Clinical Trials; Cohort Studies; Communities; Data; Disease Progression; Estradiol; Estrogens; Face; Feces; Future; General Population; Glucuronides; Gold; Gonadal Steroid Hormones; Grant; HIV; HIV Infections; Hormonal; Human; Immune; Individual; Lead; Link; Mass Spectrum Analysis; Measurement; Measures; Menopausal Status; Menopause; Menstruation; Metabolic; Modeling; Mucosal Immunity; Operations Research; Pathogenesis; Phenotype; Plasma; Population; Postmenopause; Premenopause; Prevotella; Reproductive Endocrinology; Research; Sampling; Science; Serum; Shotgun Sequencing; Shotguns; Statistical Methods; Testosterone; Therapeutic Intervention; Training; Ultrasonography; Woman; Women' s Interagency HIV Study; base; cardioprotection; cardiovascular disorder risk; cardiovascular risk factor; career; career development; cohort; dysbiosis; gut microbiome; gut microbiota; high risk; hormone therapy; intimal medial thickening; men; metagenomic sequencing; microbial; microbiome; microbiome composition; microorganism; mortality; new therapeutic target; novel; ovarian reserve; sex; skill acquisition; stool sample

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.

项目概要/摘要 感染艾滋病毒的女性比未感染艾滋病毒的女性面临更高的心血管疾病 (CVD) 风险 与感染艾滋病毒的女性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 艾滋病毒感染女性的研究表明，更年期会改变肠道微生物组和微生物易位，这可能 导致 CVD 风险。然而，还没有研究调查更年期和性激素与 肠道微生物组组成和微生物易位，也没有考虑对CVD风险的影响。这是 在艾滋病毒感染的情况下特别相关，其中肠道微生物群失调和微生物易位 被认为会导致持续的免疫失调并增加患心血管疾病和其他慢性疾病的风险。 在这里，我们探讨了更年期和性激素通过调节 CVD 风险的新假设 肠道微生物群和微生物易位，特别是在艾滋病毒感染中。利用持续的肠道微生物组 和妇女跨机构艾滋病毒研究 (WIHS) 中的 CVD 项目，该项目将： 1) 纵向调查 感染和未感染艾滋病毒的女性绝经状态导致肠道微生物组发生变化； 2）检查关系 性类固醇激素与肠道微生物组和可溶性 CD14 (sCD14)（微生物的生物标志物）的关系 易位； 3）检查更年期和性激素相关肠道的关联 微生物组/微生物易位特征和亚临床 CVD。这些目标将利用预先存在的数据， 包括 WIHS 队列收集的全面人口统计和临床数据、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测序数据 来自 B 型超声的介质厚度数据。我们还提出了 14 种性类固醇的新测量方法 使用金标准质量测定血清中的激素，包括肾上腺前体、雄激素和雌激素 对 200 名绝经后妇女进行光谱测定。为了促进我的职业发展，我还将追求 以下领域的培训： 1) HIV 和 CVD 科学； 2）生殖内分泌学； 3）生物信息学和 统计方法； 4）临床研究业务； 5) 授予发展技能。拟议的研究将 揭示更年期、性激素和亚临床 CVD 之间与微生物组相关的新联系 感染和未感染艾滋病毒的女性。该奖项中提出的培训和研究将直接为 WIHS 中的更大规模研究，更全面地评估肠道微生物组、微生物组的纵向变化 易位和绝经过渡期间的其他心血管风险生物标志物，并将纵向相关 HIV 感染和 CVD 进展的轨迹和微生物组-生物标志物相互作用；以及支持 未来在其他人群（例如艾滋病毒感染者、非艾滋病毒感染者）和临床试验中的研究。最终，这 研究可能会带来针对肠道微生物组的治疗干预的新途径，以降低心血管疾病风险 患有或不患有艾滋病毒的绝经后妇女。