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: 10481848
• 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/10481848
• 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; Persons; Phenotype; Plasma; Population; Postmenopause; Premenopause; Prevotella; Reproductive Endocrinology; Research; Sampling; Science; Serum; Shotgun Sequencing; Shotguns; Statistical Methods; Testosterone; Therapeutic Intervention; Training; 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; ultrasound

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.

项目摘要/摘要 艾滋病毒的妇女面临的心血管疾病（CVD）的风险特别高于未感染的妇女 与艾滋病毒女性的卵巢储备和性类固醇激素的较低水平有关。我们的初步发现 在艾滋病毒的女性中，更年期会改变肠道微生物组和微生物易位，这可能 有助于CVD风险。然而，尚无研究调查更年期和性激素的关联 肠道微生物组组成和微生物易位，也不认为对CVD风险的影响。这是 在HIV感染的情况下特别相关，其中不植物肠道微生物组和微生物易位 被认为会导致持续的免疫失调和CVD和其他慢性疾病的风险增加。 在这里，我们探讨了新颖的假设，即更年期和性激素通过调制来影响CVD风险 肠道菌群和微生物易位，尤其是在HIV感染中。利用正在进行的肠道微生物组 和妇女间艾滋病毒研究（WIHS）中的CVD项目，该项目将：1）调查纵向 患有和没有艾滋病毒的妇女的绝经状态的肠道微生物组的变化； 2）检查关系 具有肠道微生物组和可溶性CD14（SCD14）的性类固醇激素的生物标志物 易位； 3）检查更年期和性激素相关的肠道的关联 微生物组/微生物易位特征和亚临床CVD。这些目的将利用现有的数据， 包括WIHS队列收集的综合人口统计学和临床​​数据，16S rRNA基因 从粪便样品，血清SCD14以及颈动脉斑块和内膜的测序和shot弹枪测序数据 B模式超声波的媒体厚度数据。我们还提出了14个性类固醇的新测量 血清中的激素，包括肾上腺前体，雄激素和雌激素，使用金标准质量 光谱法测定法，200名绝经后妇女。为了促进我的职业发展，我也将追求 在以下领域进行培训：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）临床研究操作； 5）授予发展技能。拟议的研究将 发现更年期，性激素和亚临床CVD之间的新型微生物组相关连接 患有和没有艾滋病毒的妇女。该奖项提出的培训和研究将直接为 在WIHS中进行的大型研究，以更全面地评估肠道微生物组的纵向变化 更年期过渡期间的易位和其他心血管风险生物标志物，并与纵向联系 与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，非HIV队列）和临床试验中进行的研究。最终，这个 研究可能导致针对肠道微生物组的治疗干预措施的新途径，以降低CVD风险 在有或没有艾滋病毒的绝经后妇女中。