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.

项目总结/摘要 感染艾滋病毒的妇女比未感染的妇女面临特别高的心血管疾病（CVD）风险， 与HIV感染妇女卵巢储备和性类固醇激素水平较低有关。我们的初步研究结果 表明绝经改变了肠道微生物组和微生物易位，这可能 增加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 特别是在HIV感染的情况下，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，增加心血管疾病和其他慢性疾病的风险。 在这里，我们探讨了一个新的假设，即绝经和性激素通过调节 肠道微生物群和微生物移位，特别是在艾滋病毒感染中。利用正在进行的肠道微生物组 妇女机构间艾滋病毒研究（WIHS）中的CVD项目，该项目将：1）调查纵向 在有和没有艾滋病毒的妇女中，通过绝经状态改变肠道微生物组; 2）检查关系 性类固醇激素与肠道微生物组和可溶性CD 14（sCD 14）的关系， 易位;和3）检查绝经和性生活相关肠道的关联 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学和临床数据，16 S rRNA基因 粪便样本、血清sCD 14、颈动脉斑块和内膜的测序和鸟枪测序数据， 来自B模式超声的介质厚度数据。我们还提出了14种性类固醇的新测定方法 血清激素，包括肾上腺前体、雄激素和雌激素，使用金标准质量 光谱分析，在200绝经后妇女。为了促进我的职业发展，我还将追求 在以下领域的培训：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;和5）赠款开发技能。拟定的研究将 揭示绝经期，性激素和亚临床CVD之间的新型微生物群相关联系， 感染和未感染艾滋病毒的妇女。在这个奖项中提出的培训和研究将直接为一个 在WIHS中进行的一项更大规模的研究，旨在更全面地评估肠道微生物组的纵向变化， 易位和其他心血管风险生物标志物，以及相关的纵向 轨迹和微生物组-生物标志物相互作用对HIV感染和CVD进展的影响;以及支持 未来在其他人群（例如，男性艾滋病毒感染者、非艾滋病毒队列）和临床试验中的研究。最终这 研究可能会导致针对肠道微生物组的治疗干预的新途径，以降低CVD风险 在绝经后妇女中，无论是否携带艾滋病毒。