High-Resolution Plasma Metabolomics to Determine Linkages between Estrogen-Induced Bone Loss and Intestinal Barrier Integrity in HIV

高分辨率血浆代谢组学确定 HIV 中雌激素引起的骨质流失与肠屏障完整性之间的联系

• 批准号: 9927115
• 负责人: Jessica Alejandra Alvarez
• 金额: $ 7.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927115
• 关键词: AIDS/HIV problem; Address; Age; Animal Model; Animals; Antigens; Automobile Driving; Bacteria; Bioinformatics; Biological Markers; Blood Circulation; Bone Density; Bone Diseases; Bone Resorption; Butyrates; C-terminal; Caring; Cell Wall; Centers of Research Excellence; Clinical; Collagen; Collection; Complex; Complication; Connexins; Data; Demography; Development; Enzyme-Linked Immunosorbent Assay; Epidemic; Estrogens; Fracture; Functional disorder; Funding; Future; Goals; Grant; Gut Mucosa; HIV; HIV Infections; HIV antiretroviral; Health; Hip Fractures; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Intestinal permeability; Knowledge; Leaky Gut; Ligands; Lipopolysaccharides; Medical; Menopause; Metabolic; Metabolic Pathway; Metabolism; Morbidity - disease rate; N-terminal; NF-kappa B; Osteocalcin; Osteogenesis; Osteopenia; Osteoporosis; Outcome; Parents; Pathway Analysis; Pathway interactions; Patients; Permeability; Plasma; Population; Postmenopausal Osteoporosis; Postmenopause; Procollagen; Production; Quality of life; Research; Resolution; Risk; Role; Serum; Sex Differences; Specialized Center; TNF gene; Tumor necrosis factor receptor 11b; United States National Institutes of Health; Volatile Fatty Acids; Woman; Women' s Health; age related; aging population; antiretroviral therapy; bone; bone loss; bone turnover; cohort; comorbidity; cytokine; design; dysbiosis; fracture risk; gut bacteria; gut microbiome; hip bone; improved; insight; intestinal barrier; metabolomics; microbial; microbiome; receptor; side effect; tartrate-resistant acid phosphatase

PROJECT SUMMARY/ABSTRACT With improved medical care, including the introduction of successful antiretroviral therapies (ART), the age demography of HIV/AIDS has shifted so that it is projected that over half of all individuals living with HIV are now over 50 years old. A new landscape of HIV is now apparent, with a high rate of age-related comorbidities that are exacerbated by HIV infection and side effects of ART. Bone loss and resulting osteopenia/ osteoporosis and bone fracture risk are alarmingly high in individuals with HIV, especially postmenopausal women where both estrogen deficiency and HIV infection/ART contribute to inflammation-induced bone loss. Recent research implicates dysregulation of the gut microbiome and worsening gut mucosal permeability (“leaky gut”) causing influx of inflammatory mediators, such as lipopolysaccharide (LPS), as contributors to bone loss. By contrast, a healthy microbiome may protect against bone loss via production of bacterial-derived short chain fatty acids (SCFA) that stimulate bone formation (bone anabolic). Furthermore, studies suggest that estrogen deficiency and HIV infection both independently contribute to loss of gut barrier integrity. The specific interactions between gut permeability, estrogen deficiency, and HIV-infection are, however, not known. We hypothesize that bone loss in women with HIV infection is due, in part, to gut dysbiosis driving imbalance between bone catabolic and bone anabolic bacterial metabolites, and exacerbated by estrogen insufficiency/deficiency. Recent advances in high-resolution metabolomics (HRM) provide a unique opportunity to broadly explore metabolism and underlying pathways relevant to HIV and women's health. The purpose of this study is to use plasma HRM with advanced bioinformatics to interrogate the interrelationships between circulating gut bacterial-derived metabolites, bone mineral density (BMD) and biomarkers of bone formation and loss, and estrogen deficiency in women living with HIV. Aim 1 will assess the association of circulating bacterial-derived metabolites and HIV status with bone turnover and BMD, while Aim 2 will assess the interactions of estrogen on these relationships. The overall goal of this project is to obtain new insight into HIV- and estrogen deficiency-induced bone loss that will inform the design of future interventions to reduce the risk of osteoporosis and fracture among women living with HIV. This project will provide outstanding preliminary data for subsequent studies focusing on the pathophysiology of bone disease among women living with HIV and the development of new strategies to improve health and quality of life in this aging population.

项目概要/摘要 随着医疗保健的改善，包括成功的抗逆转录病毒疗法 (ART) 的引入，年龄 艾滋病毒/艾滋病的人口结构已经发生变化，因此预计一半以上的艾滋病毒感染者 现在50多岁了。艾滋病毒的新格局现已显现，与年龄相关的合并症发病率很高 HIV 感染和 ART 的副作用会加剧这种情况。骨质流失和由此导致的骨质减少/ 艾滋病毒感染者，尤其是绝经后患者，骨质疏松和骨折的风险非常高 雌激素缺乏和艾滋病毒感染/抗逆转录病毒治疗都会导致炎症引起的骨质流失的女性。 最近的研究表明肠道微生物组失调和肠道粘膜通透性恶化 （“肠漏”）导致脂多糖（LPS）等炎症介质大量涌入 骨质流失。相比之下，健康的微生物组可以通过产生细菌源性物质来防止骨质流失 刺激骨形成（骨合成代谢）的短链脂肪酸 (SCFA)。此外，研究表明 雌激素缺乏和艾滋病毒感染都会独立地导致肠道屏障完整性的丧失。这 然而，肠道通透性、雌激素缺乏和艾滋病毒感染之间的具体相互作用尚不清楚。 我们假设感染艾滋病毒的女性骨质流失部分是由于肠道菌群失调导致失衡 骨分解代谢和骨合成代谢细菌代谢物之间，并因雌激素而加剧 不足/不足。高分辨率代谢组学 (HRM) 的最新进展提供了独特的机会 广泛探索与艾滋病毒和妇女健康相关的新陈代谢和潜在途径。目的 这项研究是利用血浆 HRM 和先进的生物信息学来探究之间的相互关系 循环肠道细菌衍生代谢物、骨矿物质密度 (BMD) 和骨形成的生物标志物 感染艾滋病毒的女性的雌激素缺失和雌激素缺乏。目标 1 将评估循环的关联性 细菌衍生的代谢物和 HIV 状态以及骨转换和 BMD，而目标 2 将评估 雌激素对这些关系的相互作用。该项目的总体目标是获得对艾滋病毒的新见解 和雌激素缺乏引起的骨质流失，这将为未来干预措施的设计提供信息，以降低风险 感染艾滋病毒的女性中骨质疏松和骨折的情况。该项目将提供出色的初步 后续研究的数据，重点关注艾滋病毒感染者女性骨病的病理生理学 以及制定新战略以改善老龄化人口的健康和生活质量。