Menopause-related increase in gut leak and its relation to immune activation, bone density decline and fractures

更年期相关的肠漏增加及其与免疫激活、骨密度下降和骨折的关系

• 批准号: 10561328
• 负责人: Albert Shieh
• 金额: $ 68.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-25 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561328
• 关键词: Acceleration; Antigens; Area Under Curve; Biological Assay; Biological Response Modifiers; Bone Density; C-reactive protein; CD14 gene; Cell Wall; Cells; Circulation; Enterocytes; Epithelial Attachment; Estrogen decline; Estrogens; Exposure to; Fracture; Future; Gram-Negative Bacteria; Gut Mucosa; Histologic; Human; IL17 gene; Immune; Immunologic Markers; Individual; Inflammatory; Interleukin-6; Intervention; Lead; Leaky Gut; Ligands; Lipopolysaccharides; Longitudinal Studies; Measures; Menopause; Microbe; Mus; Nuclear; Osteoclasts; Osteoporosis; Osteoporosis prevention; Participant; Pathway interactions; Perimenopause; Phenotype; Pilot Projects; Plasma; Postmenopause; Production; Proteins; Publishing; Research; Sampling; Study of Women' s Health Across the Nation; TNF gene; Testing; Time; Tumor Necrosis Factor Receptor; Tumor necrosis factor receptor 11b; Woman; Work; antagonist; bone; bone loss; bone turnover; combat; cytokine; disability; fatty acid-binding proteins; fragility fracture; gastrointestinal epithelium; gut microbes; immune activation; inflammatory marker; intestinal barrier; longitudinal analysis; microbial; microbial products; microorganism antigen; mortality; mouse model; osteoclastogenesis; outcome prediction; phenotypic biomarker; predictive test; prevent; receptor

PROJECT SUMMARY/ABSTRACT This study endeavors to answer the following, potentially paradigm-changing question: in humans, does gut leak increase during the menopause transition (MT); and if so, does gut leak lead to immune activation, bone mineral density (BMD) decline and fractures? In murine models, a newly uncovered mechanism of bone loss is a menopause-related diminution of gut barrier integrity, and its downstream sequelae, which include translocation of gut microbe-derived antigens, immune activation, osteoclastogenesis, and bone loss. This study will further investigate whether this leaky gut pathway of hypogonadal bone loss in mice also occurs in humans; our pilot work suggests that it does. In a longitudinal study of 65 women from the Study of Women's Health Across the Nation (SWAN), we found that a “leaky gut phenotype,” characterized by diminished gut barrier integrity and translocation of gut microbe-derived antigens, increases during the MT. We investigated the leaky gut phenotype using a plasma marker of decreased gut barrier integrity (fatty acid binding protein 2 [FABP2]), and a plasma marker of translocation of microbial antigens (soluble CD14 [sCD14]). FABP2 and sCD14 increased from pre- to postmenopause, and greater levels were associated with higher C-reactive protein (a non-specific inflammation marker available in SWAN) and lower BMD. This application proposes a vastly more definitive examination of the leaky gut phenotype across the MT and its longitudinal relations to immune activation, BMD, and fracture in a larger SWAN sample. Confirming the leaky gut phenotype is related to bone loss during the MT could open a potent avenue of osteoporosis prevention because: 1) average BMD loss during the MT and early postmenopause (~6 years) totals 1 T-score unit; and 2) faster BMD decline during this interval relates to fractures, independent of peak BMD. We will measure FABP2, sCD14, and a panel of immune markers salient to the leaky gut pathway of bone loss using banked plasma collected from 1,054 SWAN participants before, during, and after the MT. Aim 1 will characterize the trajectory of change in each marker of the leaky gut phenotype from pre- to postmenopause. Aim 2 examines whether within-individual increases in leaky gut phenotype markers are associated with increased immune activation. Aim 3 tests whether within-individual increases in the leaky gut phenotype are associated with decreased BMD. Aim 4 assesses whether larger increases in the markers of the leaky gut phenotype during the MT are associated with greater rates of future fracture. Completing these Specific Aims will substantiate whether the leaky gut phenotype is associated with immune activation, bone loss, and fracture in women. Positive results would motivate future studies that could tests interventions aimed at maintaining gut barrier integrity and lessening the amount of translocated gut microbe-derived antigens. This research agenda could ultimately generate a new way to combat osteoporosis: by blocking a MT-related increase in the leaky gut phenotype, before substantial bone loss occurs.

项目摘要/摘要 这项研究努力回答以下可能改变范式的问题：在人类中， 更年期过渡期间的泄漏增加（MT）；如果是这样，肠道泄漏会导致免疫激活，骨头 矿物质密度（BMD）下降和断裂？在鼠模型中，新发现的骨质流失机制是 肠道屏障完整性及其下游后遗症的更年期相关尺寸，其中包括 肠道微生物衍生的抗原，免疫激活，破骨细胞生成和骨质流失的易位。 这项研究将进一步研究小鼠性泄漏的肠道骨质损失的肠道漏洞 发生在人类中；我们的飞行员工作表明确实如此。在一项对65名妇女的纵向研究中 全国妇女健康（天鹅），我们发现一种“漏水表型”，其特征是 在MT期间，肠道屏障完整性和肠道微生物衍生的抗原的易位增加。我们 使用降低肠道屏障完整性（脂肪酸）的等离子体标记研究了漏水表型 结合蛋白2 [Fabp2]）和微生物抗原易位的等离子体标记（可溶性CD14 [SCD14]）。 FABP2和SCD14从结肠前到后期增加，与更高的水平相关 较高的C反应蛋白（SWAN中可用的非特异性炎症标记）和较低的BMD。 该应用建议对MT泄漏的肠道表型进行更明确的检查 及其与较大天鹅样品中免疫激活，BMD和断裂的纵向关系。确认 泄漏的肠道表型与MT期间的骨质流失有关 预防是因为：1）MT期间的平均BMD损失和绝经早期（〜6年）总计1 T评分 单元; 2）在此间隔中，BMD的速度更快，与裂缝有关，与峰值BMD无关。 我们将测量Fabp2，SCD14和一组免疫标志物，突出骨骼渗漏的肠道途径 在MT之前，之中和之后，使用1,054个天鹅参与者收集的银行等离子体的损失。目标1意志 表征从前期到绝经后泄漏的肠道表型的每个标记的变化轨迹。 AIM 2考试是否与泄漏的肠道表型标记相关 免疫激活增加。 AIM 3测试是否在泄漏的肠道表型中个体内部增加是否增加 与BMD降低有关。 AIM 4评估是否较大的肠道标记物增加 MT期间的表型与更高的未来骨折率有关。 完成这些特定目标将证实是否与 女性的免疫激活，骨质流失和骨折。积极的结果将激发未来的研究 旨在维持肠道屏障完整性并减少易位肠道量的测试干预措施 微生物衍生的抗原。该研究议程最终可能会产生一种打击骨质疏松症的新方法： 通过阻止在大量骨质流失之前阻止MT相关的肠道肠道表型的增加。