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.

项目总结/摘要 这项研究试图回答以下可能改变范式的问题：在人类中， 在绝经过渡期（MT）泄漏增加;如果是这样，肠道泄漏是否会导致免疫激活，骨 矿物质密度（BMD）下降和骨折？在小鼠模型中，一种新发现的骨丢失机制是 绝经期相关的肠道屏障完整性降低及其下游后遗症，包括 肠道微生物衍生抗原的移位、免疫激活、破骨细胞生成和骨丢失。 本研究将进一步研究小鼠性腺功能减退性骨丢失的漏肠途径是否也 发生在人类身上;我们的试点工作表明它确实如此。在一项对65名女性的纵向研究中， 全国妇女健康（SWAN），我们发现一种“漏肠表型”，其特征是 减少肠道屏障完整性和肠道微生物源性抗原的易位，在MT期间增加。我们 使用肠屏障完整性降低的血浆标志物（脂肪酸）研究了漏肠表型 结合蛋白2 [FABP 2]）和微生物抗原易位的血浆标志物（可溶性CD 14 [sCD14]）。从绝经前到绝经后，FABP 2和sCD 14增加， C-反应蛋白（SWAN中可用的非特异性炎症标记物）较高，BMD较低。 本申请提出了一个更明确的检查漏肠表型在整个MT 以及在更大的SWAN样本中其与免疫激活、BMD和骨折的纵向关系。确认 漏肠表型与MT期间的骨丢失相关，可能会导致骨质疏松症 预防，因为：1）MT和绝经后早期（约6年）的平均BMD损失总计1个T评分 单位; 2）在此期间BMD下降较快与骨折有关，与峰值BMD无关。 我们将测量FABP 2、sCD 14和一组对骨漏肠途径显著的免疫标志物， 使用从1，054名SWAN参与者在MT之前，期间和之后收集的库存血浆进行损失。目标1将 描述漏肠表型的每个标志物从绝经前到绝经后的变化轨迹。 目的2：检测个体内漏肠表型标志物的增加是否与 增强免疫激活。目的3：检测个体内漏肠表型的增加是否是 与骨密度下降相关。目标4评估是否漏肠标志物的较大增加 MT期间的表型与未来骨折的更高发生率相关。 完成这些特定目的将证实漏肠表型是否与 免疫激活、骨质流失和女性骨折。积极的结果将激励未来的研究， 测试旨在维持肠道屏障完整性和减少肠道易位量的干预措施， 微生物来源的抗原。这项研究议程最终可能会产生一种新的方法来对抗骨质疏松症： 通过在大量骨丢失发生之前阻断MT相关的漏肠表型增加。