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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要这项研究致力于回答以下可能改变范式的问题：在人类中，肠道是否更年期过渡期间（MT）渗漏增加；如果是这样，肠道渗漏是否会导致免疫激活、骨骼矿物质密度（BMD）下降和骨折？在小鼠模型中，新发现的骨质流失机制是与更年期相关的肠道屏障完整性下降及其下游后遗症，其中包括肠道微生物衍生抗原的易位、免疫激活、破骨细胞生成和骨质流失。这项研究将进一步研究小鼠性腺功能减退性骨质流失的肠漏途径是否也研究人员对 65 名女性进行的一项纵向研究显示，这种情况确实发生在人类身上。全国女性健康 (SWAN)，我们发现“肠漏表型”，其特征是肠道屏障完整性减弱，肠道微生物衍生抗原易位，在 MT We 期间增加。使用肠道屏障完整性降低的血浆标记物（脂肪酸结合蛋白 2 [FABP2]），以及微生物抗原易位的血浆标记（可溶性 CD14 [sCD14]) FABP2 和 sCD14 从绝经前到绝经后增加，并且更高的水平与较高的 C 反应蛋白（SWAN 中可用的非特异性炎症标记物）和较低的 BMD。该应用提出了对跨 MT 的漏肠表型进行更加明确的检查及其与免疫激活、BMD 和骨折的纵向关系在更大的 SWAN 样本中得到证实。肠漏表型与 MT 期间的骨质流失有关，可能为骨质疏松症开辟一条有效途径预防的原因是：1) MT 期间和绝经后早期（~6 年）期间的平均 BMD 损失总计 1 T 分数单位；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 FABP2、sCD14 和一组对骨漏肠通路显着的免疫标记物使用从 MT 目标 1 之前、期间和之后收集的 1,054 名 SWAN 参与者收集的血浆进行损失。描述绝经前至绝经后漏肠表型每个标志物的变化轨迹。目标 2 检查个体内漏肠表型标记物的增加是否与目标 3 测试个体内漏肠表型是否增加。目标 4 评估漏肠标记物是否有较大增加。 MT 期间的表型与未来更高的骨折率相关。完成这些具体目标将证实漏肠表型是否与女性的免疫激活、骨质流失和骨折的积极结果将推动未来的研究。测试旨在维持肠道屏障完整性和减少肠道移位量的干预措施该研究议程最终可能会产生一种对抗骨质疏松症的新方法：在大量骨质流失发生之前，阻断与 MT 相关的漏肠表型增加。