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

项目摘要/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，肠道 在更年期(MT)期间渗漏增加；如果是这样，肠道渗漏是否会导致免疫激活、骨骼 骨密度(BMD)下降和骨折？在小鼠模型中，一种新发现的骨丢失机制是 与更年期相关的肠道屏障完整性降低，及其下游后遗症，包括 肠道微生物来源的抗原移位、免疫激活、破骨细胞形成和骨丢失。 这项研究将进一步研究小鼠性腺下段骨丢失的这种肠道渗漏途径是否也 发生在人类身上；我们的试点工作表明确实如此。在一项对65名女性的纵向研究中， 在全国妇女健康(Swan)中，我们发现一种“漏肠表型”，其特征为 在MT期间，肠道屏障完整性降低和肠道微生物衍生抗原移位增加。我们 使用一种降低肠道屏障完整性(脂肪酸)的血浆标志物研究肠漏的表型 结合蛋白2[FABP2])和微生物抗原易位的血浆标记物(可溶性CD14 [sCD14]))。FABP2和sCD14从绝经前到绝经后升高，更高的水平与 较高的C反应蛋白(天鹅体内的一种非特异性炎症标志物)和较低的BMD。 这项应用提供了一种对MT的肠漏表型的更明确的检查 在更大的天鹅样本中，它与免疫激活、骨密度和骨折的纵向关系。确认 肠漏表型与骨丢失有关在MT期间可能打开一条有效的骨质疏松途径 预防原因：1)MT患者和绝经后早期(~6年)的平均骨密度丢失总计为1个T分 2)在此期间骨密度下降较快与骨折有关，与峰值骨密度无关。 我们将检测FABP2、sCD14和一组突出于骨骼泄漏肠道途径的免疫标记物 使用从1,054名天鹅受试者收集的银行血浆在MT之前、期间和之后进行损失。目标1将 描述从绝经前到绝经后渗漏肠道表型的每个标志物的变化轨迹。 目标2检查个体内渗漏肠道表型标志物的增加是否与 增强免疫活性。Aim 3测试漏肠表型的个体内增加是否 与骨密度降低有关。目标4评估渗漏肠道标志物的较大增加 MT期间的表型与更高的未来骨折发生率相关。 完成这些特定的目标将证实肠漏表型是否与 女性的免疫激活、骨丢失和骨折。积极的结果将激励未来的研究，可能 测试旨在保持肠道屏障完整性和减少移位的肠道数量的干预措施 微生物来源的抗原。这一研究议程最终可能产生一种抗击骨质疏松症的新方法： 在大量骨质流失发生之前，通过阻断MT相关的渗漏肠道表型的增加。

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.