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

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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.