Document text
Principal Investigator: Albert Shieh
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $659,999
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <(TNF)-α><Acceleration><Antigens><Area Under Curve><Assay><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bioassay><Biological Assay><Biological Response Modifiers><Biomodulators><Blood Plasma><Bone Density><Bone Mineral Density><C-reactive protein><CD14><CD14 gene><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Cachectin Receptors><Cell Body><Cell Wall><Cells><Circulation><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Enterocytes><Epithelial Attachment><Estrogen decline><Estrogens><Exposure to><Fracture><Future><Gram-Negative Bacteria><Gut Epithelium><Gut Mucosa><HPGF><Hepatocyte-Stimulating Factor><Histologic><Histologically><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-6><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL6 Protein><Immune><Immune Cell Activation><Immune Markers><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immunes><Immunologic Markers><Individual><Inflammatory><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Interleukin-6><Intervention><Intervention Strategies><Intestinal Leakage><Junctional Epithelium><Lead><Leaky Gut><Ligands><Lipopolysaccharides><Longitudinal Studies><MGI-2><Macrophage-Derived TNF><Measures><Menopause><Mice><Mice Mammals><Microbe><Modern Man><Monocyte-Derived TNF><Murine><Mus><Myeloid Differentiation-Inducing Protein><Nuclear><OCIF protein><OPG protein><Osteoclasts><Osteoporosis><Osteoporosis prevention><Participant><Pathway interactions><Pb element><Perimenopausal><Perimenopause><Phenotype><Pilot Projects><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Production><Proteins><Proteins, specific or class, C-reactive><Publishing><Receptor Protein><Research><Reticuloendothelial System, Serum, Plasma><Sampling><Study of Women's Health Across the Nation><TNF><TNF A><TNF Alpha><TNF Receptor Family Protein><TNF Receptor Superfamily><TNF Receptors><TNF gene><TNF-α><TNFA><TNFR><TNFRSF11B gene product><TNFα><Testing><Therapeutic Estrogen><Time><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Tumor Necrosis Factor Receptor Superfamily Member 11B><Tumor Necrosis Factor-alpha><Tumor necrosis factor receptor 11b><Woman><Women's study><Work><after menopause><analyzing longitudinal><antagonism><antagonist><bone><bone fracture><bone loss><bone turnover><combat><cytokine><decline in estrogen><decrease estrogen><decrease in estrogen><disability><fatty acid-binding proteins><female study><following menopause><fragility fracture><gastrointestinal epithelium><gut microbes><gut microbial species><heavy metal Pb><heavy metal lead><immune activation><immune-based biomarkers><immunogen><immunological biomarkers><immunological markers><immunomodulatory biologics><inflammation marker><inflammatory marker><interferon beta 2><interventional strategy><intestinal barrier><intestinal microbes><intestinal mucosal barrier><long-term study><longitudinal analysis><longitudinal outcome studies><longterm study><menopause transition><microbial><microbial antigen><microbial products><microorganism antigen><mortality><mouse model><murine model><opg gene product><osteoclastogenesis><osteoclastogenesis inhibitory factor><osteoprotegerin><outcome prediction><past menopause><pathway><peri-menopausal><peri-menopause><phenotypic biomarker><phenotypic marker><pilot study><post-menopausal><postmenopausal><postmenopausal status><predictive assay><predictive test><prevent><prevent osteoporosis><preventing><receptor><reduced estrogen><study among females><study among women><study in females><study in women><study on females><study on women><study within women><transition to menopause><transitional menopause>