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Principal Investigator: JOHN P BILEZIKIAN
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $537,126
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY
Primary hyperparathyroidism (PHPT) is a condition caused by the excessive secretion of parathyroid hormone
(PTH) that can lead to aggressive bone loss, osteoporosis and increased risk of fractures. Intriguingly, PHPT is
a heterogeneous disease where some patients go on to develop bone loss while others do not, and few
biomarkers are available to predict the course of the disease. We recently reported in Nat. Comm. that the
intestinal microbiome is a potent factor governing the capacity of PTH to induce bone loss. Specifically, we
showed in mice that elevated levels of PTH in combination with microbial-released products potentiates the
activation of pro-inflammatory TNF producing T cells in gut tissue, which then migrate from the gut to the bone
marrow (BM). In a process that only occur if specific species of bacteria are present in the microbiome,
intestinal TNF producing T cells induce the expansion of Th17 cells in the gut. Elevated TNF in the BM induce
the expression of chemokine ligands that attract Th17 cells to the BM. Once in the BM, Th17 cells release the
osteoclastogenic factor IL-17 which causes RANKL-mediated bone loss. In human populations, there is
significant heterogeneity in gut microbiome diversity, including considerable variation in the frequency of
presence of specific bacteria that activate Th17 cell maturation. We hypothesize that this heterogeneity directly
accounts for the heterogeneous nature of PHPT-associated bone loss within populations, where only patients
that are colonized with Th17 cell-inducing bacteria experience PHPT-induced bone loss. In support of this
hypothesis, we show compelling new data that the relative frequency of a specific strain of the Th17 cell-
inducing bacteria Bifidobacterium longum correlates inversely with bone density in PHPT patients. In Aim 1, we
will test if the propensity of human patients with PHPT to develop bone loss can be predicted by the
composition of the gut microbiome. Furthermore, to demonstrate causality, we will colonize germ-free mice
with either the microbiome of PHTP patients, or Bifidobacterium longum and determine if the PHPT-induced,
and gut bacterial-dependent bone loss phenotype is transferable within the microbiome. These studies will
demonstrate that stool microbiome sequencing may be used as a novel screen to predict which PHPT patients
develop bone loss. In addition, identification of the bacteria that endow PTH with the capacity to induce bone
loss will provide a rationale for future studies where targeted antimicrobial approaches aimed at eradicating
Th17 cell-inducing bacteria may be used to prevent bone loss in PHPT patients. In Aim 2, we will use a
powerful new photosensitive murine model where we can visualize the trafficking cells, to measure the effects
of PTH on the migration of TNF producing T cells, and Th17 cells from the gut to the BM. The identification of
the mechanisms of human microbiome-induced T cells migration from the gut to the BM will yield essential
data to inform novel strategies for preventing skeletal complications associated with PHPT, based on the use
of FDA approved agents that block the egress of T cells from the gut and/or their influx into the BM.
Terms: <(TNF)-α><Affect><Bacteria><Bifidobacterium><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><Bone Density><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Mineral Density><CCL20><CCL20 gene><CCR6><CCR6 gene><CKRL3><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Causality><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Locomotion><Cell Maturation><Cell Migration><Cell Movement><Cell secretion><Cells><Cellular Migration><Cellular Motility><Cellular Secretion><Chemokine Receptor-Like 3><Chemokine, CC Motif, Ligand 20><Chemotactic Cytokines><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><Data><Disease><Disorder><Endocrine Gland Secretion><Endowment><Etiology><Exodus 1><FDA approved><Feces><Fracture><Frequencies><Future><G Protein-Coupled Receptor 29><GI microbiome><GPR29><GPRCY4><Germ-Free><Heterogeneity><Homologous Chemotactic Cytokines><Hormones><Human><Human Microbiome><Hyperparathyroidism><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Inflammatory><Infusion><Infusion procedures><Intercrines><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><Intestinal><Intestinal Mucosa><Intestines><LARC><Lamina Propria><Ligands><MIP3A><Macrophage Inflammatory Protein 3-Alpha><Macrophage-Derived TNF><Measures><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Monocyte-Derived TNF><Murine><Mus><Nature><OPGL><Osteocytes><Osteoporosis><PTH gene><Parathyrin><Parathyroid><Parathyroid Head and Neck><Parathyroid Hormone><Parathyroid gland><Patients><Phenotype><Population><Process><Production><RANKL><Reporting><Reproduction spores><Role><SCYA20><SIS cytokines><STRL22><Small Inducible Cytokine Subfamily A, Member 20><Spores><Stream><Stromal Cells><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFSF11><TNFSF11 gene><TNFα><Testing><Therapeutic Hormone><Tissues><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Up-Regulation><Upregulation><Variant><Variation><Visualization><anti-microbial><antimicrobial><bio-markers><biologic marker><biomarker><bone><bone fracture><bone loss><bowel><causation><cell motility><cellular differentiation><chemoattractant cytokine><chemokine><commensal bacteria><commensal bacterial species><digestive tract microbiome><disease causation><enteral infection><enteric infection><enteric microbiome><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><experience><fecal microbial transplantation><fecal microbiome><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><fracture risk><gastrointestinal microbiome><gut microbiome><gut-associated microbiome><hRANKL2><human-associated microbiome><infected with enteropathogen><infusions><inhibitor><intestinal biome><intestinal infection><intestinal microbiome><intestine infection><microbial><microbiome><microbiome sequencing><migration><mouse model><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><parathormone><pathogen><prevent><preventing><sOdf><skeletal><social role><stool><stool microbiome><stool-associated microbiome><thymus derived lymphocyte><trafficking>