# Role of the gut microbiome in the bone loss induced by hyperparathyroidism in mice and humans

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $559,505

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10556397
- **Project number:** 5R01DK124821-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** JOHN P BILEZIKIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $559,505
- **Award type:** 5
- **Project period:** 2021-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556397

## Citation

> US National Institutes of Health, RePORTER application 10556397, Role of the gut microbiome in the bone loss induced by hyperparathyroidism in mice and humans (5R01DK124821-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10556397. Licensed CC0.

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