Bifidobacterium longum abundance links gut microbiome composition to bone loss in primary hyperparathyroidism by expanding TNF+ T cells and Th17 cells, and may predict patients' risk of skeletal complications.
Key Findings
Results
Microbiome transfers from primary hyperparathyroidism (PHPT) patients with osteoporosis to germ-free mice replicated the human bone loss phenotype.
The study enrolled 50 primary hyperparathyroidism patients.
Fecal microbiome transplants from PHPT patients with and without osteoporosis were transferred to germ-free mice.
The mouse recipients recapitulated the bone phenotype observed in their respective human donors.
This experimental design established a causal link between the gut microbiome and bone density variation in PHPT.
Results
Microbiome transfers from PHPT patients regulated TNF+ T cells and Th17 cells in recipient germ-free mice.
Germ-free mice receiving microbiomes from osteoporotic PHPT patients showed altered levels of TNF+ T cells and Th17 cells compared to controls.
These immune cell populations are known mediators of osteoclast-driven bone resorption.
The findings suggest the microbiome regulates immune-mediated bone loss in PHPT through these specific T cell subsets.
Results
Circulating TNF+ T cells, Th17 cells, and TNF/IL-17 production predicted bone density in PHPT patients.
Measurements of circulating TNF+ T cells and Th17 cells were performed in the 50 PHPT patients.
Levels of TNF and IL-17 production were associated with bone mineral density outcomes in these patients.
This finding aligns the human immune data with the mouse experimental results.
TNF+ T cells and Th17 cells were identified as mediators of bone loss in PHPT patients.
Results
Bifidobacterium longum was identified as a key microbial mediator of bone loss in PHPT patients.
Bifidobacterium longum abundance was associated with bone loss in the cohort of 50 PHPT patients.
Bifidobacterium longum was identified alongside TNF+ T cells and Th17 cells as mediators of bone loss.
Bifidobacterium longum abundance may determine the skeletal phenotypes of patients with primary hyperparathyroidism.
The authors propose that Bifidobacterium longum abundance could allow prediction of patients' risk of bone loss.
Results
Bifidobacterium longum supplementation in mice caused PTH to expand TNF+ T cells and Th17 cells and induce bone loss.
Mice supplemented with Bifidobacterium longum and exposed to PTH showed expansion of TNF+ T cells and Th17 cells.
This PTH-driven expansion of inflammatory T cells was associated with bone loss in the supplemented mice.
The experiment mechanistically linked Bifidobacterium longum to PTH-mediated skeletal pathology.
These findings support a model in which Bifidobacterium longum sensitizes the immune system to PTH-induced bone loss.
Discussion
The heterogeneity of bone loss severity in PHPT may be explained in part by differences in gut microbiome composition, particularly Bifidobacterium longum abundance.
PHPT causes mild-to-severe bone loss, and the reason for this heterogeneity was previously unclear.
The study investigated the microbiome as a factor explaining differential skeletal outcomes among PHPT patients.
Bifidobacterium longum abundance was proposed as a potential biomarker for predicting skeletal phenotype.
The authors suggest microbiome modifications by antibiotics or precision probiotics might offer novel preventive approaches for skeletal complications of PHPT.
What This Means
Primary hyperparathyroidism (PHPT) is a hormonal condition in which overactive parathyroid glands lead to bone loss, but some patients lose much more bone than others, and scientists have not fully understood why. This research suggests that the community of bacteria living in the gut—the gut microbiome—plays an important role in determining how severely a patient's bones are affected. By transplanting gut bacteria from PHPT patients with and without osteoporosis into germ-free mice (mice with no bacteria of their own), researchers showed that the human microbiome patterns were sufficient to reproduce the human bone loss patterns in the animals, pointing to a direct causal role for gut bacteria.
The study identified a specific bacterium, Bifidobacterium longum, as a key driver of bone loss in PHPT patients. Higher levels of this bacterium were associated with greater bone loss, and when mice were given Bifidobacterium longum supplements and then exposed to parathyroid hormone (PTH), they developed more inflammatory immune cells—specifically TNF+ T cells and Th17 cells—and experienced more bone loss. In PHPT patients themselves, levels of these same inflammatory immune cells and the molecules they produce (TNF and IL-17) were linked to lower bone density, suggesting these cells serve as a biological bridge between the gut microbiome and bone health.
This research suggests that measuring Bifidobacterium longum levels in the gut could potentially help identify which PHPT patients are at greatest risk for severe bone loss before it occurs. It also opens the door to new treatment strategies: rather than only targeting the parathyroid hormone itself, future approaches might include modifying the gut microbiome through targeted antibiotics or specially designed probiotic regimens to protect bones in PHPT patients.
Dar H, Fang J, Patil S, Roy N, Agarwal S, Weitzmann M, et al.. (2026). Bacterial specificity of the gut microbiome predicts bone density in primary hyperparathyroidism.. Bone research. https://doi.org/10.1038/s41413-026-00529-1