The Gut Microbiome-Bone Axis: An Emerging Frontier in Bone Health and Disease

The human gut microbiome has emerged as a key player in various physiological processes, including digestion, immunity, and mental health. Recent research highlights its role in skeletal health, forming a dynamic interconnection termed the gut microbiome-bone axis. This bidirectional relationship suggests that the gut microbiota influences bone homeostasis through complex biochemical and immunological pathways.

In this review, we explore recent findings on the gut microbiome’s impact on bone metabolism, the role of short-chain fatty acids (SCFAs), bile acids, and microbial metabolites, and how gut dysbiosis contributes to bone diseases such as osteoporosis and osteoarthritis. We also examine potential therapeutic strategies targeting the gut microbiome to improve bone health.

1. The Gut Microbiome and Bone Metabolism

1.1 The Link Between the Gut and Bone
The gut microbiota influences bone health through multiple mechanisms, including:

• Nutrient Absorption: Microbial fermentation enhances the bioavailability of key minerals like calcium and magnesium, essential for bone strength (Yu et al., 2025).
• Immune Modulation: The gut microbiome regulates immune responses, thereby influencing bone remodeling through inflammatory mediators such as cytokines (Jha et al., 2025).
• Hormonal Influence: The gut microbiota affects the secretion of serotonin and parathyroid hormone (PTH), which regulate bone metabolism (Feng et al., 2024).

1.2 Short-Chain Fatty Acids and Bone Health
SCFAs—primarily acetate, propionate, and butyrate—are fermentation byproducts of dietary fiber that modulate bone metabolism. Butyrate, in particular, has been shown to:

• Enhance osteoblast activity and suppress osteoclast differentiation (Feng et al., 2024).
• Regulate gut permeability, preventing systemic inflammation that accelerates bone loss.
• Improve calcium absorption in the intestines, thus increasing bone mineral density.

1.3 Bile Acids and Bone
Recent studies show that bile acids, produced in the liver and metabolized by gut bacteria, influence bone metabolism by modulating the farnesoid X receptor (FXR). Dysregulation of bile acid metabolism has been linked to osteopenia and osteoporosis (Yu et al., 2025).

2. The Role of Gut Dysbiosis in Bone Diseases

2.1 Osteoporosis and Gut Microbiome Imbalance
Osteoporosis is a bone disorder characterized by decreased bone mass and increased fracture risk. Recent research highlights the role of gut dysbiosis in osteoporosis pathogenesis. Disruptions in microbial diversity lead to:

• Increased gut permeability, allowing inflammatory mediators to reach bone tissues.
• Altered SCFA production, reducing bone anabolic activity.
• Dysregulated immune responses, leading to chronic low-grade inflammation and bone loss (Jha et al., 2025; Ticinesi et al., 2024).

2.2 Osteoarthritis and Microbiome Involvement
Beyond osteoporosis, the gut microbiome has been implicated in osteoarthritis (OA). The microbiome influences OA progression by modulating:

• Inflammatory pathways, particularly IL-6 and TNF-α, contribute to cartilage degradation (Meléndez-Oliva et al., 2025).
• Oxidative stress and mitochondrial dysfunction, leading to impaired chondrocyte function.
• Gut permeability, allowing microbial metabolites to enter circulation and exacerbate joint inflammation.

3. Experimental and Clinical Evidence

3.1 Animal Studies

Animal models have provided robust evidence for the gut-bone axis:

• Exercise and Microbiome Interaction: Studies on mice show that exercise-induced bone protection is partly mediated by gut microbiota and bile acid metabolism (Yu et al., 2025).
• Antibiotic-Induced Bone Loss: Antibiotic-induced gut dysbiosis results in reduced bone mass, reinforcing the role of microbial diversity in skeletal health (Villarreal & Chan, 2025).
• Microbiota Transplantation: Fecal microbiota transplantation (FMT) from healthy donors to osteoporotic mice has been shown to reverse bone loss, suggesting a causal relationship between gut bacteria and bone density (Zheng et al., 2025).

3.2 Human Studies

• Gut Microbiota in Postmenopausal Osteoporosis: Studies indicate that postmenopausal women with osteoporosis exhibit distinct microbial signatures, with decreased SCFA-producing bacteria and increased pro-inflammatory taxa (Ticinesi et al., 2024).
• Probiotics for Bone Health: Clinical trials have demonstrated that probiotic supplementation, particularly Lactobacillus rhamnosus GG, improves bone mineral density and reduces inflammatory markers in osteoporotic individuals (Mehvish et al., 2025).

4. Targeting the Gut Microbiome for Bone Health

Given its pivotal role in bone metabolism, the gut microbiome is emerging as a therapeutic target for skeletal diseases. Several interventions show promise:

4.1 Probiotics and Prebiotics

• Probiotics (Live beneficial bacteria): Lactobacillus and Bifidobacterium strains have been shown to enhance bone mineralization and reduce inflammation.
• Prebiotics (Fibers that nourish beneficial bacteria): Inulin and resistant starch improve SCFA production, indirectly benefiting bone health.
   

4.2 Dietary Modifications

• High-fiber diets rich in plant-based foods support SCFA production, essential for gut and bone health.
• Fermented foods (yogurt, kimchi, kefir) enhance gut microbial diversity.
   

4.3 Fecal Microbiota Transplantation (FMT)
FMT has been explored as an intervention for osteoporosis. By transplanting gut microbiota from healthy individuals, researchers have observed improvements in bone density and reductions in inflammatory markers in osteoporotic patients (Zheng et al., 2025).

4.4 Pharmacological Approaches

• SCFA-based therapies: Synthetic SCFA analogs are being tested as potential bone-preserving agents.
• Microbiome-targeting drugs: Agents that modulate gut permeability and reduce inflammation may be osteoporosis treatments (Chen et al., 2024).

5. Future Directions and Challenges

Despite promising findings, several challenges remain:

1. Individual Variability: The gut microbiome varies significantly among individuals, complicating generalized treatment strategies.
2. Causal Mechanisms: More research is needed to establish causality rather than correlation in the gut-bone relationship.
3. Long-Term Effects of Interventions: While probiotics and FMT show promise, their long-term safety and efficacy remain unclear.

Future research should focus on:

• Personalized microbiome-based therapies, tailored to an individual’s gut microbial composition.
• Large-scale clinical trials, to validate microbiome-targeted interventions for osteoporosis and osteoarthritis.
• Exploring the gut-bone-brain axis, as emerging evidence suggests that neurohormonal pathways link gut microbiota, bone metabolism, and cognitive function.

Conclusion

The gut microbiome-bone axis represents a novel paradigm in skeletal health, offering exciting disease prevention and treatment possibilities. Gut microbes play a fundamental role in maintaining bone integrity by influencing nutrient absorption, immune regulation, and hormonal pathways. Emerging research highlights the potential of microbiome-based interventions, such as probiotics, prebiotics, dietary changes, and FMT, in treating osteoporosis and related disorders.

As we advance in our understanding, integrating microbiome science with precision medicine could revolutionize osteoporosis and osteoarthritis management, ultimately improving the quality of life for millions worldwide.

References

1. Jha, S.S., Jeyaraman, N., & Jeyaraman, M. (2025). Cross-talks between osteoporosis and gut microbiome. ResearchGate.
2. Feng, B., Lu, J., Han, Y., et al. (2024). The role of short-chain fatty acids in the regulation of osteoporosis: A review. LWW Journal.
3. Yu, C., Sun, R., Yang, W., et al. (2025). Exercise ameliorates osteopenia in mice via gut microbiota. NIH.
4. Ticinesi, A., Siniscalchi, C., Meschi, T., et al. (2024). Gut microbiome and bone health. Springer.