Healthy bones via the gut

Mystery - Stock.adobe.com

A growing body of scientific literature has been drawing connections between the health of the gut microbiome and other physiological systems, including brain, skin, and heart health. Emerging research is also pointing to the microbiome’s impact on bone health.

Bones are both structural and serve as a reservoir for minerals such as calcium and phosphorous. These minerals give the bones their “hardness,” while proteins such a collagen give bones “softness,” allowing them to sustain some mechanical pressure without breaking easily.¹ Cells called osteoblasts are responsible for bone formation by producing collagen, which serve as a scaffold for calcium and phosphorous to deposit into. Osteoclasts are cells that resorb bone, adhering to the bone to dissolve and release mineral deposits. In a healthy system, there is a constant interaction between osteoblasts and osteoclasts. However, when this homeostasis is disrupted, conditions such as osteopenia, characterized by lower-than-normal bone mineral density, or even osteoporosis can occur. This is typically caused by the over activation of osteoclasts, degrading more bone than osteoblasts can rebuild.

Bone mass naturally decreases with age, but bone health is influenced by a number of factors, including nutrition and physical activity. Another potential factor impacting bone mass, researchers are finding, is the microbial composition of the gastrointestinal tract. A dysbiotic gut microbiome has been associated with bone diseases such as osteoporosis. Research has shown that people with osteoporosis have a significantly higher microbiome diversity (in this case, not a good thing), characterized by an abundance of Firmicutes. Animal studies have shown that the administration of antibiotics to deplete the gut microbiome was found to restore bone mass.²

That said, a healthy functioning gut microbiome does beneficially impact bone health. For example, the microbiome is a source of vitamin K2, required for osteocalcin function and bone formation through the stimulation of osteoblasts. A different animal study also found that a decrease in vitamin K2 levels following antibiotic-induced microbiome depletion was associated with reduced osteocalcin and bone strength in mice.³ Additionally, while antibiotics may reduce the population of detrimental bacteria, they do the same for beneficial bacteria, such as butyrate producing bacteria, which is a short chain fatty acid (SCFA) associated with bone formation.⁴ For example, antibiotics can cause the depletion of Bacteroidetes. The reduced abundance of this bacteria is also associated with inflammatory bowel diseases and type 1 diabetes, which are populations that experience excessive bone loss.⁴

Mechanisms

The gut microbiome can influence bone remodeling both directly and indirectly. For example, the release of microbial metabolites such as SCFAs is one direct mechanism by which the microbiome influences bone remodeling, while indirectly, the gut microbiome can regulate bone remodeling through its interaction with immune cells such as T helper cells 17 or T regulatory cells, as well as hormones such as estrogen.⁴

SCFAs are produced through microbial fermentation of non-digestible dietary fibers. The production of some SCFAs is limited to specific bacterial strains. For example, researchers have linked the production of the SCFA propionate to Akkermansia muciniphila, Eubacterium dolichum, Ruminococcus bromii (R. bromii), Bacteroides eggerthii, Bacteroides fragilis, and Veillonella parvula. Butyrate producing bacteria belong to specific bacterial families, namely Clostridiaceae, Eubacteriaceae, Lachnospiraceae, and Ruminococcaceae. Propionate, butyrate, and acetate are SCFAs that have been demonstrated to increase bone mass through inhibiting the production of osteoclasts through a variety of distinct mechanisms.⁴

The gut interacts with the immune system via the intestinal epithelium. Inflammation in the gut can impact the secretion of immune cells. For example, it can result in the production of inflammatory immune phenotypes such as T-helper 17 cells, which produce the proinflammatory cytokines interleukin-17 (IL-17).1 The increase of T-helper 17 cells and IL-17 in bone marrow has been shown to promote bone degradation by stimulating the differentiation of osteoclasts in the bone marrow. On the other hand, T regulatory cells can have a beneficial impact on bone health because of their immunosuppressive functions. Evidence shows that certain microbes can regulate bone remodeling by changing the balance between T-helper 17 cells and T regulatory cells. T regulatory cells work by inhibiting osteoclastogenesis and promoting bone formation through the secretion of anti-inflammatory cytokines, such as IL-4, IL-10, and transforming growth factor-beta.

Human Research

A recently published study using two large human cohorts identified a potential link between specific bacteria and bone density/strength.5 In the study, researchers investigated the association between the gut microbiome and scans of radius and tibia of two large human cohorts using high resolution peripheral quantitative computed tomography. The cohorts were the Framingham Heart Study (FHS) with 1227 participants between the ages of 32 and 89, and the Osteoporosis in Men Study (MrOS), with 836 participants between the ages of 78 and 98. Results showed that there were 37 microbial genera in the FHA and 4 in the MrOS cohort whose abundance was associated with skeletal health measures.

Meta-analysis of the taxa-bone association found that greater abundance of Akkermansia and Clostridiales bacterium DTU089 were associated with lower radius volumetric bone mineral density (vBMD) and tibia cortical vBMD, respectively, while a higher abundance of Lachnospiraceae NK4A136 group, and Faecalibacterium was associated with greater tibia cortical vBMD. The researchers also observed that there was a great number of bacteria that were negatively associated with bone density but positively associated with bone size, which they speculate could indicate that certain microbes help promote the growth of bones at the expense of bone density as a person ages. While the study finds some interesting patterns, more research is necessary to draw any conclusions about the relationship between specific microbes and bone health. As the body of research grows, the relationship between the gut microbiome and bone health offers exciting new possibilities for product development.

References

1. Cooney, O.D.; Nagareddy, P.R.; Murphy, A.J.; Lee, M.K.S.Healthy Gut, Healthy Bones: Targeting the Gut Microbiome to Promote Bone Health. Front Endocrinol (Lausanne). 2020, 11, 620466. DOI: 10.3389/fendo.2020.620466

2. Pytlik, M.; Folwarczna, J.; Janiec, W. Effects of doxycycline on mechanical properties of bones in rats with ovariectomy-induced osteopenia. Calcif Tissue Int. 2004, 75 (3), DOI:10.1007/s00223-004-0097-x

. Guss, J.D.; Taylor, E.; Rouse, Z.; Roubert, S.; Higgins, C.H.; Thomas, C.J.; Baker, S.P.; Vashishth, D.; et al. The Microbial Metagenome and Bone Tissue Composition in Mice with Microbiome-Induced Reductions in Bone Strength. Bone. 2019, 127, 146-154. DOI: 10.1016/j.bone.2019.06.010

4. Lyu, Z.; Hu, Y.; Guo, Y.; Liu, D. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Nature. 2023, 11, 31. DOI: 10.1038/s41413-023-00264-x

5. Okoro, P.C.; Orwoll, E.S.; Huttenhower, C.; Morgan, X.; Kuntz, T.M.; McIver, L.J.; Dufour, A.B.; Bouxsein, M.L.A two-cohort study on the association between the gut microbiota and bone density, microarchitecture, and strength. Front. Endocriniol. 2023, 14. DOI:10.3389/fendo.2023.1237727