Estrogen Deficiency

Beyond Estrogen Deficiency: The Role of Gut Microbiota in Postmenopausal Bone Loss

Published On: January 13, 2025Categories: PLMI Blog

A recent 2024 study published in Frontiers in Endocrinology by Wang et al. provides compelling evidence of the profound and complex relationship between the gut microbiome and osteoporosis in postmenopausal women, underscoring novel and impactful insights for addressing this prevalent condition (1).

Overview of Postmenopausal Osteoporosis

Postmenopausal osteoporosis (PMOP) is a systemic, widespread bone disorder that affects a significant portion of women following menopause, often as a result of marked reductions in estrogen. Estrogen plays a crucial role in governing healthy bone metabolism and maintaining bone density, with deficits resulting in imbalances in bone production and degradation. Bone remodeling is present, where the body isn’t producing bone at the same rate at which it is losing it.

PMOP is characterized by diminished bone mass, deterioration of bone microarchitecture, increased bone fragility, and risk of fractures. In fact, globally at least one-third of women have experienced a fracture as a result of postmenopausal osteoporosis (1). While this condition is indeed associated with reduced estrogen levels, the novel findings presented in this study emphasize the significance of beneficial gut microbiota in also influencing and modulating bone metabolism, through a number of interconnected mechanisms that have roles rooted in its etiology.

The Interplay Between Gut Microbiota & Bone Health

A healthy host-gut microbiome balance is essential for modulating vast, integral processes in the body, necessary for metabolic, nervous, immune, and hormonal functions (2). This diverse ecosystem (the gut microbiome) inhabits more than 100 trillion microorganisms, with 1000 diverse species, encoding an estimated five million genes (3-4). In addition to its roles in digestion and nutrient absorption, the gut microbiome has been demonstrated to exert profound influence on bone health through various processes—including immune, metabolic, and hormone modulation—all of which influence bone metabolism (5-6).

The findings of this primary study demonstrate the profound influence gut microbiota have in governing the immune system and endocrine functions, which in turn affect bone metabolism and bone density (1). The microbiota’s ability to influence immune function appears to be especially important in governing healthy bone turnover. This research suggests that the immune system can modulate the activity of osteoclasts and osteoblasts, the cells responsible for bone resorption (or degradation) and formation, respectively (4). Results also demonstrate the significant roles beneficial microbiota have in hormone secretion and modulation, as well as the regulation of metabolism and systemic inflammation—factors that also greatly influence bone health.

Disruptions in host gut-microbiota homeostasis can, therefore, impede these processes, compromising bone health and metabolism. This research provides novel and encouraging strategies to address and reduce postmenopausal osteoporosis (PMOP) by favorably influencing microbiome health (1).

Findings from Germ-Free Mice & Bone Density

Research on germ-free mouse models, which lack gut microbiota, provides valuable insights into the role of microbiota in governing bone health. These studies demonstrated that germ-free mice exhibited increased bone density, suggesting that the presence of gut microbiota plays a crucial role in modulating homeostasis between the activity of cells that degrade bone tissue and those that form tissue. These findings further underscore the role of the microbiota in regulating bone metabolism (6).

Gut Microbiota Influence Bone Metabolism Via Multiple Mechanisms

Further research echoes how the gut microbiota influences bone health through these vast interrelated mechanisms, including modulation of host metabolism, appropriate immune response, and hormone secretion relative to bone remodeling (7). These findings also include the microbiome’s impact on nutrient absorption, the gut-brain axis, and its immunomodulatory effects on the balance between osteoblasts and osteoclasts (1, 8). A healthy, diverse microbiome is important for modulating homeostasis among these bone-forming and bone-resorbing cells, necessary for sufficient bone metabolism.

Gut microbiota are demonstrated to modulate the immune system of the host by influencing bile acid metabolism, particularly through the regulation of colonic FOXP3+ regulatory T cells, integral for regulating overall metabolism and immunity (10). Beneficial gut microbiota are also shown to secrete short-chain fatty acids, including butyrate and propionate, with integral anti-inflammatory properties. Further metabolites produced by gut microbiota enhance bone density by modulating hormone secretion and balance, as well as influencing calcium absorption. Microbiota also have roles in synthesizing Vitamin K and biotin, which are integral for governing bone metabolism.

A balanced and diversified microbiome further supports immune balance via tryptophan metabolism. Tryptophan and its metabolites, including indole and serotonin, promote modulation of intestinal immunity and govern microbiota balance—functions necessary for regulating bone metabolism (11). Beneficial microbes have also been demonstrated to support gut barrier function and reduce systemic inflammation. These findings underscore the role microbes have in governing systemic balance and bone health (1, 5). The absence of beneficial strains of microbiota was found to disrupt bone resorption and formation, through interactions with the immune system (1, 9).

Metabolic and Hormonal Pathways

The gut microbiota’s impact on bone health extends beyond immune modulation, with findings revealing its influence through metabolic pathways, particularly through bile acid metabolism and the gut-bone axis. The gut-bone axis—the interplay between the gut microbiome and bone health—modulates bone metabolism by influencing the secretion of hormones and metabolites that can affect bone cell activity, nutrient absorption, and bone remodeling. It serves a communication pathway among microbes and bone tissue through nervous, immune, metabolic, and hormonal processes.

The gut microbiome, therefore, also drives bone physiology through the modulation of integral hormones and metabolites. These processes support homeostasis of healthy immune responses and hormonal signaling that influence bone formation and resorption, including the secretion of estrogen and insulin-like growth factor 1 (8-9).

Burkholderia & Other Microbial Species Influence Bone Cell Activity

A remarkable finding in this primary study is the role of the Burkholderia genus in supporting bone metabolism. This microbial strain has been associated with improved measures of bone health, including the activation of bone-forming cells. An increased abundance of this microbial strain demonstrated a protective effect against osteoporosis, reducing risk. Bacillales was also shown to be associated with a decreased risk of developing this condition. Whereas microbial species of the Lactobacillales order, Allisonella genus, and Eubacterium xylanophilum group demonstrated positive correlations with osteoporosis. The Inverse Variance Weighted (IVW) method further revealed significant associations between these microbial species and bone cell activity, underscoring the microbiome’s complex role in bone metabolism (12).

Exploration of Key Genes Linked to Bone Health

In addition to identifying specific microbial species, the study also highlighted the role of genes in mediating the relationship between gut microbiota and bone health. The study employed Mendelian Randomization (MR) to explore the causal relationship between gut microbiota and PMOP, providing further evidence in support of these findings (11). By utilizing the random allocation of genetic variants, MR helps reduce confounding and reverse causation factors, enabling stronger causal inferences (12). In the context of PMOP, Mendelian Randomization provided insight into how specific microbiota species influence osteoclast activity and bone density, utilizing data from large-scale Genome-Wide Association Studies (1, 13).

Through Mendelian randomization and gene analysis, four key genes—EPT1, FMNL2, SRBD1, and RGPD6—were found to influence the relationship among gut microbiota and PMOP, with EPT1 and FMNL2 demonstrating a positive correlation with osteoporosis risk, while SRBD1 suggested a protective effect. Further validation using single-cell data revealed that FMNL2 and SRBD1 were predominantly expressed in osteoclasts, supporting their role in bone metabolism, whereas EPT1 was not detected in these clusters, suggesting it may not directly influence osteoclast function.

Overall, analysis from this research revealed FMNL2 and SRBD1 as having pivotal roles in bone metabolism. Beneficial gut microbiota modulate expression of these genes, thereby influencing bone health.

The Significance of the Gut Microbiome Composition

This study offers novel and compelling insights into the intricate relationship between gut microbiota and postmenopausal osteoporosis, presenting encouraging strategies for intervention. These findings demonstrate the pivotal role the gut microbiota have in regulating bone metabolism, with specific microbial groups, such as Burkholderiales, offering notably protective benefits. Furthermore, key genes including FMNL2 and SRBD1, were revealed as having significant roles in influencing osteoclast regulation, offering targeted microbiota-based treatments for osteoporosis.

The findings by Wang et al. 2024 enhance our understanding of the gut-bone axis by demonstrating how specific gut microbiota can influence bone health, particularly postmenopausal osteoporosis (PMOP), through their effects on modulating bone cell activity (1). The findings of this study demonstrated that microbial communities, including Lactobacillales, Allisonella, and Eubacterium xylanophilum may be associated with increased risk of osteoporosis, while Burkholderiales and Bacillales were associated with reduced risk.

This suggests that beneficial microbiome composition has protective roles against bone loss by influencing bone metabolism through modulation of immune functions, inflammation, and hormone secretion regulation. These findings underscore the complex relationship between gut microbiota and bone health, offering new insights into how improving microbial composition may support reducing osteoporosis risk and maintaining bone health (1).

The Gut Microbiome as a Therapeutic Target for Osteoporosis

This study provides compelling evidence that specific gut microbiota can influence bone health, particularly in postmenopausal osteoporosis. These findings highlight the significant role of microbial communities in modulating bone cell activity and influencing bone remodeling. Of note, the Burkholderiales species appears to be especially protective against bone loss, providing insight into how gut microbiota composition can be positively influenced to improve health. The connection between microbiota’s influence on expressing notably impactful genes for bone health is also remarkable.

These results underscore the importance of addressing osteoporosis from a whole-body systems approach.  Following a balanced nutrient dense, anti-inflammatory diet, with an abundance of plants and sufficient amounts of pre and probiotics, supports the diversity of the microbiome, as well as bone health, through a number of intricate mechanisms. Synbiotics are also emerging as a novel approach for improving bone metabolism.

While nutrition is pivotal, adequate sleep, regular exercise, and reducing stress are also incredibly impactful for modulating gut microbiome composition, as well as the gut-bone axis. These lifestyle factors help to regulate metabolic, immune, neural, and hormonal processes- having vast implications for supporting bone metabolism. In fact, sleep has a bidirectional effect on the microbiome, underscoring its foundational role (14).

Join our webinar, Enhancing Bone Health: Exploring the Role of Synbiotic Therapy, on January 14th at 5:00 pm PST, with experts Susan Bukata, MD, Eric Schott, PhD, and Jeff Bland, PhD as they dive further into the emerging research findings on this compelling and relevant topic. Novel and targeted strategies for reducing bone loss, such as synbiotics, will be explored with a focus on supporting the gut-bone axis.

References:

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