Gut microbiome and orthopaedic health: Bridging the divide between digestion and bone integrity

Abstract

The gut microbiome, a complex ecosystem of microorganisms in the digestive tract, has emerged as a critical factor in human health, influencing metabolic, immune, and neurological functions. This review explores the connection between the gut microbiome and orthopedic health, examining how gut microbes impact bone density, joint integrity, and skeletal health. It highlights mechanisms linking gut dysbiosis to inflammation in conditions such as rheumatoid arthritis and osteoarthritis, suggesting microbiome modulation as a potential therapeutic strategy. Key findings include the microbiome’s role in bone metabolism through hormone regulation and production of short-chain fatty acids, crucial for mineral absorption. The review also considers the effects of diet, probiotics, and fecal microbiota transplantation on gut microbiome composition and their implications for orthopedic health. While promising, challenges in translating microbiome research into clinical practice persist, necessitating further exploration and ethical consideration of microbiome-based therapies. This interdisciplinary research aims to link digestive health with musculoskeletal integrity, offering new insights into the prevention and management of bone and joint diseases.

Key Words: Gut microbiome; Orthopaedic health; Bone density; Dysbiosis; Inflammation; Microbiome modulation

Core Tip: The gut microbiome plays a crucial role in orthopaedic health by influencing bone density, joint integrity, and inflammation. Modulating the microbiome through diet, probiotics, and other interventions offers promising therapeutic strategies for preventing and managing musculoskeletal disorders. Understanding the gut-bone axis could revolutionize orthopaedic care, leading to more personalized and effective treatments for bone and joint diseases.

INTRODUCTION

The human gut microbiome, a complex community of microorganisms living in the digestive tract, has emerged as a significant area of study for understanding human health. The foundational understanding of the gut microbiome’s importance has its roots in early 21^st century research, which began to unravel the complex interactions between these microorganisms and their human hosts. The landmark study by Turnbaugh et al[1] in 2006 showcased the gut microbiome’s vital role in health, particularly its influence on metabolism and obesity, marking a pivotal shift in scientific focus towards the microbiome’s impact on various health outcomes, including metabolic and autoimmune diseases. Further supporting this, the Human Microbiome Project, launched by the National Institutes of Health in 2007, aimed to characterize microbial communities at various body sites, including the gut, and to analyze their role in human health and disease[2]. This vast influence of gut microbiome in health-promoting and disease-modulating activities opens a new niche to explore its connection to orthopaedic health, offering potential insights into the prevention and treatment of bone and joint diseases. The evidence of gut microbiome composition affecting bone mass, points to a significant interplay between gut microbial communities and skeletal health[3]. Additionally, research by Collins et al[4] in 2017 indicates that modifications in the gut microbiome can mitigate inflammation and bone degradation in arthritis, suggesting that manipulating the gut microbiome could offer novel therapeutic strategies for orthopaedic conditions. These findings underscore the gut microbiome’s role in orthopaedic health, opening avenues for research and treatment that could transcend traditional approaches to bone and joint disorders.

Hence this research initiative aimed at elucidating the complex interactions between the gut microbiome and orthopaedic health will examine four key mechanistic pathways through which the gut microbiome influences skeletal health: (1) The regulation of calcium homeostasis and bone mineral density through bacterial metabolite production, particularly short-chain fatty acids (SCFAs); (2) The modulation of immune responses affecting osteoclast and osteoblast activity; (3) The influence of gut microbial communities on systemic inflammation through lipopolysaccharide production and its impact on bone metabolism; and (4) The gut-bone axis signaling through neuroendocrine pathways, specifically focusing on serotonin production and its effects on bone formation. This comprehensive mechanistic analysis aims to transform the prevention and management of various orthopaedic conditions. This systematic exploration opens new avenues for therapeutic interventions that leverage the gut microbiome to enhance bone health and orthopaedic outcomes, and provides a holistic approach to treating and understanding bone-related diseases. The detailed examination of these mechanisms will facilitate the development of targeted interventions, ranging from specific probiotic strains to dietary modifications, that can optimize bone health through microbiome modulation.

THE GUT MICROBIOME: AN OVERVIEW

The composition and diversity of the gut microbiome are complex and variable, reflecting the influence of genetic, dietary, and environmental factors[5,6]. This rich ecosystem is predominantly composed of bacteria from the phyla Firmicutes and Bacteroidetes, although it also includes organisms from the Actinobacteria, Proteobacteria, and Verrucomicrobia phyla, among others[7,8]. The diversity within an individual’s gut microbiome is a critical indicator of health, as a higher microbial diversity is often associated with improved health outcomes. The fundamental role of the microbiome revolves around metabolism, immunology, and neurology. This complex community of microorganisms helps in the breakdown of dietary fibers, synthesis of essential vitamins, and production of SCFAs that are crucial for gut health[9,10]. It helps in the fermentation of non-digestible fibers, SCFAs that regulate energy homeostasis and insulin sensitivity. The microbiome’s composition has been linked to varying responses to diet, suggesting a role in metabolic diseases including diabetes[11-13]. It educates the immune system to distinguish between pathogens and non-harmful antigens, thereby preventing excessive inflammatory responses that could lead to autoimmune diseases[14,15]. The microbiome also enhances resistance to infections by outcompeting pathogenic bacteria for nutrients and attachment sites[16-18]. Neurologically, through the gut-brain axis, the microbiome influences brain function and behavior[19]. It affects the central nervous system by producing neurotransmitters and modulating the immune response, which can impact mood and cognitive functions[20]. This connection has opened new research avenues for treating psychiatric and neurological disorders through microbiome modulation[21,22].

Beyond its established roles in metabolism, immunity, and neurology, the gut microbiome significantly influences various other aspects of human health, revealing its extensive systemic impact. The gut-skin axis, for instance, links gut microbial imbalances to skin disorders like acne and psoriasis, suggesting the microbiome’s role in systemic inflammation affects dermatological health[23-25]. Cardiovascular health is also impacted by the microbiome’s ability to metabolize dietary components into compounds such as trimethylamine N-oxide, which is associated with an increased risk of cardiovascular diseases[26,27]. Additionally, the microbiome aids in detoxifying harmful substances and drugs, affecting drug efficacy and reducing toxicity[28]. It plays a role in hormonal regulation, influencing stress responses, metabolic processes, and even reproductive health by modulating hormone levels such as estrogen through the secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms[29,30]. Recent research points to the microbiome’s contribution to aging and longevity, with a balanced microbiome associated with healthy aging and reduced incidence of age-related diseases[31,32]. Moreover, it may influence exercise performance and recovery, suggesting microbial profiles could be optimized for enhanced athletic performance[18]. Technological advancements in meta-omics approaches have enabled more detailed analysis and understanding of host-microbiome interactions. Integrating data from metagenomics, metatranscriptomics, and metaproteomics provides insights into the microbial functions and their interactions with the host, enhancing our understanding of their contributions to health and disease[33]. These multifaceted roles underscore the gut microbiome’s broad influence on health and disease, highlighting its potential as a target for interventions aimed at improving a wide range of health outcomes.

MECHANISMS LINKING GUT MICROBIOME TO ORTHOPAEDIC HEALTH

Inflammatory pathways play a pivotal role in the pathogenesis and progression of various orthopaedic conditions, such as osteoarthritis (OA) and rheumatoid arthritis (RA), mediating both pain and tissue degradation. Central to these pathways is the activation of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, which are key drivers of inflammation and joint destruction[34,35]. The gut microbiome’s role in inflammatory orthopaedic conditions, such as RA and OA, is garnering increasing attention for its potential to influence disease onset, progression, and response to treatment. Recent studies suggest that dysbiosis, or imbalances in the gut microbial community, can contribute to systemic inflammation, thereby exacerbating joint inflammation and degradation[36]. Particular bacteria might drive inflammation or, conversely, offer protective effects[36,37]. The gut microbiome plays a significant role in maintaining hormonal balance and influencing bone density, showcasing its far-reaching impact on overall health beyond the digestive system as shown in Figure 1. Emerging research indicates that the microbiome interacts with the endocrine system to regulate hormones that are crucial for bone metabolism, including estrogen. Specific gut bacterial strains can metabolize phytoestrogens into equol, a nonsteroidal estrogen that has been linked to improved bone density. This interaction suggests that the gut microbiome could influence the risk of osteoporosis and other bone-related conditions, especially in postmenopausal women, who are particularly susceptible to bone density loss due to decreased estrogen levels[38,39]. This complex community of microorganisms aids in the breakdown of dietary fibers, resistant starches, and other complex carbohydrates that human enzymes cannot digest, converting them into absorbable nutrients and beneficial compounds including SCFAs and butyrates, propionate, and acetate, that are not only a vital energy source for colon cells but also facilitate the absorption of minerals like calcium, magnesium, and iron, which are essential for various bodily functions, including bone health and oxygen transport. It also plays a role in synthesizing vitamins, such as vitamin K and certain B vitamins, which are crucial for blood clotting, energy production, and DNA synthesis[40].

Figure 1  Mechanisms of bone homeostasis as maintained by a healthy microbiome.

CLINICAL EVIDENCE OF GUT MICROBIOME INFLUENCE ON ORTHOPAEDIC CONDITIONS

The gut microbiome’s influence on orthopaedic conditions highlights the intricate interplay between systemic inflammation and musculoskeletal health. In RA, for instance, dysbiosis has been identified as a contributing factor to disease pathogenesis, an overrepresentation of Prevotella copri in affected individuals, suggesting a potential trigger for autoimmune responses leading to joint inflammation and degeneration as shown in Figure 2. Similar microbial patterns have been noted in OA, where it is demonstrated that gut microbiome alterations could influence the disease’s progression by modulating systemic and local inflammation. Furthermore, the microbiome’s impact extends to bone health, illustrating how microbiota-derived metabolites influence bone density and remodeling, thereby affecting conditions like osteoporosis as shown in Figure 3. These insights not only underscore the gut microbiome’s role in the development and exacerbation of various orthopaedic conditions but also opens new avenues for therapeutic interventions aimed at modulating the gut microbiome to improve the musculoskeletal health and mitigate disease. Dysbiosis as a source of pathogenesis and treatment modality offers promises in treating these conditions as summarised in the Table 1. Additionally, the impact of the gut microbiome on chronic constriction injury-induced neuropathic pain has been confirmed, with findings indicating that antibiotic pretreatment can reproduce the protective effect of gut microbiome depletion. This effect is correlated with changes in intestinal SCFAs acid concentrations, microglia activation, and inflammatory cytokine concentrations in both the spinal cord and the hippocampus[41].

Figure 2 Dysbiosis as a source of inflammation and degeneration through the established gut-bone axis. IFN: Interferon; Ig: Immunoglobulin; IL: Interleukin; MMP: Matrix metalloproteinase; RANKL: Receptor activator of nuclear factor kappa ligand; Th: T-helper; TNF: Tumor necrosis factor.

Figure 3 Mechanism of healthy and dysbiotic microbiome resulting in osteogenesis and osteoclastogenesis respectively. 1 representing transforming growth factor-beta from the healthy microbiome promotes proliferation and early differentiation of bone marrow-derived mesenchymal stromal cells and matrix production. 2 representing interleukin-10 from the healthy microbiome inhibits differentiation and maturation of osteoclasts through upregulation of osteoprotegerin. 3 representing tumor necrosis factor-α from the T cells of dysbiotic microbiome results in the secretion of chemokines by bone marrow-derived mesenchymal stromal cells that increases the recruitment of monocytes into the bone marrow. 4 representing active differentiation of the monocytes into osteoclasts resulting in enhanced bone resorption and osteoclastogenesis. LPS: Lipopolysaccharide; Ig: Immunoglobulin; IL: Interleukin; BM-MSCs: Bone marrow-derived mesenchymal stromal cells; TNF: Tumor necrosis factor; TGF-β: Transforming growth factor-beta; OC: Osteoclast.

Table 1 Role of gut microbiome in various orthopaedic conditions.

Ref.	Orthopedic condition	Key findings on microbiome composition	Significance
Scher et al[36], 2013	Rheumatic arthritis	Increased abundance of prevotella copri	Influence in triggering autoimmunity
Manasson et al[58], 2018	Spondyloarthritis	Enrichment of the family Lachnospiraceae and associated genera such as Blautia, Coprococcus, Roseburia, along with the genus Collinsella	Dysbiosis as one of the reasons for pathogenesis of the disease
Collins et al[4], 2017	Post menopausal osteoporosis	Lactobacillus, Enterococcus, Bacillus, Escherichia, and Bifidobacterium	Improvement in condition by supplementation
Ramires et al[59], 2022	Osteoarthritis	Lower proportion of Bacteroidetes and higher Firmicutes bacterial populations	Correlation between microbiome and bone mass
Le et al[60], 2023	Osteosarcoma	Family Lachnospiraceae had the second strongest negative net average change and Firmicutes/Bacteroidota ratio alteration	Interplay between the gut microbiome and osteosarcoma

This table summarizes the existing studies investigating the gut microbiome composition in patients with different orthopaedic conditions and their association. Each entry provides a concise overview of the orthopaedic condition focus, key microbiome findings, and the main conclusion drawn by the author.

DIET, PROBIOTICS, AND ORTHOPAEDIC HEALTH

Interventions that alter the gut microbiome are diverse, targeting various aspects of microbial composition and activity to influence health outcomes. These interventions can be broadly categorized into dietary modifications, probiotic and prebiotic supplementation, antibiotic treatments, and faecal microbiota transplantation (FMT), each with distinct mechanisms of action and implications for health. Diet plays a critical role in shaping the composition and functionality of the gut microbiome, with profound implications for health and disease. Dietary patterns, particularly the intake of fiber-rich foods, prebiotics, and fermented products, can significantly influence microbial diversity and abundance. High-fiber diets, for example, promote the growth of beneficial bacteria such as Bacteroidetes and Firmicutes, which are adept at fermenting dietary fibers into SCFAs, compounds known for their anti-inflammatory properties and beneficial effects on gut barrier integrity[42]. Conversely, diets high in saturated fats and processed foods can lead to reduced microbial diversity and an increase in pathogenic bacteria[43]. The Mediterranean diet has been highlighted for its positive impact on gut microbiota diversity, potentially offering protective effects against inflammatory diseases and contributing to overall health[44].

Prebiotics and probiotics represent targeted interventions aimed at improving gut health through the modulation of the gut microbiome. Prebiotics, nondigestible food components such as inulin and fructooligosaccharides, serve as fuel for beneficial gut bacteria, promoting their growth and activity. Probiotics, on the other hand, are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. The consumption of probiotics has been associated with a range of health benefits, including improved digestive health, enhanced immune function, and a reduced risk of certain infections. Clinical trials and meta-analyses have supported the use of specific probiotic strains for the treatment and prevention of gastrointestinal disorders, underscoring the potential of probiotic’s use as a therapeutic tool for gut health[45,46]. FMT is a more direct approach to altering the gut microbiome, involving the transfer of stool from a healthy donor to a recipient with a dysbiotic gut microbiome. FMT has been primarily used in the treatment of recurrent Clostridium difficile infection, with a high success rate. The procedure has also been explored as a potential treatment for other conditions associated with gut microbiome dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome. While the mechanisms by which FMT exerts its effects are not fully understood, it is believed to restore microbial diversity and functionality, thereby re-establishing a healthy gut ecosystem. Ongoing research and clinical trials continue to investigate the safety, efficacy, and long-term outcomes of FMT for various other indications[47,48].

While antibiotics are essential for treating bacterial infections, their indiscriminate use can disrupt the gut microbiome, leading to a decrease in microbial diversity and the proliferation of resistant strains. Therefore, the use of antibiotics represents a double-edged sword, with significant implications for microbiome health. Targeted antibiotic therapies that minimize the impact on the microbiome, along with post-antibiotic interventions to restore microbial balance, are critical areas of research. These interventions, which include dietary changes, prebiotics and probiotics supplementation, FMT, and usage of antibiotics, represent promising strategies for the modulation of the gut microbiome. By leveraging the complex interplay between diet, microbial inhabitants of the gut, and overall health, these approaches offer potential pathways to treat and prevent a wide range of diseases, highlighting the importance of the gut microbiome in human health and disease[47].

CHALLENGES AND CONSIDERATIONS IN MICROBIOME RESEARCH

Researching the gut microbiome presents a unique set of challenges that stem from its complex nature and the intricate interplay between microbial communities and host health. One of the primary challenges is the vast diversity and variability of the gut microbiome across individuals, which can be influenced by a myriad of factors including diet, genetics, age, and environment. This variability makes it difficult to establish universal gut microbiome profiles associated with health or disease states. This dynamic nature of the microbiome, emphasizes the need for large-scale studies to capture this diversity and understand the implications for human health[49]. The identification of causal relationships between specific microbial communities and health outcomes is further complicated by this variability, requiring sophisticated analytical tools and methodologies. Another significant challenge is distinguishing between correlation and causation in microbiome studies. Many studies have identified associations between certain microbial patterns and health conditions but proving that these microbes directly cause or contribute to these conditions is far more complex. This difficulty is due in part to the challenge of replicating human microbiome complexity in animal models, which are often used to test causality. While animal models, particularly germ-free mice, offer invaluable insights into the microbiome’s role in health and disease, they cannot fully replicate the complexity and diversity of the human gut microbiome[50]. This limitation underscores the need for innovative experimental designs and methodologies that can more accurately mimic human microbial ecosystems.

Technological and methodological limitations also pose significant challenges to microbiome research. High-throughput sequencing technologies, such as 16S rRNA gene sequencing and whole-genome shotgun sequencing, have revolutionized our understanding of the gut microbiome. However, these technologies have limitations, including biases introduced during DNA extraction and amplification, as well as challenges in accurately annotating and interpreting the vast amounts of data generated. Improving bioinformatic tools and databases is crucial for overcoming these challenges, enabling more accurate identification and characterization of microbial species and their functional potential[51]. While shotgun metagenomics identifies a broader spectrum of species, it tends to yield fewer taxa at the family and genus levels compared to 16S rRNA sequencing. Conversely, 16S rRNA sequencing offers higher within-sample diversity specifically at the genus level. Each method comes with its own set of advantages and limitations, and the selection between them hinges on the specific research inquiry and the resources accessible for the study[52]. Translating microbiome research into clinical practice presents its own set of challenges. While there is great potential for microbiome-based interventions to prevent or treat diseases, the development of such therapies is complex. Factors such as individual variability in microbiome composition, the potential for unintended effects on the microbiome, and the need for personalized approaches complicate the path from research to clinical application. Integrating microbiome research findings into clinical practice requires a multidisciplinary approach, combining insights from microbiology, immunology, genetics, and medicine, as well as careful consideration of ethical and regulatory issues. Bridging the gap between microbiome research and clinical application will be crucial for realizing the full potential of microbiome-based therapies in improving human health[50].

Another challenge lies in ensuring the safety and efficacy of interventions like FMT or probiotic supplementation. While promising, these approaches require rigorous clinical trials to assess their therapeutic potential and possible side effects in humans. The regulatory landscape for such treatments also remains uncertain, adding another layer of complexity to their clinical application[53]. The interaction between the gut microbiome and pharmaceuticals presents another layer of complexity. Certain medications, including non-steroidal anti-inflammatory drugs commonly used in orthopaedic conditions, can alter the gut microbiome’s composition. Understanding these interactions is essential for developing integrated treatment plans that consider both the benefits and potential microbiome-mediated effects of these medications[54].

FUTURE DIRECTIONS IN GUT MICROBIOME AND ORTHOPAEDIC HEALTH RESEARCH

As research into the gut microbiome and its impact on orthopaedic health continues to evolve, several key future directions are poised to transform our understanding and management of musculoskeletal diseases. First, the development of precision microbiome therapies tailored to individual patient profiles holds immense promise. By identifying specific microbiome configurations associated with favorable orthopaedic health outcomes, researchers can design targeted probiotic or prebiotic treatments to restore or maintain a healthy microbiome balance. Such precision approaches could mitigate the risk of conditions like osteoporosis and inflammatory arthritis, as highlighted by research indicating the microbiome’s influence on bone metabolism and immune modulation[55]. The integration of machine learning and artificial intelligence in analyzing complex microbiome data sets could revolutionize the identification of patterns and interactions that are not apparent through traditional analytical methods. This could lead to the discovery of novel microbial markers for early detection and risk assessment of orthopaedic conditions, enabling proactive management and potentially altering disease trajectories[56,57].

Exploring the therapeutic potential of FMT in orthopaedic disorders represents an intriguing frontier. While FMT has garnered attention for its efficacy in treating conditions like Clostridioides difficile infection, its application in modulating the gut microbiome to influence orthopaedic health outcomes is an area ripe for exploration. Investigating the safety, efficacy, and long-term outcomes of FMT for conditions such as RA could open new therapeutic pathways. Unraveling the gut-microbiome-skin-bone axis will expand our understanding of how systemic interactions influence orthopaedic health. Recent studies suggest a complex interplay between the gut microbiome, skin microbiota, and bone health, implicating a broader systemic network in musculoskeletal disease processes. Future research focused on these crosstalk mechanisms may reveal multifaceted intervention strategies that encompass diet, lifestyle, and microbial modulation to support orthopaedic health. Finally, the ethical, legal, and social implications of utilizing gut microbiome information in clinical practice necessitate careful consideration. As microbiome-based diagnostics and treatments advance toward clinical application, addressing concerns related to privacy, consent, and the potential for microbiome data to influence insurance and employment necessitates a multidisciplinary approach. Ensuring that advancements in microbiome research translate into equitable and ethical healthcare practices will be paramount. Together, these future directions underscore the vast potential of gut microbiome research to revolutionize orthopaedic health care, offering hope for innovative treatments, improved diagnostic tools, and personalized preventive strategies that could significantly impact individuals’ quality of life worldwide.

The exploration of the gut microbiome’s impact on orthopaedic health marks a significant stride in understanding the intricate connections between our digestive system and skeletal integrity. This burgeoning field of research has uncovered fascinating insights into how the composition and activity of gut microbiota can influence the development, progression, and management of various orthopaedic conditions, from inflammatory arthritis to osteoporosis. Studies have elucidated the mechanisms through which the microbiome modulates immune responses, systemic inflammation, and bone metabolism, offering promising avenues for novel therapeutic strategies that extend beyond conventional treatments[57]. As we delve deeper into the gut-joint axis, the potential for probiotics, prebiotics, and diet-based interventions to positively affect bone health and mitigate orthopaedic diseases becomes increasingly apparent, underscoring the importance of a holistic approach to patient care. However, this field also faces significant challenges, including the need for longitudinal studies to capture the microbiome’s dynamic nature and the translation of preclinical findings into effective clinical applications. Addressing these challenges will require a concerted effort from researchers, clinicians, and policymakers to develop standardized methodologies, navigate ethical considerations, and foster public education on the importance of the gut microbiome in orthopaedic health. Furthermore, the potential interactions between the microbiome and pharmaceuticals highlight the complexity of integrating microbiome-based interventions with existing treatments, necessitating a comprehensive understanding of these relationships to optimize patient outcomes.

CONCLUSION

The intersection of gut microbiome research and orthopaedic health presents a promising frontier that holds the potential to revolutionize our approach to musculoskeletal disorders. By bridging the divide between digestion and bone integrity, this interdisciplinary field opens new pathways for prevention, diagnosis, and treatment, moving towards more personalized and holistic care strategies. As we continue to unravel the complexities of the gut microbiome and its systemic effects, the future of orthopaedic health care looks increasingly promising, with the potential to significantly enhance the quality of life for individuals affected by orthopaedic conditions.