Musculoskeletal Microbiology: The Utility of the Microbiome in Orthopaedics

Abstract

The past 15 years has witnessed a renaissance in the study of the microbes that colonize the human body. The vast majority of the human microbiome resides within the gut. Alterations to the gut microbiome have been associated with the pathogenesis and progression of wide-ranging diseases throughout the body – including atherosclerosis, depression, and obesity. Our understanding of the effects of the gut microbiome on the musculoskeletal system remains in its infancy, but preclinical work has demonstrated an effect of the gut microbiome on the success of orthopaedic surgical procedures, osteoporosis, osteoarthritis, and muscle mass. In this perspective I review preclinical findings demonstrating that an impaired presurgical gut microbiome can increase the likelihood of developing periprosthetic joint infection and how alterations in the gut microbiome can reduce bone strength by impairing bone tissue material properties. In addition to discussing these examples I review the hypothesis that many chronic non-communicable diseases have become more prevalent in modern industrialized societies as a result of changes in the composition of the gut microbiome resulting from changes in environment/lifestyle (diet, sanitation, antibiotic use). The most burdensome musculoskeletal disorders are chronic and non-communicable and may therefore be related to generational shifts in the composition of the gut microbiome, a possibility I illustrate by reviewing changes in the prevalence of osteoarthritis over the last century. Microbiome based therapeutics are potentially innocuous, inexpensive and have the potential to be effective with only occasional use, making them attractive for addressing the needs of chronic and/or slowly progressing musculoskeletal disorders.

Introduction

In 2007 the US National Institutes of Health (NIH) launched the ten year-long Human Microbiome Project with the goal of surveying the microbial communities occupying the human body. The Human Microbiome Project has led to major discoveries related to the pathogenesis and treatment of infectious disease, autoimmune disorders, digestive disease, respiratory disease, urogenital disease and cancer ¹. Despite the success of the Human Microbiome Project, its application to musculoskeletal and/or orthopaedic conditions has been cursory ^1,2. Here I briefly review recent findings demonstrating a role of the microbiome in regulating the maintenance and function of musculoskeletal tissues. I propose that the field of “Musculoskeletal Microbiology” has the potential to address long-standing challenges in the field.

The human body hosts microbes at all interfaces with the external environment including skin, lung, urogenital tract, the oral cavity, and the gastrointestinal tract. The genomic components of these commensal microbes compose the microbiome. The microbes themselves (bacteria, archea, fungi, etc.) are known collectively as the microbiota. The vast majority of the human microbiome is located within the gut ³. The gastrointestinal tract of an individual typically hosts as many as 1000 distinct microbial species. Colonization of the body by microbes starts at birth, and is dominated by exposure to the maternal microbiota, although exposure to other sources of microbes in the diet and environment can also influence the composition of the microbiota ^3,4. Once a stable microbial community is established in an individual, small fluctuations occur on an hourly or daily basis, but the overall content of the microbial community remains the same unless a potent or prolonged stimulus shifts the microbial community into a new stable state ⁴.

The microbiome has generated considerable interest within the biomedical community because of its potential as: 1) a mediator of disease pathogenesis; 2) a biomarker for disease/disease progression; and 3) a target for novel therapeutic approaches ^2,4,5 (Fig. 1). I will use the term “microbiome-based therapeutic” to refer to interventions that either directly target gut microbes (for example pharmaceuticals that influence commensal bacteria but not the host) as well as interventions that modify the composition and/or function of the commensal microbes. Microbiome-based therapeutics are especially enticing because they have the potential to be inexpensive and have few side effects ⁶. Currently available microbiome-based therapeutics include prebiotics and probiotics which increase the abundance and/or function of organisms that are beneficial to the host. However, existing prebiotic and probiotic supplements are rapidly removed from the gut ⁷ after dosing so while they influence the function of the gut microbiota, in general the effect is temporary and therefore requires frequent/daily dosing to sustain benefits for the host. Microbiome-based therapeutics, however, have the potential to be much more potent than existing pre- and probiotics. Fecal microbiota transplantation transfers an entire microbial community into the recipient, in essence establishing an entirely new state of the host microbial community that is often stable enough to be maintained for 6–12 months or longer^8–10. The ability of fecal microbiota transplant to cause long-term changes in the composition of the gut microbiota demonstrates the feasibility of a perhaps less invasive microbiome-based therapeutic that could possibly be applied as often as a vaccine or screening colonscopy. The promise of continuous health benefits from an occasional, inexpensive intervention is especially attractive for musculoskeletal disorders which develop over months or years. Achieving such a microbiome-based therapeutic will require a much better understanding of gut microbial communities and the mechanisms through which they regulate musculoskeletal health.

Figure 1.

The microbial community within the gut can be viewed as a balance between a composition that is beneficial or detrimental to host physiology. As the detrimental composition of the gut microbiota increases the microbiome provides a greater contribution to the pathogenesis of musculoskeletal disease. A microbiome-based therapeutic may increase the beneficial components of the gut microbiome, thereby reducing the contribution to musculoskeletal disorders. Additionally, the composition of the gut microbiota and/or microbial molecular products has potential as a biomarker. Red arrows indicate research areas of great interest.

The past eight years have seen a number of studies establishing links between the gut microbiome and the health and function of the musculoskeletal system, especially in the areas of osteoporosis, osteoarthritis and orthopaedic surgery. Preclinical studies have shown that the absence of a gut microbiome or severe reductions in gut microbial populations can partially prevent bone loss during estrogen depletion and glucocorticoid treatment – two of the primary contributors to the pathogenesis of osteoporosis ^11–16. A recent randomized, double-blinded placebo controlled trial (n = 249 individuals) found that a one year of a microbiome-based intervention (daily oral probiotics) reduced postmenopausal bone loss in the lumbar spine ¹⁷. Additionally, preclinical studies have indicated that the gut microbiome can influence osteoarthritis: germ-free mice (animals never exposed to microbes) experience less cartilage damage after surgically-induced osteoarthritis (destabilization of the medial meniscus)¹⁸. Furthermore, manipulation of the gut microbiome using a beneficial prebiotic was recently shown to prevent obesity-induced increases in joint degeneration following surgically induced osteoarthritis ¹⁹. In a study, manipulation of the gut microbiome using oral antibiotics completely prevented the development of osteoarthritis in one study group (TLR5 deficient animals)²⁰. Muscle mass and function are also influenced by the gut microbiota; a recent study found that germ free mice display muscle atrophy, a condition that can be reversed through transfer of a normal gut microbiota ²¹. Additionally, recent studies have suggested that the presurgical state of the patient gut microbiome can influence the success of gastrointestinal surgeries ^22,23, and has recently been shown to influence the success of orthopaedic surgery in animals ²⁴.

Here I raise three questions in the field of musculoskeletal disease and discuss recent preclinical studies suggesting the potential of the gut microbiome in musculoskeletal health and orthopaedic surgery.

Can the Microbiome Help Prevent Periprosthetic Joint Infection?

Periprosthetic joint infection (PJI) is the most devastating complication of total joint arthroplasty. Although rigorous sterile procedures during surgery have reduced the incidence of PJI to 1–2% during primary joint replacement ^25,26, PJI is the most common reason for revision total knee arthroplasty and is the third most common reason for revision total hip arthroplasty ^27,28. The need for improved preventive approaches is so severe that many surgeons use antibacterial strategies with known toxic effects on local cells/tissues (excessive vancomycin powder, soap washes, etc.) ^29,30. However, clinical studies suggest that even perfect adherence to infection prevention protocols are unlikely to reduce the incidence of infection in elective surgeries below 1–2% (the current rates of PJI) ^31,32. Further advances in sterile technique and even the use of robotic surgery will not remove the greatest source of microbial contamination: the patient. Related to this finding, the 2018 International Consensus Meeting on Musculoskeletal Infection generated a list of “high priority” research questions, half of which focus on modifiable patient factors including the microbiome and/or host immunity ³².

The gut microbiome is in regular contact with the host immune system, both at the gut endothelial barrier as well as through microbial products and proteins that are generated in the gut and then distributed throughout the body ³³. By regulating the host immune system the gut microbiome can influence resistance to infectious disease ^34–37. In mice, depletion of the gut microbiota (99–100% removal) leads to severe reductions in phagocyte populations, making animals more susceptible to systemic infection by Listeria monocytogenes or Staphylococcus aureus ³⁶. In addition, immune cells from mice with depleted gut microbiota are less effective at killing S. aureus and S. pneumoniae ³⁴. In humans, the diversity of the gut microbiome before stem cell transplantation has been associated with risk of sepsis and mortality post procedure ³⁸.

With regard to periprosthetic joint infection, the presence of S. aureus in the nasal microbiome has long been recognized as a risk factor for infection, and decolonizing the patient prior to surgery is an accepted and effective intervention to reduce the presence of S. aureus during surgery ^39,40. While reducing the presence of S. aureus is useful, other patient factors can also influence risk of infection. The other major risk factors for PJI (diabetes, obesity, malnutrition, smoking, etc.) are also associated with substantial differences in the constituents of the gut microbiome as compared to healthy individuals ^41–45. But is it even possible that the gut microbiome could influence PJI? The answer is yes. In a recent preclinical study, we showed that susceptibility to PJI was increased by almost 50% in mice with a disrupted gut microbiome community ²⁴ (Fig. 2A). Furthermore, those mice with a disrupted gut microbial community that went on to develop PJI showed a reduced systemic immune response to infection (measured by serum markers and immune cell populations in the spleen). This finding suggests that disruption of the gut microbiome may increase susceptibility to PJI by reducing the capacity of the host immune response to bacterial challenge. Furthermore, it suggests a potential microbiome-based contribution to the limitations of systemic markers for diagnosing PJI ³². Although the mechanisms linking the gut microbiome to susceptibility to infection remain to be identified, this preclinical study suggests that the presurgical gut microbiome – a previously unconsidered factor – could influence the patient’s ability to resist infection. Further study is required to determine how many arthroplasty patients present with a gut microbiome that can impair the success of surgery and if treating the microbiome prior to surgery could improve outcomes.

Figure 2.

(A) Using an animal model of knee arthroplasty, mice with an impaired gut microbiota (ΔMicrobiome) showed reduced ability to resist bacterial challenge by S. aureus, as shown by the increased count of colony forming units at the implant surface. (B) Mice with an impaired gut microbiome (ΔMicrobiome) showed reductions in bone tissue strength indicating impaired bone tissue quality (no noticeable changes in bone quantity were observed). Tissue strength was assessed as bending moment divided by section modulus.

What causes poor bone tissue quality?

Fragility fractures are caused by low energy loading events such as a fall from standing height. Although risk of falling is an important contributor to the incidence of fragility fracture, the ability of the bone to resist failure during loading is also a major contributor. A key indicator of risk of fragility fracture is low bone density ⁴⁶. Over the last three decades a combination of ground-breaking basic science, clever translational studies and rigorous clinical studies have resulted in a broad array of pharmaceutical treatments for osteoporosis that increase bone mass and density and can reduce the risk of fragility fractures by as much as 50%. These osteoporosis interventions have been successful by addressing the greatest cause of bone fragility: reduced bone mineral density (BMD). However, there remain large segments of the population in which fragility fractures occur in the absence of low bone mineral density ⁴⁶. Fragility fracture in these individuals is commonly attributed to poor bone quality. The term “bone quality” refers to impaired aspects of microarchitecture and/or bone tissue material properties that can make the bone less resistant to fracture despite adequate bone mineral density ⁴⁷. Bone tissue material properties are a major contributor to bone quality and fracture risk and are not currently assessed clinically ^46,48. Bone tissue material properties are known to change with tissue age (the length of time since the bone matrix was formed, not to be confused with the age of the individual), but relatively little is known about other factors that regulate bone tissue material properties (Alliston ⁴⁹ provides one of the few discussions of the topic).

A recent series of studies from my group shows that the gut microbiome can regulate bone tissue mechanical properties. Guss and colleagues found that changes in the constituents of the gut microbiome in growing mice lead to impaired bone tissue strength at skeletal maturity – in the absence of noticeable changes in bone quantity ⁵⁰ (Fig. 2B). The finding has been confirmed in subsequent studies ⁵¹ and early evidence suggests that factors produced by gut microbes may directly regulate bone tissue quality ⁵². We recently found that the effect of the gut microbiome on bone tissue material properties is not limited to growing mice; alterations to the gut microbiome in aged mice (modified from 1–2 years of age) also lead to similar reductions bone tissue mechanical properties ⁵³. Although these studies have focused on the potential detrimental effects of changes in the gut microbiome, they raise the possibility that microbiome-based therapies could improve resistance to fragility fracture by addressing bone tissue quality. If confirmed in future studies, the effects of the gut microbiome on bone tissue quality could be used to further reduce bone fragility beyond what is possible with current osteoporosis interventions.

Could the Microbiome Drive Prevalence of Musculoskeletal Disease?

A number of chronic, non-communicable diseases have increased in prevalence in the U.S. over the past decades, an effect attributed to increases in lifespan and changes in lifestyle (diet, activity levels, etc.). The changes in lifestyle of the U.S. population over the past 100 years include alterations in diet (fiber content, processed foods, etc.), sanitation (filtered and chlorinated water) as well as antibiotic use, three factors that are known to have dramatic effects on the constituents of the gut microbiome. These observations has led to the hypothesis that modifications to the gut microbiome associated with changes in lifestyle are a major contributor to changes in disease prevalence over this period ^54–56. Although prior discussions of this hypothesis have focused on diabetes, obesity, and asthma, the findings reviewed above suggest that the prevalence of musculoskeletal disorders may be influenced by the gut microbiome ⁵⁷.

The idea that changes in the gut microbiome can influence the prevalence of musculoskeletal disease has long been hypothesized in the context of rheumatoid arthritis. Archeological specimens indicate that rheumatoid arthritis was present in pre-Columbian North American populations, but did not appear in European populations until after the “discovery” of the New World ⁵⁸. Scher, Abramson and others have argued that the appearance of rheumatoid arthritis in Europe may have been a result of introduction of commensal microbes originating in the Western Hemisphere and distributed to Europe through trade and changes in diet ⁵⁸. Although difficult to test from a historical perspective, this line of thought illustrates how the introduction of commensal microbes to a population could “transmit” a non-communicable disease such as arthritis.

Osteoarthritis is the most common form of arthritis. Unlike rheumatoid arthritis which is an autoimmune disease, osteoarthritis is commonly attributed to mechanical wear and tear on the joint over time and accentuated by increased joint loading from overuse, obesity or abnormal joint kinematics. Age and obesity are therefore major risk factors for osteoarthritis. Recent evidence suggests, however, that systemic factors, including those associated with metabolic syndrome and alterations to the gut microbiome can influence the development of osteoarthritis independent of loading and obesity ^19,20,59. In a provocative study, Wallace and colleagues examined the prevalence of osteoarthritis in the U.S. using skeletal collections from modern postindustrial periods (years 1976–2015) as well early industrial periods (years 1905–1940) ⁶⁰. They observed a prevalence of knee osteoarthritis in modern postindustrial populations more than twice as great as that seen in individuals from the early industrial period after accounting for differences in age and body mass index (BMI). In other words, osteoarthritis is more common in the U.S. now than it was 100 years ago. This finding demonstrates that osteoarthritis is likely one of many non-communicable chronic diseases with increased prevalence in industrialized societies. Berenbaum and colleagues provide an excellent review of the alterations in levels of physical activity, changes in diet and rates of obesity and metabolic syndrome as potential explanations for the increased prevalence of osteoarthritis in current populations ⁵⁷ and mention potential contributions of changes in the gut microbiome associated with obesity, metabolic syndrome and the modern Western diet. However, major changes in public hygiene between the two cohorts examined by Wallace and colleagues could, by itself, cause changes to the gut microbiota that are relevant to osteoarthritis. For example, filtered and chlorinated public water supplies became available to larger proportions of the population in the early 1900s (Fig. 3). Treated water has fewer pathogens but can also reduces exposure to other organisms which could colonize the gut.

Figure 3.

A timeline in which shaded regions indicate the age at death of the pre-industrial (blue) and post-industrial (red) cohorts examined by Wallace et al. is shown. The introduction of filtered/chlorinated water and rapid increases in oral antibiotics are shown. Hypothesized changes in the abundance of microbiota that could contribute to the increased prevalence of osteoarthritis in the post-industrial group is shown.

Another factor likely to differentiate the gut microbiota of the two cohorts examined by Wallace and colleagues is the initiation of widespread use of oral antibiotics in the U.S. in the 1940s (Fig. 3). Although antibiotics have greatly improved human health and longevity by addressing infections, antibiotics can also decimate a population of microbes within the gut including beneficial microbes ^54,55,61. Microbial species that are removed from an individual’s gut microbiome do not always return after the course of antibiotics. Furthermore, commensals that are not present in a mother’s microbiome cannot be transferred to a child, resulting in a generation by generation reduction in overall gut microbial diversity ⁵⁵ (a process demonstrated experimentally in mice ⁶²). Reduced diversity of the gut microbiome can promote systemic inflammation and thereby contribute to osteoarthritis ^54,56,57. While the current discussion has focused on osteoarthritis, it is possible that other chronic non-communicable musculoskeletal conditions also show increased prevalence in post-industrial societies. If confirmed, these findings would suggest that an intervention that repairs the contents of the gut microbiome could be used to slow the progression of disease and/or reduce prevalence of chronic musculoskeletal disorders ^55,61,63.

Conclusions

The gut microbiome is now widely recognized by the biomedical community as a contributor to disease pathogenesis and an enticing target for therapies and interventions. Despite the wide recognition of this factor in other medical specialties, the gut microbiome has only recently emerged as a factor in musculoskeletal health. As a result, only a few studies on the topic have been published to date.

The key next steps to understanding the role of the microbiome in orthopaedics include preclinical studies that more directly identify the mechanisms linking the microbiome to the health of musculoskeletal tissues. Furthermore, clinical studies to measure gut microbiome in patient populations are necessary to assess the potential effectiveness of microbiome-based interventions for musculoskeletal and orthopaedic conditions. Once a more mature understanding of the mechanisms linking the gut microbiome to musculoskeletal tissues is achieved, the appropriate microbiome based interventions for use in patients can be identified – a possibility that is likely given the number of musculoskeletal and orthopaedic conditions influenced by the gut microbiome in preclinical models.