Disruption of the Gut Microbiome Increases the Risk of Periprosthetic Joint Infection in Mice

Abstract

Background Periprosthetic joint infection (PJI) is one of the most devastating complications of total joint arthroplasty. Given the mortality and morbidity associated with PJI and the challenges in treating it, there has been increased interest in risk factors that can be modified before surgery. In this study, we used a novel mouse model to consider the role of the gut microbiome as a risk factor for PJI. Questions/purposes (1) Does the state of the gut microbiota before surgery influence the likelihood of developing an established infection in a mouse model of PJI? (2) How does the state of the gut microbiota before surgery influence the local and systemic response to the presence of an established infection in a mouse model of PJI? Methods Male C57Bl/6 mice were divided into two groups: those with modified microbiome ∆microbiome (n = 40) and untreated mice (n = 42). In ∆microbiome mice, the gut flora were modified using oral neomycin and ampicillin from 4 weeks to 16 weeks of age. Mice received a titanium tibial implant to mimic a joint implant and a local inoculation of Staphylococcus aureus in the synovial space (102 colony forming units [CFUs]). The proportion of animals developing an established infection in each group was determined by CFU count. The local and systemic response to established infection was determined using CFU counts in surrounding joint tissues, analysis of gait, radiographs, body weight, serum markers of inflammation, and immune cell profiles and was compared with animals that received the inoculation but resisted infection. Results A greater proportion of animals with disrupted gut microbiota had infection (29 of 40 [73%]) than did untreated animals (21 of 42 [50%]; odds ratio, 2.63, 95% CI, 1.04–6.61; p = 0.035). The immune response to established infection in mice with altered microbiota was muted; serum amyloid A, a marker of systemic infection in mice, was greater than in mice with disrupted gut microbiota with infection (689 µg/dL; range, 68–2437 µg/dL, p < 0.05); infection associated increases in monocytes and neutrophils in the spleen and local lymph node in untreated mice but not were not observed in mice with disrupted gut microbiota. Conclusions The findings from this in vivo mouse model suggest that the gut microbiota may influence susceptibility to PJI. Clinical Relevance These preclinical findings support the idea that the state of the gut microbiome before surgery may influence the development of PJI and justify further preclinical and clinical studies to develop appropriate microbiome-based interventions.

Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

“…Cells were then fixed and permeabilized with Cytofix (BD) and then labeled with antibodies against intracellular IgG (catalog number 405308) to detect intracellular IgG that are high in plasma cells (15). Gating strategies are based on our previously published work (1,11,15). While the use of intracellular staining precluded the use of DAPI to assess dead cells, parallel samples that were not fixed, but were labeled with CD45 (catalog number 103127) and DAPI (catalog number 422801) demonstrated that 95% of tendon and lymph node CD45 + cells were DAPI -, indicating that they were viable cells.…”

Musculoskeletal microbiology: The utility of the microbiome in orthopedics

“…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 (Figure 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).…”

“…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 the transfer of normal gut microbiota 21 . Additionally, recent studies have suggested that the presurgical state of the patient's gut microbiome can influence the success of gastrointestinal surgeries, 22,23 and has recently been shown to influence the success of orthopedic surgery in animals 24 …”

“…21 Additionally, recent studies have suggested that the presurgical state of the patient's gut microbiome can influence the success of gastrointestinal surgeries, 22,23 and has recently been shown to influence the success of orthopedic surgery in animals. 24…”

Bone mineral as a drug-seeking moiety and a waste dump

“…An antibiotic-induced minor change in the microbiome may increase the risk for an infection and postoperative DBJI. 79 …”