Osteoarthritis Can Also Start in the Gut:The Gut-Joint Axis

Background Osteoarthritis is a common cause of pain and disability with an increasing prevalence among the global population (Hunter and Bierma-Zeinstra in Lancet 393(10182):1745-1759, 2019; Zhang and Jordan in Clinics in Geriatric Medicine 26( 3):355-369, 2010). Altered immune responses and low-grade systemic inflammation driven by gut dysbiosis are being increasingly recognized as contributing factors to the pathophysiology of OA (Tan et al. in International Journal of Rheumatic Diseases. https://doi.org/10.1111/1756-185X.14123, 2021; Binvignat et al. in Joint, Bone, Spine 88(5):105203, 2021; Ramasamy et al. in Nutrients 13(4): 1272, 2021), which increased the interest in the so-called "gut-joint axis". The various microbiota in the gastrointestinal tract is commonly referred to as the gut microbiome. The gut microbiome is affected by age, sex, and immune system activity as well as medications, environment, and diet (Arumugam in Nature. https://doi.org/ 10.1038/nature09944, 2011). The microbiome is pivotal to maintain host health and contributes to nutrition, host defense, and immune development (Nishida et al. in Clinical Journal of Gastroenterology 11:1-10, 2018). Alterations in this microbiome can induce dysbiosis, which is associated with many human disease states including allergies, autoimmune disease, diabetes, and cancer (Lin and Zhang in BMC Immunology 18(1):2, 2017). A gut-joint axis is proposed as a link involving the gastrointestinal microbiome, the immune response that it induces, and joint health. Results Emerging evidence has shown that there are specific changes in the microbiome that are associated with osteoarthritis, including increased Firmicutes/Bacteroides ratio, Streptococcus spp. prevalence, and local inflammation (Collins in Osteoarthritis and Cartilage. https://doi.org/10.1016/j.joca.2015.03.014, 2015; Rios in Science and Reports. https://doi.org/ 10.1038/s41598-019-40601-x, 2019; Schott in JCI insight. https://doi.org/10.1172/jci.insight.95997, 2018; Boer et al. in Nature Communications 10:4881, 2019). Both the innate and adaptive immune systems are affected by the gut microbiome and can become dysregulated in dysbiosis which ultimately triggers events associated with joint OA. Conclusions The gut is an intriguing and novel target for OA therapy. Dietary modification or supplementation with fiber, probiotics, or prebiotics could provide a positive impact on the gut joint axis

Cell-Free Scaffolds as a Monotherapy for Focal Chondral Knee Defects

Chondral knee defects have a limited ability to be repaired. Current surgical interventions have been unable to regenerate articular cartilage with the mechanical properties of native hyaline cartilage. The use of a scaffold-based approach is a potential solution. Scaffolds are often implanted with cells to stimulate cartilage regeneration, but cell-based therapies are associated with additional regulatory restrictions, an additional surgical procedure for cell harvest, time for cell expansion, and the associated costs. To overcome these disadvantages, cell-free scaffolds can be used in isolation allowing native cells to attach over time. This review discusses the optimal properties of scaffolds used for chondral defects, and the evidence for the use of hydrogel scaffolds and hydrogel−synthetic polymer hybrid scaffolds. Preclinical and clinical studies have shown that cell-free scaffolds can support articular cartilage regeneration and have the potential to treat chondral defects. However, there are very few studies in this area and, despite the many biomaterials tested in cell-based scaffolds, most cell-free studies focused on a specific type I collagen scaffold. Future studies on cell-free scaffolds should adopt the modifications made to cell-based scaffolds and replicate them in the clinical setting. More studies are also needed to understand the underlying mechanism of cell-free scaffolds

Prevention of infection and disruption of the pathogen transfer chain in elective surgery

The COVID-19 pandemic has caused us all to stop our normal activities and consider how we can safely return to caring for our patients. There are many common practices (such as an increased use of personal protective equipment) which we are all familiar with that can be easily incorporated into our daily routines. Other actions, such as cleaning more surfaces with solutions such as dilute povidone iodine or changing the air filtration systems used within operating room theaters, may require more extensive efforts on our behalf. In this article, we have attempted to highlight some of the changes that arthroplasty surgeons may need to instigate when we are able to resume elective joint arthroplasty procedures in an effort to disrupt the chain of pathogen transfer

Efficacy of Limosilactobacillus fermentum in the management of vulvovaginal candidiasis: comparative analysis with topical miconazole in a single-blind randomized clinical trial

IntroductionVulvovaginal candidiasis (VVC) significantly impacts women’s quality of life and often shows a high recurrence rate despite conventional antifungal therapies. This study evaluates the efficacy of Limosilactobacillus fermentum (LF5), a probiotic, as an alternative treatment option to conventional miconazole therapy in managing VVC.MethodsThe randomized, single-blind clinical trial involved 100 premenopausal women diagnosed with VVC. Participants were assigned to either a vaginal capsule containing LF5 probiotic strain or miconazole. Treatments were administered once daily for three consecutive days. Microbiological eradication of Candida spp. and recurrence rates were assessed at 30 days post-treatment. The trial was registered with the Italian Ministry of Health.ResultsBoth treatments achieved a high rate of microbiological eradication of Candida spp. within the three-day treatment period (96% for LF5 and 94% for miconazole). Recurrence rates within 2 weeks post-treatment were low and similar between the groups (10% for LF5 and 17% for miconazole). LF5 was found to have a significantly lower incidence of local adverse reactions compared to miconazole (4 vs. 12%).DiscussionLF5 presents a viable alternative to miconazole for the treatment of VVC, offering comparable efficacy with fewer side effects. The results suggest that probiotic treatments can potentially enhance patient compliance and quality of life by reducing adverse reactions and recurrence rates. Further research is needed to confirm these findings in larger and more diverse populations

The role of the immune system in tendon healing: a systematic review.

INTRODUCTION: The role of the immune system in tendon healing relies on polymorphonucleocytes, mast cells, macrophages and lymphocytes, the 'immune cells' and their cytokine production. This systematic review reports how the immune system affects tendon healing. SOURCES OF DATA: We registered our protocol (registration number: CRD42019141838). After searching PubMed, Embase and Cochrane Library databases, we included studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results. The PRISMA guidelines were applied, and risk of bias and the methodological quality of the included studies were assessed. We excluded all the articles with high risk of bias and/or low quality after the assessment. We included 62 articles assessed as medium or high quality. AREAS OF AGREEMENT: Macrophages are major actors in the promotion of proper wound healing as well as the resolution of inflammation in response to pathogenic challenge or tissue damage. The immune cells secrete cytokines involving both pro-inflammatory and anti-inflammatory factors which could affect both healing and macrophage polarization. AREAS OF CONTROVERSY: The role of lymphocytes, mast cells and polymorphonucleocytes is still inconclusive. GROWING POINTS: The immune system is a major actor in the complex mechanism behind the healing response occurring in tendons after an injury. A dysregulation of the immune response can ultimately lead to a failed healing response. AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies are needed to shed light on therapeutic targets to improve tendon healing and in managing new way to balance immune response

Periprosthetic Joint Infection and the Trojan Horse Theory:Examining the Role of Gut Dysbiosis and Epithelial Integrity

Background: Periprosthetic joint infection (PJI) is an uncommon yet dreadful complication after total joint arthroplasty. Emerging evidence suggested a role for the gut microbiome in the pathogenesis of such infections as a reservoir of opportunistic pathogens. Methods: A secondary analysis of an ongoing trial looking at gut dysbiosis and PJI was performed on patients that had next-generation sequencing done as part of their workup. Gut permeability and dysbiosis were measured using known biomarkers such as Zonulin. Statistical analysis consisted of descriptive statistics and logistic regression modeling. Results: Among the cohort of 46 (47.8% female) patients, with a mean age of 68.47 years (range, 40 to 91) and a mean BMI 31.15 ± 6.49 kg/m2, 38 patients underwent a revision for PJI (29 chronic and 9 acute infections), and 8 patients were classified as aseptic failures. Then, a review of each of the bacteria retrieved was performed. Those known to be gut commensal based on available literature were noted. When regression modeling was performed, Zonulin levels were found to be associated with an increased probability of a similar finding (Estimate: 0.377, OR: 1.458; P = .001). Conclusion: In our study, we report the first clinical evidence of the translocation of bacteria from the gut to the joint in patients with PJI. In particular, when evaluating the microbiological profile of the NGS signal, a great number of known gut commensals were seen in patients with a highly permeable dysbiotic gut. Manipulation of the gut microbiome may become part of an essential and comprehensive approach for management of patients with PJI

Gut permeability may be associated with periprosthetic joint infection after total hip and knee arthroplasty

A growing number of recent investigations on the human genome, gut microbiome, and proteomics suggests that the loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between the gut microbiome and the immune system. This cross-talk is highly influential in shaping the host immune system function and ultimately affecting the outcome of interventions. We hypothesized that the loss of mucosal barrier in the gut may be associatedto acute and chronic periprosthetic joint infections (PJI). Zonulin, soluble CD14 (sCD14), and lipopolysaccharide (LPS) were tested in plasma as part of a prospective cohort study of patients undergoing primary arthroplasty or revision arthroplasty because of an aseptic failure or PJI (as defined by the 2018 criteria). All blood samples were collected before antibiotic administration. Samples were tested using commercially available enzyme-linked immunosorbent assays as markers for gut permeability. A total of 134 patients were included in the study of which 44 patients had PJI (30 chronic and 14 acute), and the remaining 90 patients were categorized as non-infected that included 64 patients revised for aseptic failure, and 26 patients undergoing primary total joint arthroplasty. Both Zonulin (7.642 ± 6.077 ng/mL vs 4.560 ± 3.833 ng/mL; p < 0.001) and sCD14 levels (555.721 ± 216.659 ng/mL vs 396.872 ± 247.920 ng/mL; p = 0.003) were significantly elevated in the PJI group compared to non-infected cases. Higher levels of Zonulin were found in acute infections compared to chronic PJI (11.595 ± 6.722 ng/mL vs. 5.798 ± 4.841 ng/mL; p = 0.005). This prospective study reveals a possible link between gut permeability and the 'gut-immune-joint axis' in PJI. If this association continues to be borne out with a larger cohort and more in-depth analysis, it will have a clinically significant implication in managing patients with PJI. It may be that in addition to the administration of antimicrobials, patients with PJI and other orthopaedic infections may benefit from administration of gastrointestinal modulators such as pro and prebiotics

The relation between the gut microbiome and osteoarthritis:A systematic review of literature

BACKGROUND: Along with mechanical and genetic factors, emerging evidence suggests that the presence of low-grade inflammation has a role in the pathogenesis of osteoarthritis (OA) and seems to be related to the microbiome composition of the gut. PURPOSE: To provide evidence whether there is clinical or preclinical evidence of gut-joint axis in the pathogenesis and symptoms of OA. METHODS: An extensive review of the current literature was performed using three different databases. Human, as well as animal studies, were included. The risk of bias was identified using ROBINS and SYRCLE tools, while the quality of evidence was assessed using GRADE and CAMADARES criteria. RESULTS: A total of nineteen articles were included. Multiple animal studies demonstrated that both obesity, and high-fat and high-sugar diets resulted in a gut dysbiosis status characterized by increased Firmicutes/Bacteroidetes (F/B) phyla ratio and increased permeability. These changes were associated with increased lipopolysaccharide serum levels, which consequently resulted in synovitis and OA severity. The administration of pre-and probiotics partially reversed this bacterial composition. In addition, in human studies, a decreased amount of gut Bacteroidetes, subsequent increased F/B ratio, have also been observed in OA patients. CONCLUSIONS: Our review confirms preliminary yet sound evidence supporting a gut-joint axis in OA in primarily preclinical models, by showing an association between diet, gut dysbiosis and OA radiological severity and self-reported symptoms. Clinical studies are needed to confirm these findings, and to investigate whether interventions targeting the composition of the microbiome will have a beneficial clinical effect

Gut permeability and osteoarthritis, towards a mechanistic understanding of the pathogenesis: a systematic review

Osteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, via the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis of OA. We propose that the tight junction disruption may be due to an increase in zonulin activity as already demonstrated for many other chronic inflammatory disorders. After years of unreliable quantification, one study optimised the methodology, showing a positive validated correlation between plasma lipopolysaccharide (LPS), obesity, joint inflammation, and OA severity. Chemokines show a prominent role in pain development. Our systematic review confirms preliminary evidence supporting a gut-joint axis in OA pathogenesis and progression. Being modifiable by several factors, the gut microbiota is a promising target for treatment. We propose a pathogenetic model in which dysbiosis is correlated to the bipartite graph of tight junctions and bacterially-produced products, aiming to direct future studies in the search of other bacterial products and tight junction disassembly regulators.KEY MESSAGESPrevious studies and methods have underestimated the impact of the gut-joint axis in osteoarthritis and have focussed on the characterisation of microbiota phenotypes rather than clear molecular mediators of disease.Gut dysbiosis is related to higher levels of bacterial toxins that elicit cartilage and synovium inflammatory pathways.Future research may benefit from focussing on both tight junctions and bacterially-produced products

Gut Permeability May Be Associated With Periprosthetic Joint Infection After Total Hip and Knee Arthroplasty

A growing number of recent investigations on the human genome, gut microbiome, and proteomics suggests that the loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between the gut microbiome and the immune system. This cross-talk is highly influential in shaping the host immune system function and ultimately affecting the outcome of interventions. We hypothesized that the loss of mucosal barrier in the gut may be associatedto acute and chronic periprosthetic joint infections (PJI). Zonulin, soluble CD14 (sCD14), and lipopolysaccharide (LPS) were tested in plasma as part of a prospective cohort study of patients undergoing primary arthroplasty or revision arthroplasty because of an aseptic failure or PJI (as defined by the 2018 criteria). All blood samples were collected before antibiotic administration. Samples were tested using commercially available enzyme-linked immunosorbent assays as markers for gut permeability. A total of 134 patients were included in the study of which 44 patients had PJI (30 chronic and 14 acute), and the remaining 90 patients were categorized as non-infected that included 64 patients revised for aseptic failure, and 26 patients undergoing primary total joint arthroplasty. Both Zonulin (7.642 ± 6.077 ng/mL vs 4.560 ± 3.833 ng/mL; p \u3c 0.001) and sCD14 levels (555.721 ± 216.659 ng/mL vs 396.872 ± 247.920 ng/mL; p = 0.003) were significantly elevated in the PJI group compared to non-infected cases. Higher levels of Zonulin were found in acute infections compared to chronic PJI (11.595 ± 6.722 ng/mL vs. 5.798 ± 4.841 ng/mL; p = 0.005). This prospective study reveals a possible link between gut permeability and the \u27gut-immune-joint axis\u27 in PJI. If this association continues to be borne out with a larger cohort and more in-depth analysis, it will have a clinically significant implication in managing patients with PJI. It may be that in addition to the administration of antimicrobials, patients with PJI and other orthopaedic infections may benefit from administration of gastrointestinal modulators such as pro and prebiotics