Relationship Between the Gut Microbiome, Tryptophan-Derived Metabolites, and Osteoarthritis-Related Pain: A Systematic Review with Meta-Analysis

Introduction: Osteoarthritis (OA) is the most prevalent form of arthritis and affects over 528 million people worldwide. Degenerative joint disease involves cartilage degradation, subchondral bone remodeling, and synovial inflammation, leading to chronic pain, stiffness, and impaired joint function. Initially regarded as a "wear and tear" condition associated with aging and mechanical stress, OA is now recognized as a multifaceted disease influenced by systemic factors such as metabolic syndrome, obesity, and chronic low-grade inflammation. Recent studies have focused on the gut-joint axis to investigate how the gut microbiome modulates inflammation and pain in OA. Materials and Methods: A systematic review was conducted following the PRISMA guidelines and was registered with PROSPERO (CRD42024556265). This review included studies involving adults with symptomatic OA and analyzed the relationship between the gut microbiome and OA-related pain. Randomized and non-randomized clinical trials, case reports, editorials, and pilot studies were excluded. Searches were performed in PubMed, Cochrane Library, and Web of Science without publication date restrictions, and filtered for "observational studies". The study selection and data extraction were performed by two independent researchers, and the risk of bias was assessed using appropriate tools. Results: Five observational studies were included in the systematic review, and three were included in the meta-analysis. Two studies reported an association between different tryptophan metabolites and pain levels in patients with OA. Two other studies demonstrated a correlation between lipopolysaccharide levels and pain in OA. A fifth study confirmed the relationship between Streptococcus relative abundance of Streptococcus spp. and knee pain. These results were not supported by a meta-analysis, which found no significant association between the presence of pain in OA and the presence of bacilli of the genus Streptococcus or plasma markers of the tryptophan pathway. Conclusions: Current evidence indicates a potential link between gut microbiome dysbiosis and OA-related pain. However, methodological limitations preclude definitive conclusions. Further research using advanced techniques and larger cohorts is needed to validate and extend these findings and elucidate the underlying mechanisms. Targeted manipulation of the gut microbiome may be a valuable strategy for pain management in OA patients.