Applications

Microbiota composition in Osteoarthritis

Osteoarthritis (OA) is a long-term chronic disease that is characterized by deterioration of cartilage in the joints. Degradative processes lead to destruction of articular cartilage and other tissues in the joints. This results in bone rubbing against bone which causes stiff and painful joints. OA affects roughly 7% of the global population, more than 500 million people worldwide and is responsible for 2% of the total global years lived with disability (YLD). These numbers are expected to rise in the future due to the increasing prevalence of obesity and an aging population, both of which are
strong risk factors for OA. Other risk factors include gender, joint injury, and family history. Older women with higher weight are disproportionally affected. Until recently, OA has been regarded as a mechanical wear and tear condition, however, it has become clear that it is a complex multi-tissue disease in which low-grade, chronic inflammation has a central role. Yet its cause remains unclear.

Novel evidence has been highlighted in recent research that low-grade systemic inflammation is linked to leaky gut syndrome, a condition where the gut epithelium becomes porous which leads to translocation of endotoxins from the gastrointestinal tract to the circulatory system. This syndrome has been linked to gut microbiota dysbiosis. Gut microbiota is fairly stable in healthy adults after it is established during early development. Aging and disease status as well as lifestyle changes, for example dietary change, travel or use of medications and personal characteristics of the immune system and microbiome itself can shift this composition. These shifts can cause the microbiota to become imbalanced, leading to a chronic state of dysbiosis. Obese patients are reported to have a high probability of gut microbiota dysbiosis, as well as a higher probability of developing OA. Patients with metabolic syndrome develop OA develop also in non-load bearing joints such as the hands suggesting that increased load is not the only factor that plays a role in this disease. There is also evidence that prebiotics or probiotics can relieve OA symptoms, thereby suggesting a role of the gut in disease progression. 

Recent evidence has pointed towards strong associations between OA and a shift in microbiota composition, with some bacteria reported as regulators of OA. Increased abundance of Streptococcus species and Firmicutes phylum were shown to be more abundant in OA patients’ microbiota. Particularly, the Firmicutes/Bacteroidetes ratio was shown to be higher in OA individuals supporting an association of OA with dysbiosis. Clostridium genus, part of Firmicutes phylum, was also shown to be more abundant in OA individuals in several studies, particularly Clostridium leptum. Interestingly, Bacteroidetes phylum was found more prevalent in OA microbiota in other studies disproving the F/B ratio claim from studies mentioned before. Notably, some studies did not find any significant differences in microbiota composition between OA and control groups. More correlation is found between papers investigating bacterial strains that would potentially reduce OA symptoms when supplemented. Lactobacillus species alleviated symptoms of OA in several studies, especially Lactobacillus casei Shirota and Lactobacillus paracasei M564. Other bacteria at different taxonomical levels were associated with OA or health status but aren’t mentioned here because we found no correlation of them between studies.  The heterogeneity of sampling and analysis methods present in available papers, different taxonomical levels reported and the lack of healthy controls in several studies makes it difficult to compare them and to identify key bacterial strains associated with pathogenesis of the disease and reach conclusions about a potential causal link.  A meta-analysis of all available data on the microbiota composition of patients with OA comparing with all available data of healthy subjects would help to elucidate the role of the microbiota in OA pathogenesis and progress towards novel treatments. No such study has been done to date to the best of our knowledge. 

Lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria, has been found in the synovial fluid of OA patients. Studies have shown that high levels of LPS in serum, synovial tissue and synovial fluid strongly correlate with OA severity. LPS is a powerful mediator of systemic inflammation and a driver of septic shock syndrome. It induces multiple inflammatory pathways, as it stimulates toll-like receptors such as TLR4 through which it can act as a priming signal for NLRP3 inflammasome activation and other immunomodulatory processes. It is still unknown how LPS accumulates in the synovial fluid, we hypothesize that it comes from the gut because of the leaky gut syndrome OA patients develop due to microbiota dysbiosis. We hope to connect microbiota composition of OA patients with LPS immunosignaling in the joint by establishing primary immune cell and chondrocyte cultures, treating them with LPS from bacteria identified in the microbiota analysis. After treatment we will be analyzing the shift in their cytokine production and gene expression.

Current therapeutic approaches predominantly focus on pain relief and improving structural features of affected joint tissues. However, no available therapy is able to stop OA disease progression nor offer long-lasting relief of symptoms. The most effective treatment to date is joint replacement with an artificial prosthesis, however, this is only used to treat end-stage disease. Development of novel therapeutic approaches targeting the osteoarthritic degradative and inflammatory processes in cartilage, synovium, or bone is needed to develop therapies that would stop progression of OA and ameliorate its symptoms long-term. This requires a deeper understanding of the disease progression and drivers of inflammatory processes such as patient microbiota composition and the role and mechanism of action of LPS presence. Thus, our goal with this study is to elucidate aforementioned processes and help improve treatment methods and life quality of OA patients.

year of approval

2022

institute

  • ETH Z├╝rich (CH) - Department of Department of Health Sciences and Technology

primary applicant

  • Zenobi-Wong, M.