The microbiome has been a hot area of research in rheumatology over the past decade as it became evident that certain microbes and their products can contribute to inflammatory and autoimmune conditions including spondylitis, rheumatoid arthritis, and lupus. Not to be left out, investigators in the OA field have been exploring the role of the microbiome in OA pathogenesis which was highlighted in several presentations at the ACR’s 2023 Convergence meeting. The rationale for this work is that at least two of the major risk factors for OA, increasing age and obesity, are associated with alterations in the gut microbiota, referred to as dysbiosis, as well as with increases in intestinal permeability. The latter could allow pro-inflammatory microbial products to enter the circulation to promote OA.
As reviewed by Liubov Arbeeva from the University of North Carolina in a State of the Art session, the consumption of high amounts of fat and sugars present in the typical “western” diet can shift the composition of the gut microbiota to one that has higher numbers of potentially pathogenic microbes capable of inducing a proinflammatory state in the host. Intestinal dysbiosis can also contribute to increased intestinal permeability (a “leaky gut”) resulting in microbial products such as lipopolysaccharide (LPS or endoxtoxin) entering the host circulation. Increased levels of LPS have been measured in the plasma and synovial fluid of individuals with OA.
Matlock Jefferies from the Oklahoma Medical Research Foundation, speaking in the same session, has detected microbial DNA in cartilage from OA joints, supporting the notion that microbial products from the circulation can reach the joint. He showed that injection of microbial DNA obtained from human OA cartilage into mouse knee joints increased the severity of joint degeneration in a surgical model of OA when compared to injection of microbial DNA isolated from healthy cartilage. In a Plenary session, he presented intriguing data demonstrating that fecal transfer of the microbiota from a B6 mouse strain prone to develop OA to MRL mice that are protected from OA resulted in more severe OA in the MRL mice. A protective effect was seen after fecal transfer from MRL to B6 mice. He went on to show that the fecal transfer to MRL mice from B6 mice resulted in higher levels of LPS in the MRL mice which was not seen in the MRL to B6 transfer. This provides strong evidence that differences in the composition of the gut microbiota can influence the development of OA and that LPS may be a mediating factor.
Dr. Cindy Boer from the Erasmus Medical Center in the Netherlands spoke on findings from the Rotterdam Study during the Basic and Clinical Research Conference that demonstrated an association of knee pain severity with the composition of the fecal microbiota and a particularly strong contribution of the genus Streptococcus. Synovial inflammation on knee MRIs was also associated with knee pain and the abundance of Streptococcus in fecal samples. In support of a role for the gut microbiota in hand OA, an abstract by Jie Wei and colleagues from the Xiangya Hospital Central South University in China reported metabolomic findings demonstrating differences in plasma metabolites related to tryptophan metabolism in individuals with symptomatic hand OA. Levels of specific metabolites were associated with differences in the fecal microbiota including an association of a lower level of the tryptophan metabolite indole-3-lactic acid with the presence of Bacteroides A mediterraneensis.
Despite the strong associations noted in these studies, we still have much to learn about how the gut microbiota influences the susceptibility to develop symptomatic OA and perhaps more importantly, what can be done about it. Additional studies are needed to determine the role of increased intestinal permeability and to identify the microbial products, in addition to LPS and microbial DNA, that enter the circulation and promote OA. In the meantime, a healthy plant-based diet which can promote a more healthy gut microbiota is perhaps our best solution.
Richard F. Loeser, Jr., MD is a Joseph P. Archie, Jr. Eminent Professor of Medicine in the Division of Rheumatology, Allergy and Rheumatology at the Thurston Arthritis Research Center at University of North Carolina at Chapel Hill.
Dr. Loeser has no conflicts of interest to report.
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