Cindy Boer

240 | Chapter 5.2 the molecular pathway connecting Streptococcus spp., knee inflammation and WOMAC pain, to validate or reject our postulated hypothesis (Figure. 2). Blood and joint tissue could be examined for the presence of Streptococcus MVs, metabolites, and their possible association to knee inflammation and WOMAC pain se- verity. Third, to examine whether the association found in this study is unique for knee OA pain, other quantitative pain measurements should be examined, as well as meas- urements of pain at other joints. In, addition, other inflammatory joint disorders could also be examined. Forth, due to the limited resolution of 16S rRNA-sequencing method- ology, we were unable to identify whether a specific Streptococcus species or strain was driving the association. Last, we find no association between knee OA severity (KLsum) and gastrointestinal-microbiome composition. Knee OA severity, however, was meas- ured by radiographic OA severity, and this does not include the clinical symptom of joint pain. Although considering our proposed mechanism, an effect on knee OA sever- ity could be expected, as inflammation can lead to joint damage. It is possible that our study currently lacks the power to detect such an association, or requires a longitudinal design to detect such effects on OA severity or disease progression. In sum, we demonstrate an association between greater abundance of Strepto- coccus spp. and higher osteoarthritis-related knee pain, but the causality of this asso- ciation needs to be established. A possible explanation for the found association is the induction or exacerbating of local joint inflammation by Streptococcus spp. The pre- cise mechanisms by which Streptococcus spp. may trigger joint inflammation, are not known. We hypothesized that it may involve metabolites or MVs produced by Strep- tococcus spp. in the gastrointestinal tract. As joint pain is one of the most impacting clinical OA symptoms and pain in OA has a high socioeconomic burden, it is of crucial importance to identify novel treatments that reduce clinical symptoms, in particular pain, and decrease the socioeconomic burden. Our results point to the microbiome as a therapeutic target for OA-related joint pain and possibly for other inflammatory joint pain disorders. The gastrointestinal microbiome is a promising therapeutic target, be- cause it is sensitive to change through (diet) interventions. This could offer an easily ac- cessible and safe treatment options for OA associated joint pain. Therefore, it is pivotal to explore the causal mechanism and possible translation of the present findings into clinical practice.