Fig. 2.

Proposed hypothetical me pathophysiological mechanism explaining the association between the gut microbiome (Streptococcus spp.), knee WOMAC pain and knee effusion. No causality has been established between Streptococcus spp. abundance and OA-related knee pain, however, if such causality exists, we propose the following model: Members of the Streptococcus spp. are known to produce metabolites and membrane vesicles, which both may interact with host cells. These bacterial products can pass the gut-blood barrier, and possibly either a target the knee joint through activation of macrophages in the synovial lining, leading to joint inflammation and damage, or b enter the circulation, activate macrophages to pro-inflammatory macrophages, which may trigger a low-grade systemic inflammatory state, invoking or exacerbate joint inflammation and damage, leading to increased knee pain