Knee-osteoarthritis (OA) is often associated with increased intestinal permeability, potentially causing sarcopenia, and mobility issues. Current treatments are ineffective. The objective of this study was to investigate if butyrate improves sarcopenia and physical function in knee-OA patients, and if improvements correlate with changes in gut health, specifically intestinal permeability, and bacterial load. In this double-blind study, 60 OA patients received placebo, 52 received 300 mg butyrate daily for 12-weeks. Gut health (zonulin), and systemic bacterial load (lipopolysaccharide-binding proteins (LBP)) were assessed. Handgrip strength (HGS), Oxford knee scores (OKS), and short physical performance battery (SPPB) were measured at the beginning and end of the study to assess physical functionality. Patients taking butyrate showed improvement in HGS, walking speed, OKS scores, and maintained a better balance, walking ability and no decline in rising from chair, according to SPPB-scores. Butyrate lowered blood levels of zonulin, LBP, and CRP as markers of intestinal permeability, bacterial load, and inflammation, respectively (all p <
0.05). Regression analysis exhibited marked correlations of zonulin with HGS, OKS, walking speed, and SPPB scores in the butyrate-treated group. These observations suggest that butyrate could serve as a therapeutic option for sarcopenia and physical decline in OA, potentially by improving intestinal barrier function.