Effect of Prebiotic Supplementation With and Without Physiotherapy on Pain and Pain Sensitivity in People with Knee Osteoarthritis

<b>Background</b>: Emerging evidence links the gut microbiome to chronic pain processing. Inulin, a prebiotic fibre, modulates the gut microbiome, while physiotherapy-supported exercise (PSE) improves pain and function. We evaluated the effects of inulin supplementation with and without PSE on knee osteoarthritis (OA) pain. <b>Methods</b>: In a 2 × 2 factorial RCT, 117 community-dwelling adults with knee OA received 6 weeks of: (A) 20 g/day inulin, (B) digital PSE (Joint Academy™), (C) inulin +PSE, or (D) 10 g/day maltodextrin. Primary outcome: pain (Numerical Rating Scale). Secondary: 30 s sit-to-stand (30-CST), timed up and go (TUG), grip strength, and quantitative sensory testing. Serum short-chain fatty acids (SCFAs) and glucagon-like peptide-1 (GLP-1) were measured. The study was not powered to detect synergistic interaction. <b>Results</b>: A total of 117 participants (58.1% female; mean ± SD age = 67.5 ± 9.4 years; BMI = 29.5 ± 5.3 kg/m²; NRS = 3.96 ± 2.67) completed the trial. Pain improved with inulin (baseline-adjusted between-group mean difference (Δ) = -1.11 [95%CI -2.18, -0.04], <i>p</i> = 0.045) and PSE (Δ = -1.55 [95%CI -2.52, -0.58], <i>p</i> = 0.002) compared to placebo, with no synergistic effect. PSE improved TUG (<i>p</i> = 0.02) and 30-CST (<i>p</i> = 0.0004), while inulin improved grip strength (<i>p</i> = 0.002), pressure pain thresholds (<i>p</i> = 0.009) and temporal summation (<i>p</i> = 0.025) compared to placebo and had significantly lower dropout rates (3.6%) compared with PSE (21% <i>p</i> < 0.01). Only inulin increased SCFA butyrate (<i>p</i> = 0.0248) and GLP-1 (<i>p</i> = 0.0109), and higher GLP-1 was associated with improved grip strength, suggesting a gut-muscle link. <b>Conclusions</b>: Inulin and PSE each produced meaningful pain reductions. Only inulin improved pain sensitivity and grip strength, the latter paralleled by increased GLP-1, and had much higher rates of retention compared to PSE.