OBJECTIVE: To examine whether gut microbes were associated with postsurgery-sustained knee pain in patients with knee osteoarthritis (OA) by a gut microbiomics approach. METHODS: Patients receiving total knee replacement (TKR) because of primary knee OA were recruited. Sustained knee pain status at ≥ 1 year after TKR was defined by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Fasting plasma and fecal samples were collected. Metabolomic profiling was performed on fasting plasma. 16S rRNA sequencing was performed on fecal samples to determine microbial composition. RESULTS: Twenty patients with TKR because of primary knee OA were included in the study, with 10 experiencing sustained postsurgery pain and 10 without such pain. Age, sex, and BMI (kg/m) were matched. Linear discriminant analysis of microbiome data identified 13 bacterial taxa that were highly abundant in the pain group and 5 that were highly abundant in the nonpain group ( < 0.05 for all). Plasma metabolomic profiling measured 622 metabolites. The correlation analysis indicated the 18 taxa were significantly correlated with 231 metabolites ( < 0.05 for all). Sparse partial least squares discriminant analysis showed that 30/231 metabolites explained 29% of total variance and can be used to clearly separate patients with sustained knee pain from patients in the nonpain group. Pathway enrichment analysis showed that these significant metabolites were enriched in the arachidonic acid metabolic pathway, bile acid biosynthesis, and linoleic acid metabolism. CONCLUSION: Gut microbes may play a significant role in sustained knee pain in patients with knee OA after TKR, potentially through their activation of inflammatory pathways, lipid metabolism, and central sensitization.