Objective: To investigate the correlation between serum tripartite motif-containing protein 22 (TRIM22) and intestinal barrier function markers [D-lactate, diamine oxidase (DAO), and endotoxin] in patients with ulcerative colitis (UC), and to evaluate the incremental value of TRIM22 in assessing disease activity.Methods: A total of 120 UC patients admitted from June 2024 to June 2026 were enrolled as the observation group, and 60 healthy individuals undergoing physical examination during the same period were selected as the control group. Serum levels of TRIM22, D-lactate, DAO, and endotoxin were compared between the two groups. UC patients were divided into remission, mild, moderate, and severe groups according to the Mayo score, and the above indicators were compared among patients with different disease activity. Pearson correlation analysis was used to analyze the correlations of TRIM22 with intestinal barrier markers and Mayo score. With Mayo score ≥6 defined as moderate-to-severe activity, a multivariable logistic regression model was constructed to evaluate the incremental value of TRIM22 in assessing disease activity. Results: Serum TRIM22, D-lactate, DAO, and endotoxin levels in the UC group were significantly higher than those in the control group (P<0.05). Among 120 UC patients, 29 were in remission, 37 had mild disease, 31 had moderate disease, and 23 had severe disease. With increasing disease activity, serum TRIM22, D-lactate, DAO, and endotoxin levels increased gradually (P<0.05). Pearson correlation analysis showed that serum TRIM22 was positively correlated with D-lactate, DAO, endotoxin, and Mayo score in UC patients (all P<0.05), and D-lactate, DAO, and endotoxin were also positively correlated with Mayo score (all P<0.05). The moderate-to-severe group had significantly higher serum TRIM22, D-lactate, DAO, and endotoxin levels than the non-moderate-to-severe group (P<0.05). Logistic regression analysis showed that TRIM22, D-lactate, DAO, and endotoxin were independent factors associated with moderate-to-severe activity (P<0.05). ROC curve analysis showed that the area under the curve (AUC) of TRIM22 combined with D-lactate, DAO, and endotoxin for assessing moderate-to-severe UC was 0.938, with a sensitivity of 87.70% and a specificity of 90.90%, which was higher than that of each indicator alone.Conclusion: Serum TRIM22 is closely associated with intestinal barrier function markers and disease activity in UC patients. Combined detection can improve the performance of disease activity assessment and has incremental value.