Sex differences in inflammation and gut–brain barrier dysfunction in adolescent depression: implications for predicting non-suicidal self-injury

Background Adolescent depression shows clear sex differences, with females having higher prevalence and more severe symptoms than males. The biological basis of these differences, particularly involving inflammation and the gut–brain axis, remains poorly understood. This study investigated sex-specific clinical and biological features and their value in predicting non-suicidal self-injury (NSSI) in adolescents with major depressive disorder (MDD). Methods Ninety-two adolescents with MDD were assessed using the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. Serum levels of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-4, IL-8), gut barrier markers (iFABP, LBP), and blood–brain barrier (BBB) markers (S100β, claudin-5) were measured. Associations were examined using Spearman correlation, and logistic regression was applied to identify predictors of NSSI in females. Results Female patients had more severe depressive and anxiety symptoms and higher TNF-α levels than males. Gut and BBB markers were positively correlated, indicating gut–brain axis involvement. Logistic regression showed that younger age (OR < 1) and higher S100β levels (OR > 1) significantly predicted NSSI in females. The gut–brain biomarker model showed the best predictive performance (AUC = 0.844). Conclusion Adolescents with MDD exhibit sex-specific clinical and biological profiles. Younger age and increased BBB permeability, reflected by elevated S100β, are key predictors of NSSI in females. Gut–brain axis biomarkers may aid early risk identification and targeted intervention in adolescent depression.