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

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). 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. 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). 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. • Female adolescents with major depressive disorder (MDD) exhibit more severe depressive and anxiety symptoms, along with significantly higher levels of the pro-inflammatory cytokine TNF-α, compared to males. • Markers of gut barrier integrity (iFABP, LBP) and blood-brain barrier permeability (S100β, claudin-5) are positively correlated, supporting the involvement of gut-brain axis dysfunction in adolescent depression. • In female adolescents, younger age and elevated serum S100β—a biomarker of BBB permeability—are significant predictors of non-suicidal self-injury (NSSI), with a gut-brain biomarker model showing high predictive accuracy (AUC = 0.844).