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

Mar 12, 2026Journal of affective disorders

Sex differences in inflammation and gut-brain barrier problems in teen depression linked to self-injury risk

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Abstract

Female adolescents with major depressive disorder exhibited higher TNF-α levels compared to males.

Female patients demonstrated more severe depressive and anxiety symptoms than male patients.
There is a positive correlation between gut and blood-brain barrier markers, suggesting involvement of the gut-brain axis.
Younger age and elevated S100β levels significantly predict non-suicidal self-injury in females.
The gut-brain biomarker model achieved a predictive performance with an area under the curve of 0.844.

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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.

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

Abstract

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