Alterations in short-chain fatty acid-associated gut microbiota and tight junction integrity in adolescent major depressive disorder

Major depressive disorder (MDD) often begins during adolescence, a critical developmental period during which nearly 50% of lifetime cases emerge. Despite its high prevalence and impact, objective diagnostic biomarkers for adolescent MDD remain limited, particularly those related to gut microbiota. Our study examined potential co-diagnostic biomarkers from peripheral blood and fecal samples in adolescents with MDD. We enrolled drug-naïve adolescents with first-episode MDD (n = 46, aged ≤18 years, 71.74% female) and age-/sex-matched healthy controls (HCs, n = 44). The levels of tight junction proteins (Claudin-5, Zonulin, FABP) and inflammatory biomarkers (IL-6, IL-8, TNF-α, and CRP) were markedly elevated in the plasma of adolescents with MDD, indicating gut barrier dysfunction and systemic inflammation. The microbiome in MDD patients exhibited a lower Firmicutes-to-Bacteroidetes ratio. At the genus level, Intestinimonas and Barnesiella were significantly enriched, while Dialister and Collinsella were considerably reduced. Integrating Collinsella abundance with tight junction proteins and inflammatory markers significantly improved diagnostic performance, achieving an area under the curve (AUC) of 0.964. Moreover, Collinsella negatively correlated with sex, Claudin-5, and TNF-α. Claudin-5 was strongly associated with short-chain fatty acids (SCFAs)-related pathways, including alanine, aspartate, glutamate metabolism, D-glutamine and D-glutamate metabolism, and autophagy regulation. Treatment of Caco-2 cells with propionate and butyrate confirmed the regulatory effects of SCFAs on tight junction biomarkers. These findings suggest the interplay between gut dysbiosis, barrier dysfunction, and inflammation in adolescent MDD and support microbiota-host biomarkers as a promising strategy for improving MDD diagnostic precision.