LAUSR

OBJECTIVE This study examined gut permeability in unmedicated adolescents with and without major depressive disorder. METHOD Medically healthy, non-medicated, 12-17 year-old females in a major depressive episode (MDE) or healthy controls, without any psychiatric condition, were enrolled. They completed the Children's Depression Rating Scale-Revised (CDRS-R) and underwent a clinical interview. Preejection period (PEP) and respiratory sinus arrhythmia (RSA) data were collected to measure autonomic nervous system activity. Following an overnight fast, participants ingested lactulose and mannitol and collected urine for 4 hours while still fasting, to examine gut permeability. Plasma cytokines (interleukin 1β, interleukin 6, and tumor necrosis factor α) were measured. Correlational analyses were used to examine the associations between relevant variables. RESULTS 41 female participants (age: 14.8 ± 1.6 years, n = 25 with MDE) were enrolled. PEP, but not RSA, was inversely associated with neurovegetative symptom severity on the CDRS-R (r = -0.31, p < 0.06). In the 30 participants with gut permeability data, the lactulose to mannitol ratio (LMR) was significantly positively associated with depression severity, particularly neurovegetative symptom severity (r = 0.37, p < 0.05). Notably, the association between neurovegetative symptom severity and PEP was substantially reduced after adjusting for LMR. Additionally, depression severity was significantly associated with circulating cytokines. CONCLUSIONS This is the first study to examine gut permeability in unmedicated adolescents, offering preliminary support for a mechanistic pathway linking sympathetic nervous system activation to increased gut permeability and activation of the innate immune system, likely contributing to the emergence of neurovegetative symptoms of depression.