A kynurenine immune-metabolic subtype of depression defined by childhood maltreatment and IDO2: Evidence from multi-omics profiling

Abstract

Abstract Background Major depressive disorder (MDD) is a complex disorder caused by genetic and environmental factors. Previous evidence implicates a potential depression subtype from interaction between childhood maltreatment (CM) and kynurenine pathway (KP) gene. Here, we investigated the top-down multi-omics KP alterations for this subtype. Methods A total of 142 patients with MDD receiving monotherapy were included. Individuals carrying IDO2 rs2340953 TT genotype and reporting CM were classified as IDO2-CM group, whereas the remaining patients were categorized as non-IDO2-CM group. Plasma KP metabolites, DNA methylation, KP-related protein, and inflammatory protein were profiled. Group differences were examined using regression models adjusting for relevant covariates. Results Thirty patients met criteria for the IDO2-CM group. Compared with non-IDO2-CM, IDO2-CM individuals exhibited significantly poorer response rate to antidepressant at weeks 4 and 8. Metabolite analyses revealed a significantly elevated quinolinic acid (QA)/kynurenine (KYN) ratio and QA/kynurenic acid (KYNA) ratio in IDO2-CM group (β = 0.086, SE = 0.042, P = 0.023; β = 0.164, SE = 0.045, P = 0.0006). Epigenetic analyses of KP genes demonstrated coordinated methylation shifts favoring QA production (hypomethylation of KMO and AFMID; hypermethylation of ACMSD) and suppression of KYNA related enzymes (hypermethylation of CCBL1, CCBL2, AADAT, and GOT2). Proteomic profiling identified reduced circulating levels of KYNU and VCAM1 in IDO2-CM group. Conclusions CM interacting with IDO2 genotype defines a biologically distinct MDD subtype characterized by poor antidepressant response and convergent multi-omics evidence of KP bias toward neurotoxic metabolism. These findings support a stratification strategy and highlight the KP as a potential target for precision treatment in depression.