Integrative multi-kingdom gut microbiome analysis uncovers clinical signatures of major depressive disorder.

BACKGROUNDAccumulating evidence indicates that gut microbiome is significantly altered in major depressive disorder (MDD). However, most studies have focused on bacteria, while the functional and ecological contributions of eukaryotes, archaea, and viruses in MDD remain poorly understood.

METHODSFecal samples were collected from 121 first-episode, drug-naïve young adults with MDD and 117 healthy controls (HC) with matched demographic characteristics for shotgun metagenomic sequencing. Clinical data included the Hamilton Depression Scale (HAMD) and the MATRICS Consensus Cognitive Battery (MCCB). We systematically explored the multi-kingdom gut microbiome, functional genes, and metabolic pathways in MDD and their clinical associations, further assessing their diagnostic potential via machine learning.

RESULTSMDD patients showed significant alterations in multi-kingdom microbiota diversity, accompanied by coordinated diversity relationships across microbial kingdoms relative to HC. In addition, we further identified 19 bacterial, 16 eukaryotic, 15 archaeal, and 10 viral species, as well as 22 functional genes and 32 metabolic pathways, that differed between groups. Importantly, five bacterial and four viral species were significantly associated with cognitive function, such as a positive correlation between Bifidobacterium pseudocatenulatum and attention/vigilance in MDD. Finally, validation demonstrated that a Random Forest model integrating multi-kingdom microbiota and functional features achieved superior diagnostic performance, significantly outperforming models based solely on bacterial features.

CONCLUSIONThis study revealed extensive multi-kingdom microbial dysbiosis in MDD, providing deeper insight into disease-associated ecological disruption and highlighting the potential of microbial markers for enhancing clinical auxiliary diagnosis.