Cross-kingdom gut microbiota signatures and their associations with clinical phenotypes in adolescents with bipolar depression.

Emerging evidence highlights the pivotal role of the gut microbiota (GM) in mental health; however, investigations into its cross-kingdom composition in adolescent bipolar disorder remain critically limited. Most studies have focused solely on bacteria, overlooking the complex interactions involving archaea, viruses, and fungi. This study aimed to comprehensively characterize the taxonomic and functional alterations in the cross-kingdom gut microbiota of adolescents with bipolar depression and examine their associations with clinical parameters. We enrolled 60 adolescents aged 12-18 years, including 30 diagnosed with bipolar depression and 30 age- and sex-matched healthy controls. Fecal samples were collected alongside detailed clinical data, including psychiatric symptomatology, cognitive assessments, and dietary habits. Metagenomic sequencing was conducted to profile microbial taxa and functional gene pathways across domains. Statistical analyses assessed differences in alpha and beta diversity, differential abundance, and correlations with clinical phenotypes. Alpha diversity was significantly reduced in the viral and fungal domains among patients, while archaeal and bacterial diversity showed no significant differences. Beta diversity analysis did not reveal global community structural shifts across domains. Taxonomic profiling identified Methanohalobium evestigatum as significantly enriched in archaea, alongside increased abundance of several Firmicutes and Actinobacteria species in the bacterial domain. Viral analysis revealed elevated levels of Brussowvirus AlQ132, Orpheovirus IHUMI LCC2, Afonbuvirus coli, Carjivirus hominis, and Carjivirus communis in the patient group. LEfSe analysis uncovered 15 significantly altered metabolic pathways, including those involved in DNA repair, energy metabolism, and immune signaling. Notably, several taxa and pathways were significantly associated with clinical parameters such as symptom severity, cognitive flexibility, sleep quality, and dietary intake. Adolescents with bipolar depression exhibit distinct alterations in cross-kingdom gut microbiota composition and function, with specific microbial taxa and metabolic pathways correlating with key clinical phenotypes. These findings underscore the potential of gut microbiome signatures as biomarkers and therapeutic targets in early-onset mood disorders and highlight the importance of including archaea, fungi, and viruses in future microbiome-based mental health research.