Novel insights into gut microbiota alterations in major depressive disorder with suicidal ideation: a metagenomic analysis

Introduction Suicidal ideation in major depressive disorder (MDD) is common, yet its biological mechanisms and biomarkers remain unclear. The gut microbiota, a key component of the gut-brain axis, has been implicated, but current evidence is limited. Methods We analyzed fecal samples from 141 participants, including 52 healthy controls (HCs) and 89 first-episode, drug-naïve MDD patients, further classified into suicidal ideation (SI, n = 57) and non-suicidal ideation (NSI, n = 32) groups using the Beck Scale for Suicide Ideation (BSSI). Shotgun metagenomic sequencing with HUMAnN3-based taxonomic and functional profiling was performed. Microbial diversity, differential abundance, and partial correlation analyses with suicidal ideation severity were conducted to identify key microbial taxa associated with suicidal ideation. For functional difference analysis, MaAsLin2 was employed across four levels: KEGG Orthology (KO), KEGG pathways, CAZy, and MetaCyc pathways. Mediation analysis was used to assess potential mediating effects between suicidal ideation and key microbial taxa after adjustment for age, sex, education, and BMI. Results No significant differences were observed in overall microbial diversity. Bacteroides cellulosilyticus was enriched in HCs and showed a significant negative association with suicidal ideation severity. Functionally, compared with the NSI group, patients with suicidal ideation exhibited reduced microbial capacities related to peptidoglycan biosynthesis. Mediation analysis further indicated that B. cellulosilyticus may modulate suicidal ideation through pathways involved in carbohydrate transport and metabolism, vitamin K2 biosynthesis, and DNA repair. Conclusion Bacteroides cellulosilyticus may act as a potentially protective microbial species, negatively regulating suicidal ideation, possibly by enhancing carbohydrate metabolism and short-chain fatty acid production. Notably, this species has received limited attention in the context of psychiatric disorders, highlighting its potential as a novel microbial target. These findings provide new microbiome-based insights into suicidal ideation in MDD.