Continuous Alterations in the Gut Microbial Landscape Associated With Suicidal Ideation in First-Episode Drug-naïve Major Depressive Disorder.

BACKGROUNDMajor depressive disorder (MDD) has been closely associated with gut microbiota dysbiosis; however, the role of the gut microbiota in the progression from depression to suicidal ideation (SI) remains unclear.

METHODSWe enrolled a well-characterized clinical cohort of first-episode, drug-naïve MDD patients, explicitly classified into those without SI (MDDNSI) and those with SI (MDDSI), and matched with healthy controls (HC) on demographic variables. A severity-ordered HC-MDDNSI-MDDSI framework was established to capture progressive microbial and functional shifts, and correlation analyses were used to evaluate their relationships with clinical symptoms and cognitive function.

RESULTSWe identified a group of taxa showing clear severity-related trends, with the potential pathogenic species Bacteroides stercoris and Bacteroides eggerthii increasing across the clinical spectrum, while seven species, including Faecalibacillus intestinalis and Dialister massiliensis, showed a steady decrease. Functional annotation indicated that several major metabolic pathways, such as the bacterial secretion system, weakened progressively with disease severity and formed stable microbe-pathway modules together with pathways involved in energy metabolism and signal transduction. These differential taxa and pathways showed strong associations with clinical features, with Bacteroides stercoris positively correlated with SI, whereas Bifidobacterium pseudocatenulatum displayed a negative association. In addition, mediation analysis further showed that Bacteroides stercoris indirectly influenced SI through the bacterial secretion system pathway, suggesting a meaningful mediating role in SI.

CONCLUSIONThese results revealed progressive alterations in gut microbial composition and metabolic function associated with SI, indicating that gut dysbiosis serves as a potential biological marker for suicide risk in MDD.