Abstract
Major depressive disorder (MDD) and irritable bowel syndrome (IBS) exhibit high comorbidity, yet their shared pathophysiology remains unclear. Previous studies have primarily focused on the psychological health in the IBS population, without considering psychiatric diagnoses or stratifying different psychological states, potentially leading to biased findings. This study employed multi-omics approaches to characterize gut microbiota and serum metabolites in 120 MDD patients (47 with IBS and 73 without IBS) and 70 healthy controls (HCs). MDD with IBS patients showed significantly higher depression (Hamilton depression scale [HAMD-17]) and anxiety (Hamilton anxiety scale [HAMA-14]) scores than MDD-only patients (P < 0.05). Metagenomic sequencing of fecal samples revealed increased alpha diversity (Chao1/Shannon indices) and Firmicutes dominance in both MDD groups vs HC, while Actinobacteria enrichment specifically marked MDD with IBS. Functionally, MDD with IBS uniquely activated D-amino acid/glycerolipid metabolism pathways (Kyoto Encyclopedia of Genes and Genomes). Serum metabolomics identified comorbid-specific perturbations: downregulation of bile acids (CDCA, GCDCA, GCDCA-3S) and upregulation of glyceric acid/glutaconic acid. Our study also found that Eggerthella lenta and Clostridium scindens are differentially abundant bacteria that are involved in bile acid metabolism, and that microbial genes (e.g., K03738) are associated with glyceric acid production. These findings implicate gut microbiota-driven bile acid/glyceric acid dysregulation in MDD with IBS comorbidity, supporting the gut-brain axis as a therapeutic target for probiotics or microbiota transplantation.IMPORTANCEMajor depressive disorder (MDD) exhibits a high comorbidity rate with irritable bowel syndrome (IBS). Our study, conducted on 120 MDD patients (47 of whom were comorbid with IBS) and a control group of 70 individuals, revealed that MDD-IBS comorbid patients demonstrated significantly higher depression/anxiety scores. Multi-omics analysis indicated substantial alterations in the gut microbiota (e.g., Firmicutes, Actinobacteria) and serum metabolites (e.g., bile acids, glyceric acid) among MDD-IBS patients, which were associated with specific metabolic pathways. Therefore, the new aspect of this study was the inclusion of patients with MDD but without IBS symptoms, which provided a deeper understanding of the intestinal microbiota dysregulation associated with comorbid IBS and MDD. These findings suggest that there may be involvement of the gut-brain axis, providing new research directions for potential therapeutic targets.CLINICAL TRIALSThis study is registered with the Chinese Clinial Trial Registry as ChiCTR2100041598.