Gut microbiome enterotypes associate with distinct metabolomic landscapes and clinical outcomes in inflammatory bowel disease: a multi‑omics dissection

The gut microbiota contributes to inflammatory bowel disease (IBD), but patient‑to‑patient variation in microbial dysbiosis remains poorly characterised. The gut‑brain axis is implicated in the high rate of psychiatric comorbidities in IBD, though the microbial and metabolic mediators are not fully defined. We recruited 71 healthy individuals and 178 IBD patients (104 ulcerative colitis, 74 Crohn’s disease) and performed faecal metagenomic and untargeted metabolomic sequencing. Non‑negative matrix factorisation (NMF) consensus clustering defined gut microbiome enterotypes, followed by integrative multi‑omics and clinical correlation analyses. NMF identified two robust enterotypes within IBD patients: GET‑B (Bacteroidaceae‑enriched, n = 112) and GET‑E (Enterobacteriaceae‑enriched, n = 66). GET‑B microbiota resembled healthy controls, whereas GET‑E had lower α‑diversity, more complex co‑occurrence networks, higher clinical symptom scores (GSRS, disease severity), and higher anxiety/depression scores (HAMA, HAMD/PHQ-9). Metabolomics revealed that GET‑B patients were enriched in protective metabolites, including secondary bile acids tauroursodeoxycholic acid (TUDCA), tryptophan derivatives (indole‑3‑propionic acid [IPA], indole‑2‑carboxylic acid [I2CA]), butyrate, and L‑dopa. Conversely, GET‑E had elevated tyramine. Integrative network analysis showed that Bacteroidetes species positively correlated with protective metabolites and negatively with disease severity and psychiatric scores; Proteobacteria species (especially Escherichia coli and Klebsiella pneumoniae ) showed the opposite pattern. A random forest model using nine bacterial species distinguished the two enterotypes with high accuracy (AUC = 0.964, 95% CI: 0.919—1.000). IBD patients segregate into two clinically distinct enterotypes with markedly different metabolomic landscapes. The GET‑E enterotype, marked by Proteobacteria expansion and depletion of protective microbial metabolites, associates with more severe disease and psychiatric comorbidity. These results offer a microbiome‑based stratification framework for IBD and highlight candidate metabolic pathways that may link gut dysbiosis to the gut‑brain axis.