Enterotype-based stratification identifies clinically distinct microbial subtypes in inflammatory bowel disease

Abstract Background Inflammatory bowel diseases (IBDs) are heterogeneous disorders in which gut microbial dysbiosis may influence disease activity and clinical outcomes. However, it remains unclear whether microbiome-based stratification identifies clinically relevant IBD subtypes. Methods We profiled the gut microbiome of a cohort comprising patients with IBD (n = 260), at-risk individuals (n = 166), and healthy control individuals (n = 57) using 16S rRNA gene amplicon sequencing. Unsupervised clustering was used to define gut microbial enterotypes. Associations with clinical characteristics and outcomes, including fecal calprotectin levels and medication step-up, were evaluated. Statistical and machine learning approaches were applied to identify enterotype-specific microbial signatures. Results Four enterotypes were identified and labeled according to their most discriminative genera: Faecalibacterium and Blautia, Prevotella, Phocaeicola, and Bifidobacterium with reduced Faecalibacterium (Bif + Faec-low). Faecalibacterium and Blautia and Prevotella were enriched in healthy control individuals, Phocaeicola was enriched in at-risk individuals, and Bif + Faec-low was enriched in patients with IBD. The Bif + Faec-low enterotype was associated with lower body mass index, higher fecal calprotectin levels, and an increased risk of medication step-up (hazard ratio, 1.71; 95% confidence interval, 1.10-2.66). Microbial composition and network analyses identified distinct enterotype-specific taxa and hub genera, suggesting functional divergence among enterotypes. Conclusions Gut microbial enterotypes are associated with distinct clinical phenotypes and treatment escalation in IBD, and exhibit enterotype-specific microbial community structures and alterations across disease states. Enterotype-based stratification may provide a clinically relevant framework for assessing risk assessment and guiding personalized disease management.