Escherichia-Shigella expansion and metabolite dysregulation in type 3c diabetes: linking microbiome alterations to exocrine pancreatic insufficiency

Emerging evidence supports a bidirectional gut–pancreas axis in which microbial dysbiosis, barrier dysfunction, and altered metabolite fluxes contribute to pancreatogenic diabetes (T3cDM). Whether gut microbial changes reflect systemic metabolic disturbances or primarily arise from exocrine pancreatic insufficiency (EPI) remains unclear. We profiled the gut microbiome of 48 outpatients with T3cDM, type 1 diabetes (T1DM), and healthy controls. Genus-level 16S rRNA data were analyzed using cross-validated LASSO logistic regression and patient-specific community metabolic models. T3cDM showed reduced α-diversity and distinct β-diversity compared with T1DM and controls. Key compositional shifts included enrichment of Enterobacteriaceae (notably Escherichia–Shigella ) and Streptococcaceae in T3cDM. LASSO models discriminated T3cDM from T1DM (AUC 0.867; accuracy 0.818), highlighting Blautia, Escherichia–Shigella, Streptococcus, Clostridium, and Faecalibacterium as predictors. Metabolic modelling indicated elevated Escherichia–Shigella growth in T3cDM and disease-specific metabolite fluxes. Gut microbial shifts in T3cDM predominantly reflect EPI rather than systemic metabolic disturbances characteristic of T1DM, underscoring the central role of exocrine pancreatic dysfunction in shaping the gut microbiome and its metabolic activity.