Longitudinal Gut Microbiota Changes in Mouse Models of Chronic Colitis, Colitis‐Associated Cancer, and Chemotherapy‐Induced Diarrhea

Background Gut microbiota contributes to intestinal pathologies, but microbial and metabolic differences distinguishing inflammation‐associated tumorigenesis from chronic colitis remain unclear. This study mapped stage‐dependent microbiota dynamics and metabolic perturbations across three independent mouse models: chronic ulcerative colitis (CUC), AOM/DSS‐induced colitis‐associated cancer (CAC), and chemotherapy‐induced diarrhea (CID). Methods CUC, CAC, and CID were induced by cyclic DSS, AOM/DSS, and CPT‐11, respectively. Disease progression was monitored via endoscopy, histopathology, and Disease Activity Index. Gut microbiota was profiled by 16S rRNA sequencing across three stages (R01–R03); metabolic and inflammatory changes were assessed by RT‐qPCR and metabolite assays. Mediation analysis was used to explore whether the associations between microbial abundance and host metabolic/inflammatory markers were statistically consistent with an indirect pathway. Results CID showed distinct acute transient injury and a unique microbiota structure separate from CUC/CAC. In CUC and CAC, microbiota restructured stage‐dependently: beneficial genera ( Akkermansia ) declined, while pathobionts ( norank_o_Clostridia_UCG‐014 ) increased. CAC showed upregulation of glycolysis genes (HK2, PKM2, LDHA, Glut1) together with elevated colonic lactate concentrations, and elevated colonic concentrations of the pro‐inflammatory cytokines IL‐17A and IL‐22, indicating distinct colonic metabolic and inflammatory changes associated with gut dysbiosis. Mediation analysis showed that norank_o__Clostridia_UCG‐014 showed consistently positive indirect effects, irrespective of the glycolytic enzyme and lactate enantiomer examined; and Allobaculum had a consistently positive indirect effect on both IL‐17A and IL‐22. Conclusion These findings reveal distinct stage‐specific microbial and metabolic signatures distinguishing AOM/DSS tumor‐bearing mice from nonneoplastic chronic colitis and acute chemotherapy intestinal injury.