The study aimed to verify the effect of Tirzepatide (Tzp, a dual agonist GIP/GLP-1) on intestinal health and microbiota balance in an obese diabetic ovariectomized (Ovx) mice model. Female C57BL/6 mice with Ovx and diet-induced obesity with diabetes were treated with Tzp (10 nmol/kg) for four weeks. Control (C) and obese-diabetic subgroups (Od) were formed (group abbreviations: O, Ovx; T, Tzp; n = 30/group): C, CT, CO, COT, Od, OdT, OdO, OdOT. The ileum was structurally and molecularly studied, and cecal feces had microbial DNA determined. Tzp improved the intestinal barrier structure and protection. Cldn12 (Claudin 12) increased, and Muc2 (Mucin 2) decreased. JamA (junctional adhesion molecules) and Ocln (Occludin) increased. Tzp mitigated macrophage activation and inflammation, altered composition, and the contribution to microbiota: Firmicutes decreased, and Bacteroidetes increased, changing the Firmicutes / Bacteroidetes ratio. Proteobacteria, Actinobacteria, Bifidobacterium, and Clostridium increased. In addition, Bacteroides, Prevotella, and Akkermansia increased. PCA indicated a significant action of Cd14, Muc2, and Tlr4 on CO and Il17 on OdO; Il10, Cd206, Cd12, Ocln, and JamA in Od. Bacteroides, Bifidobacterium, Clostridium, Actinobacteria, and Bacteroides were enhanced in CT and COT, Provotella, Proteobacteria, and Firmicutes in CO, Od, OdT, OdO, and Akkermansia in OdOT. In conclusion, the intestinal barrier function in our model is compromised by alterations in phylogenetic diversity and intestinal microbiota, which characterize dysbiosis and potentially enable the influx of toxins into other tissues. Treatment with Tzp demonstrated the ability to reverse intestinal dysbiosis, help repair intestinal barrier integrity, and mitigate possible endotoxemia through anti-inflammatory signaling pathways.
