The role of gut microbiota in Tirzepatide-mediated alleviation of high-fat diet-induced obesity.

PURPOSE: In this study, we aim to explore the effects of tirzepatide on the gut microbiota in mice with obesity induced by a high-fat diet. METHODS: Forty male C57BL/6J mice, aged six weeks, were randomly assigned to one of four experimental groups: normal control diet, normal control diet with tirzepatide treatment (NCD + TZP), high-fat diet and high-fat diet with tirzepatide treatment (HFD + TZP). Mice in the HFD group were fed a high-fat diet for ten weeks to establish an obesity model. Subsequently, the NCD + TZP and HFD + TZP groups received subcutaneous tirzepatide injections for 14 days, while the NCD and HFD groups were administered an equivalent volume of saline solution. RESULTS: The results showed that tirzepatide significantly suppressed weight gain, reduced the area under the curve in glucose tolerance tests, improved insulin resistance, and decreased adipose tissue mass in mice. Moreover, tirzepatide effectively attenuated lipid deposition and fat droplet formation in the livers of obese mice while modulating the expression of genes implicated in abnormal glucose metabolism. Regarding gut microbiota, tirzepatide alleviated high-fat diet-induced dysbiosis by altering microbial composition and diversity. Following high-fat diet exposure, the abundance of certain bacterial genera-including Akkermansia, Bacteroides, Mucispirillum, Enterococcus, and Alistipes-significantly declines, whereas Faecalibaculum, Allobaculum, and Ileibacterium exhibit notable increases. Tirzepatide intervention facilitated the restoration of gut microbiota homeostasis after high-fat diet exposure. Additionally, correlation analyses revealed that Akkermansia, Bacteroides, and Enterococcus levels negatively correlate with weight gain, blood glucose levels, and various obesity-related indicators, whereas Ileibacterium and Allobaculum abundance positively associates with obesity-related traits. CONCLUSION: In summary, our findings indicate that tirzepatide has the potential to alleviate high-fat diet-induced gut microbiota dysbiosis in mice. Furthermore, changes in the abundance of specific microbial communities linked to obesity-related outcomes may play a role in the anti-obesity effects of tirzepatide.