Inhibition of YAP1 increases abundance of intestinal AKK bacteria and improves mechanism of PD-1 monoclonal antibody-related liver damage
10.3969/j.issn.1000-484X.2025.03.005
- VernacularTitle:抑制YAP1提高肠道AKK菌丰度改善PD-1单抗相关肝损伤的机制
- Author:
Junlan LU
1
;
Yi GONG
;
Yuman ZHANG
;
Yuting GAO
;
Yanguang YANG
;
Hua LIANG
;
Yuan YUE
;
Jiali YANG
;
Xinli SHI
Author Information
1. 河北中医学院基础医学院,石家庄 050200
- Publication Type:Journal Article
- Keywords:
PD-1 monoclonal antibody;
Yes-associated protein 1;
Akkermansia muciniphila;
Liver injury
- From:
Chinese Journal of Immunology
2025;41(3):540-544,550
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the mechanism of improving liver injury by enhancing the abundance of Akkermansia mu-ciniphila(AKK bacteria)with hepatocyte-specific Yap1 knockout during PD-1 monoclonal antibody treatment.Methods:Hepatocyte-specific Yap1 knockout mice(genotype Yap1Flox/Flox;albumin-Cre,labeled as Yap1LKO)and control mice(genotype Yap1Flox/Flox,labeled Yap1Flox),aristolocholic acidⅠ(AAⅠ)and CCl4 were used to induce liver injury,Yap1LKO mice and Yap1Flox mice were randomly di-vided into control group and PD-1 monoclonal antibody group.After the intervention,real-time PCR detected changes in the abun-dance of AKK bacteria in the fecal microbial DNA of mice,16S rRNA gene sequencing further analyzes intestinal flora changes,the livers of mice were made into wax blocks for HE staining to observe the histopathological changes of the liver.Results:Yap1Flox mice exhibited balloon-like edema degeneration of hepatocytes and infiltration of inflammatory factors in the manifold area,compared with Yap1Flox mice,Yap1LKO mice had reduced the abundance of AKK bacteria in the intestine,fibrosis of the liver,and the degree of dam-age was more serious;PD-1 monoclonal antibody treatment alone did not increase the abundance of AKK bacteria in the intestines of mice,and fibrosis appeared in the liver;however,the abundance of intestinal AKK bacteria in Yap1LKO mice treated with PD-1 mono-clonal antibody increased,the ratio(F/B value)of Firmicutes to Bacteroides at the phylum level decreased,and the morphology of he-patocytes returned to normal and the degree of liver damage decreased.Conclusion:In AAⅠ and CCl4 induced liver injury mice,he-patocyte-specific Yap1 knockout reduced the abundance of AKK bacteria in the intestine,and the degree of liver injury was more se-vere than that in Yap1Flox mice.When treated with PD-1 monoclonal antibody,hepatocyte-specific Yap1 knockout could increase the abundance of AKK bacteria in the intestine,change the composition of intestinal flora,maintain intestinal homeostasis and ameliorate liver injury.
