中国免疫学杂志2025，Vol.41Issue(3)：540-544,550,6.DOI:10.3969/j.issn.1000-484X.2025.03.005
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
Inhibition of YAP1 increases abundance of intestinal AKK bacteria and improves mechanism of PD-1 monoclonal antibody-related liver damage
摘要
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.关键词
PD-1单抗/YAP1/Akkermansia muciniphila/肝损伤Key words
PD-1 monoclonal antibody/Yes-associated protein 1/Akkermansia muciniphila/Liver injury分类
临床医学引用本文复制引用
路峻岚,龚艺,张钰曼,高玉亭,杨彦广,梁华,岳圆,杨佳丽,石新丽..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[J].中国免疫学杂志,2025,41(3):540-544,550,6.基金项目
国家自然科学基金面上项目(82274315) （82274315）
河北省重点研发计划项目卫生健康创新专项(21377735D). （21377735D）
