Gut Microbiota Mediates the Therapeutic Effect of Monoclonal Anti-TLR4 Antibody on Acetaminophen-Induced Acute Liver Injury in Mice

Microbiology Spectrum

Qian Cui¹  Yulong Wu²  Jin Zhu³  Zhan Yang³  Xuewei Sun³  Tingting Zhou³  Xiaoguang Liu⁴  Ke OuYang⁵  HuaYing Huang⁵  Juan Ni⁵ 

[1]Air Force Hospital of Eastern Theater, Nanjing, China

[2]Binzhou Medical University, Yantai, China

[3]Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China

[4]Department of Respiratory and Critical Care Medicine, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China

[5]The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China

关键词: gut microbiota;    acetaminophen;    acute liver injury;    TLR4;   

DOI  :  10.1128/spectrum.00647-22

来源: DOAJ

【 摘 要 】

ABSTRACT Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies show that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the gut microbiota and their metabolic pathway, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury compared with the mice receiving feces from the APAP group. ATAB therapy also improved the gut barrier functions in mice and reduced the expression of protein zonulin. Our results revealed that gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found the monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through the change of the gut microbiota, metabolic pathways, and gut barrier function. This work suggested the gut microbiota can be the therapeutic target of the APAP-induced acute liver injury, and we performed the fundamental research for further research.

【 授权许可】

Unknown