Gut microbiota accelerates cisplatin-induced acute liver injury associated with robust inflammation and oxidative stress in mice

Shenhai Gong,Meiping Pan,Rong Wu,Songhua Yuan,Jingrui Chen,Fangjie He,Yunong Zeng,Jiuling Lu,Yinglin Feng,Huanrui Zhang,Xia Chen,Siyou Zhang

doi:10.1186/s12967-021-02814-5

Abstract

BackgroundGut microbiota has been reported to be disrupted by cisplatin, as well as to modulate chemotherapy toxicity. However, the precise role of intestinal microbiota in the pathogenesis of cisplatin hepatotoxicity remains unknown.MethodsWe compared the composition and function of gut microbiota between mice treated with and without cisplatin using 16S rRNA gene sequencing and via metabolomic analysis. For understanding the causative relationship between gut dysbiosis and cisplatin hepatotoxicity, antibiotics were administered to deplete gut microbiota and faecal microbiota transplantation (FMT) was performed before cisplatin treatment.Results16S rRNA gene sequencing and metabolomic analysis showed that cisplatin administration caused gut microbiota dysbiosis in mice. Gut microbiota ablation by antibiotic exposure protected against the hepatotoxicity induced by cisplatin. Interestingly, mice treated with antibiotics dampened the mitogen-activated protein kinase pathway activation and promoted nuclear factor erythroid 2-related factor 2 nuclear translocation, resulting in decreased levels of both inflammation and oxidative stress in the liver. FMT also confirmed the role of microbiota in individual susceptibility to cisplatin-induced hepatotoxicity.ConclusionsThis study elucidated the mechanism by which gut microbiota mediates cisplatin hepatotoxicity through enhanced inflammatory response and oxidative stress. This knowledge may help develop novel therapeutic approaches that involve targeting the composition and metabolites of microbiota.

Highlights

Gut microbiota has been reported to be disrupted by cisplatin, as well as to modulate chemotherapy toxicity
We described a new mechanism through which gut microbiota significantly promote cisplatin hepatotoxicity by enhancing the host inflammatory response and oxidative stress, in order to shed light on the potential therapeutic strategies against cisplatin-induced liver injury by targeting the gut microbiota
The results are expressed as mean ± standard error of the mean (SEM). n = 3–12 per group. *P < 0.05 the mice that received faeces from the cisplatin-treated group showed more apoptosis, as revealed by transferase dUTP nick end labelling (TUNEL) staining (Fig. 6n). These results indicated that the dysbiosis of gut microbiome induced by cisplatin treatment could promote the progression of cisplatin-induced liver failure

Summary

Introduction

Gut microbiota has been reported to be disrupted by cisplatin, as well as to modulate chemotherapy toxicity. The precise role of intestinal microbiota in the pathogenesis of cisplatin hepatotoxicity remains unknown. A first-generation platinum-containing drug, is effective in the treatment of various solid tumours, including lung, testicular, and ovarian tumours, as well as malignant pleural mesothelioma and breast cancer [1, 2]. Mounting evidence suggests the existence of severe toxicity and undesirable adverse effects with the use of cisplatin [5]. Its toxicities mainly include ototoxicity, gastrotoxicity, nephrotoxicity, and hepatotoxicity, all of which severely limit clinical application [6, 7]. Drug-induced liver injury is a significant health problem because of its unpredictable nature and possible fatal outcome [8].

Methods

Results

Conclusion