Involvement of oxidative stress, lipid dysmetabolism and gut microbiol dysbiosis in oxaliplatin-induced fatty liver disease: evidence from a tree shrew model

Background

Oxaliplatin is cornerstone treatment for colorectal cancer, yet a significant proportion of patients develop drug-induced fatty liver disease (DILI). How it induces such liver injury is poorly understood and whether the gut microbiome is involved remains unknown.

Methods

A male tree shrew model of oxaliplatin-induced DILI was established by six intraperitoneal injections (7 mg/kg every two weeks). During the early and late phases of liver injury, liver tissue was analyzed in terms of histopathology, oxidative stress and transcriptional profiling, while feces were subjected to microbial profiling based on 16S rRNA sequencing.

Results

The model recapitulated key features of DILI, including severe hepatocyte steatosis and ballooning in the early phase after the final treatment, mild hepatic steatosis with sinusoidal dilatation in the late phase, and persistent hepatic oxidative stress during both phases. Transcriptional analysis of liver tissue identified 1503 differentially expressed genes (DEGs) between oxaliplatin-treated and control animals, of which 601 DEGs differed between treated animals in the early or late phases after the final treatment of DILI. Pathway enrichment revealed significant dysregulation in oxidative stress (e.g. NDUFA12, OSR1, MPO) and lipid metabolism (e.g., LDAH, ACACB, CH25H, LIPE) genes. Gut microbiota profiling showed an increase in the relative abundance of potentially harmful bacteria (e.g., Parabacteroides, Rikenella, Alistipes and Faecalitalea) and a concurrent decrease in the abundance of anti-oxidative bacteria (e.g., Lactococcus and Flavobacterium). Notably, abundance of several microbial genera in the gut correlated with liver expression of genes involved in oxidative stress and lipid metabolism as well as with levels of oxidative stress markers, and/or fat deposition in the liver.

Conclusion

Our results suggest that our tree shrew model can faithfully replicate key characteristics of oxaliplatin-induced fatty liver disease, and that such disease involves oxidative stress and lipid dysmetabolism in the liver as well as dysbiosis of microbiota in the gut.