Abstract
Background Most patients with hepatocellular carcinoma (HCC) lose the chance of survival due to lack of timely diagnosis and effective treatment. The specific gut microbiota (GM) spectrum may become the target of early diagnosis and treatment of HCC. However, the metabolic mechanisms that affect the occurrence of liver cancer are still unclear.
Methods In this study, we called the dataset of HCC, and 1,091 serum metabolites 309 metabolite ratios as well as 211 GM taxa through GWAS instrumental variables for Mendelian randomization causal association analysis and metabolome intermediary effects exploration. Through functional enrichment of intermediate metabolites, the effects of metabolic pathways involved in GM on HCC were analyzed. Inverse variance weighting (IVW) was the main model for establishing causal associations. Additionally horizontal pleiotropy test, linkage disequilibrium test and sensitivity analysis were employed to test the explanatory power of instrumental variables (SNPs).
Results Our study found Coriobacteriia class, Coriobacteriales order, Coriobacteriaceae family, and 4 specific genera were strongly related to HCC (P < 0.05). Meanwhile, through two samples-MR Analysis , 49 metabolites levels/ratios were shown to be closely related to the development of HCC. A total of 10 related metabolic intermediary factors have been selected, and 4 metabolic pathways of Pyrimidine (P = 0.0031), Caffeine(P = 0.0072), Urea Cycle (P = 0.0105) and Glutamate (P = 0.0298) were significantly enriched in this GM related HCC process.
Conclusion Coriobacteriia class and its lower taxa were associated with the risk factors of developing HCC through the regulation of Pyrimidine, Caffeine, Urea Cycle and Glutamate metabolic pathways. These biomarkers may become targets for HCC early diagnosis and immunotherapy.