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Association of Gut Microbiome and Primary Liver Cancer: A Two-sample Mendelian Randomization and Case-control Study.

BACKGROUND & AIMS
Observational epidemiology studies suggested a relationship between the gut microbiome and primary liver cancer. However, the causal relationship remains unclear because of confounding factors and reverse causality. We aimed to explore the causal role of gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).


METHODS
A Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWAS) of gut microbiome and liver cancer, and sequencing data from a case-control study validated the findings. A 5-cohort GWAS study in Germany (N=8,956) served as exposure, while the UK biobank GWAS study (N=456,348) served as outcome. The case-control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from Dec. 2018 to Oct. 2020, included 184 HCC patients, 63 ICC patients, and 40 healthy controls.


RESULTS
A total of 57 features were available for MR analysis, and protective causal associations were identified for Family_Ruminococcaceae (OR=0.46 [95%CI, 0.26-0.82]; P=0.009) and Genus_Porphyromonadaceae (OR=0.59 [95%CI, 0.42-0.83]; P=0.003) with HCC, and for Family_Porphyromonadaceae (OR=0.36 [95%CI, 0.14-0.94]; P=0.036) and Genus_Bacteroidetes (OR=0.55 [95%CI, 0.34-0.90]; P=0.017) with ICC, respectively. The case-control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (P=0.00033), Family_Porphyromonadaceae (P=0.0055), and Genus_Bacteroidetes (P=0.021) than the liver cancer patients.


CONCLUSIONS
This study demonstrates that Ruminococcaceae, Porphyromonadaceae, and Bacteroidetes are related to a reduced risk of liver cancer (HCC or ICC), suggesting potential significance for the prevention and control of liver cancer.