Association of gut microbiome and primary liver cancer: A two‐sample Mendelian randomization and case–control study

Abstract

Background and 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 the gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).Methods: Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWAS) of the gut microbiome and liver cancer, and sequencing data from a case-control study validated the findings. A 5-cohort GWAS study in Germany (N = 8956) served as exposure, whilst the UK biobank GWAS study (N = 456 348) served as an outcome. The case-control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from December 2018 to October 2020 and 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 = .009) and Genus_Porphyromonadaceae (OR = 0.59 [95% CI, 0.42-0.83]; p = .003) with HCC, and for Family_Porphyromonadaceae (OR = 0.36 [95% CI, 0.14-0.94]; p = .036) and Genus_Bacteroidetes (OR = 0.55 [95% CI, 0.34-0.90]; p = .017) with ICC respectively. The case-control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (p = .00033), Family_ Porphyromonadaceae (p = .0055) and Genus_Bacteroidetes (p = .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.

Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A bidirectional Mendelian randomization study

“…Genus_Odoribacter is positively involved in non-ribosomal peptide structures and negatively involved in the metabolism of phenylalanine and cyanoamino acids. Family_Porphyromonadaceae has been identified as a potential biomarker for CRC recurrence and patient prognosis (28); casecontrol study results showed that healthy controls had a higher relative abundance of family_Porphyromonadaceae than primary liver cancer patients (29), and combined analysis with our study confirmed its potential as a biomarker in cancer. Family_ Peptococcaceae and genus_Terrisporobacter have been lacking in studies of the human immune system, so it is possible that we found microbes that can be applied as new biomarkers for PD-1/PD-L1 therapy or precancerous diagnosis.…”

Association Between Gut Microbiota and Digestive System Cancers: A Bidirectional Two-Sample Mendelian Randomization Study

“…Digestive system cancers (DSCs) comprise gastrointestinal cancers (esophageal cancer, gastric cancer, small intestinal cancer, colorectal cancer) and hepatobiliary-pancreatic cancers (liver cancer, gallbladder cancer, biliary duct cancer, pancreatic cancer). In general, DSCs are the most commonly diagnosed cancers and the leading cause of cancer deaths throughout the world, as they account for > 26.4% of the new cancer cases and > 36.3% of the new cancer deaths factors for liver cancer, and the researchers further validated the ndings by a case-control study [9]. Nonetheless, the current studies did not systematically examine the relationships between gut bacteria and different DSCs.…”

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

“…Interestingly, recent research has highlighted the importance of the gut microbiome in response to cancer immunotherapy. A study by Ma et al in 2023 showed that the abundance of Ruminococcaceae, Porphyromonadaceae and Bacteroidetes is related to a reduced risk of liver cancer (HCC or ICC), suggesting potential importance of gut microbiome regulation for the prevention and control of liver cancer 52 . Hu et al indicated that the gut microbial metabolite acetate can modulate ILC3 function through Sox13‐dependent signaling, and the combination of PD‐1/PD‐L1 blockade with acetate administration enhances antitumor immunity in HCC mouse models 53 .…”