The association of gut barrier dysfunction, gut bacteria and circulating bacteria-associated metabolites with pancreatic ductal adenocarcinoma and hepatocellular carcinoma

Recent data indicate that the gut microbiome and levels of circulating bacteria-associated metabolites are altered in pancreatic and liver cancers. However, it is unclear if these alterations are associated with cancer risk. To address this question, associations of genetically predicted abundances of 119 gut bacteria and concentrations of 109 circulating microbiome-associated metabolites with pancreatic ductal adenocarcinoma (PDAC) were investigated using two-sample Mendelian randomisation (MR) and genome-wide association study (GWAS) summary statistics from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including a total of 8,769 cases and 7,055 controls. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol, methionine, stearic acid, carnitine, hippuric acid and 3-methylhistidine. Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 and Romboutsia. Circulating markers of gut barrier disruption and inflammation were also assessed in two European PDAC case-control studies (Czech and Spanish). Markers of intestinal injury such as intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin-1 (ZO-1) exhibited inconsistent associations with PDAC, however, inflammatory cytokines including interleukin (IL)-6, IL-8 and IL-10 were consistently elevated in PDAC cases compared to the control groups. Combination models incorporating these markers demonstrated modest discriminatory power, reinforcing the central role of systemic inflammation in PDAC. Finally, the causal relationship between gut microbial taxa, microbiota-associated metabolites and hepatocellular carcinoma (HCC) risk was investigated. The latest GWAS summary statistics from FinnGen, including 609 HCC cases and 473,046 controls, and the Hepatocellular Carcinoma Epidemiology Consortium (HCCEC) study, which comprises 1,872 HCC cases and 2,907 controls were used, representing the largest investigation of its kind to date. Analyses revealed that higher levels of acetoacetate, ascorbic acid, asparagine, taurochenodeoxycholic acid and threonic acid were predicted to be inversely associated with HCC risk, whereas elevated alanine and hippuric acid were predicted to be associated with increased risk. Increased abundances of the genera Barnesiella, Catenibacterium, Enterorhabdus, Eubacterium oxidoreducens, Eubacterium rectale, Hungatella, Ruminococcus torques, Sellimonas and an unclassified genus were predicted to be associated with increased HCC risk, while Escherichia-Shigella was predicted to exhibit a protective effect.