Genetically predicted gut bacteria, circulating bacteria-associated metabolites and pancreatic ductal adenocarcinoma: a Mendelian randomisation study

Pancreatic ductal adenocarcinoma (PDAC) has high mortality and rising incidence rates. Recent data indicate that the gut microbiome and associated metabolites may play a role in the development of PDAC. To complement and inform observational studies, we investigated associations of genetically predicted abundances of individual gut bacteria and genetically predicted circulating concentrations of microbiome-associated metabolites with PDAC using Mendelian randomisation (MR). Gut microbiome-associated metabolites were identified through a comprehensive search of Pubmed, Exposome Explorer and Human Metabolome Database. Single Nucleotide Polymorphisms (SNPs) associated by Genome-Wide Association Studies (GWAS) with circulating levels of 109 of these metabolites were collated from Pubmed and the GWAS catalogue. SNPs for 119 taxonomically defined gut genera were selected from a meta-analysis performed by the MiBioGen consortium. Two-sample MR was conducted using 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. Inverse variance-weighted MR analyses were performed along with sensitivity analyses to assess potential violations of MR assumptions. Nominally significant associations were noted for genetically predicted circulating concentrations of mannitol (odds ratio per standard deviation [OR_SD] = 0.97; 95% confidence interval [CI]: 0.95-0.99, p = 0.006), methionine (OR_SD= 0.97; 95%CI: 0.94-1.00, p = 0.031), stearic acid (OR_SD= 0.93; 95%CI: 0.87-0.99, p = 0.027), carnitine = (OR_SD=1.01; 95% CI: 1.00-1.03, p = 0.027), hippuric acid (OR_SD= 1.02; 95%CI: 1.00-1.04, p = 0.038) and 3-methylhistidine (OR_SD= 1.05; 95%CI: 1.01-1.10, p = 0.02). Two gut microbiome genera were associated with reduced PDAC risk; Clostridium sensu stricto 1 (OR: 0.88; 95%CI: 0.78-0.99, p = 0.027) and Romboutsia (OR: 0.87; 95%CI: 0.80-0.96, p = 0.004). These results, though based only on genetically predicted gut microbiome characteristics and circulating bacteria-related metabolite concentrations, provide evidence for causal associations with pancreatic carcinogenesis.