Genetically Predicted Gut Microbiota and Host Metabolites Mediate the Causal Link Between Dietary Factors and Acute...

Dietary factors may have a causative influence on acute myeloid leukemia (AML), a hematologic cancer known to be highly fatal. It is still mostly unknown whether causal mechanisms connect dietary exposures to AML, particularly through the gut microbiota and host metabolism. A two-sample Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) data to assess the causal effect of 20 routine dietary factors on AML. A two-step MR framework was employed to assess the mediating roles of gut microbiota and host metabolites. Sensitivity analyses, including inverse variance weighted (IVW), MR-Egger, and MR-PRESSO, were performed to ensure the robustness of results. Processed meat consumption was causally associated with an increased risk of AML (IVW OR = 15.111; 95% CI = 1.253-182.262; p = 0.033). The gut microbiota-associated L-histidine degradation I pathway was identified as a pro-carcinogenic mediator, accounting for 19.5% of the effect. Conversely, host metabolites, including circulating glycerol levels and the free cholesterol-to-total lipids ratio in very large high-density lipoprotein (HDL), functioned as protective mediators. No substantial horizontal pleiotropy or heterogeneity was observed, thereby reinforcing the validity of these findings. This research offers a new understanding of the role of processed meat in the development of AML via the microbiota-metabolite axis and emphasizes possible metabolic compensatory pathways.