Memory B cells mediate the effect of gut microbiota glycolytic-glyoxylate pathway on lung cancer in never-smokers: A Mendelian randomization study

The rising incidence of lung cancer in never-smokers (LCINS) warrants investigation into novel etiological factors. Gut microbiota-associated metabolic pathways (e.g., glycolysis, glyoxylate degradation) and immune traits, such as the proportion of memory B cells, have been implicated in various diseases, but their causal roles in LCINS remain unclear. Using summary-level data from IEU OpenGWAS, we performed 2-sample Mendelian randomization (MR) to assess causal relationships of 412 gut microbiota features and 731 immune cell traits with LCINS. Mediation MR quantified immune cells' role in linking microbiota to LCINS. Twelve gut microbial taxa and 15 metabolic pathways (including glycolysis and glyoxylate degradation) demonstrated causal associations with LCINS (PIVW < .05). Separately, 36 peripheral immune cell traits showed causal links to LCINS. Mediation analysis further revealed that memory B cell ratio attenuated the effect of microbiota-derived metabolic pathways on LCINS by 7.53% (95% confidence interval: -2.63% to 17.70%; βmediation = -0.017, 95% confidence interval: -0.041 to 0.006). The ratio of memory B cells partially mediates the effect of gut microbiota-driven glycolysis/glyoxylate degradation on LCINS pathogenesis. These findings suggest the gut-immune-lung axis may inform preventive strategies for LCINS.