Causal Mediation Role of Immune Cells in Gut Microbiota–Pneumonia Associations: A Mendelian Randomisation Study

The gut-lung axis plays a pivotal role in pneumonia pathogenesis, with immune regulation serving as a key mechanistic link between gut microbiota and disease progression. Despite established associations among gut microbiota, immune cell traits and pneumonia, their causal interplay and underlying mechanisms remain poorly elucidated. To investigate the causal relationships between gut microbiota and pneumonia and quantify the mediating effects of immune cell traits using Mendelian randomisation (MR), we performed a two-sample MR and multivariable MR (MVMR) analysis employing inverse-variance weighted (IVW) as the primary method. Genetic instruments for 211 gut microbiota taxa and 731 immune cell traits were derived from genome-wide association studies (GWAS). Mediation analysis was conducted to estimate immune cell-mediated effects on microbiota-pneumonia associations. Genetically predicted abundance of the Oxalobacteraceae family was positively associated with pneumonia risk (OR: 1.090; 95% CI: 1.010-1.175; p = 0.026). Mediation analysis revealed that CD16⁺ monocytes significantly mediated this relationship (Mediated Effect: 0.025, proportion mediated: 29.1%). This study provides genetic evidence supporting Oxalobacteraceae as a causal risk factor for pneumonia, partially mediated through CD16⁺ monocyte regulation. These findings offer novel insights into microbiome-directed immunomodulatory strategies for pneumonia prevention.