Abstract: Objective To investigate whether immune cells mediate the causal relationship between the gut microbiota and acute glomerulonephritis ( AGN) through Mendelian randomization(MR) analysis. Methods A two-sample bidirectional MR approach was employed to assess thecausal effect of gut microbiota on AGN. Additionally, a two-step MR strategy was applied to identify potential immune cells mediating this effect. Data from genome-wide association studies ( GWAS) encompassing 473 gut microbial taxa, 731 immune cell traits, and AGN outcomes were included. The primary analysis utilized inverse variance weighted ( IVW) randomization, supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks included Cochran’s Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis. Results Fourteen gut microbial taxa and 27 immune cell types were identified as causallyassociated with AGN. Mediation analysis highlighted that 12 immune cell types mediated the relationship between 9 gut microbial taxa and AGN risk. Notably, Barnesiellaceae and Holdemania werefound to promote AGN risk through 4 immune cell mediators. Additionally, BAFF-R on IgD + CD38 - unsw mem (unswitched memory B cells) mediated the protective effect of Lactobacillus B on AGN, with a mediation effect of 2. 9 % and a mediating proportion of - 7. 50 % . Hydrogenoanaerobacterium exerted its protective effect on AGN risk via HSC AC and CD25 on CD4 Treg, mediating proportions of 10. 60 % and 7. 50 % , respectively. Conclusion This study delineates acomplex network involving gut microbiota, immune cells, and AGN, reflecting multifaceted pathophysiological interactions. The identified causal links and mediating pathways underscore potential therapeutic targets, providing a theoretical foundation for interventions aimed at modulating gut microbiota and immune responses to manage AGN.

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