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Immune thrombocytopenic purpura (ITP) is an autoimmune disorder, and recent research suggests that gut microbiota and inflammatory cytokines may play a significant role in its pathogenesis. However, the specific effects of these factors on ITP and their relationships remain unclear. We conducted a two-step, two-sample Mendelian randomization study using an inverse variance-weighted approach to investigate the causal role of the gut microbiota in ITP and the mediating effect of inflammatory cytokines on their association. The results showed that among the 473 gut microbiota species, 11 were positively associated and 12 were negatively associated with the risk of ITP. Among the 91 screened inflammatory cytokines, five (CXCL10, CXCL5, IL-12RA, TRAIL, and VEGF-A) were found to have a causal relationship with ITP. Mediation analysis revealed that the gut microbiota UBA1066 promoted the occurrence of ITP through CXCL10 mediation, with a mediation effect of 0.118932 (95% CI: 0.049471-0.188393) accounting for 9.95% of the total effect. Gut microbiota Treponema promoted ITP through VEGF-A mediation, with a mediation effect of 0.045873 (95% CI: 0.01456-0.07718) accounting for 4.28% of the total effect. Gut microbiota Haloplasma promoted the occurrence of ITP via CXCL5. The mediating effect of CXCL5 was 0.038409 (95% CI = 0.00107718-0.07575082), with a mediating ratio of 16.79%. This study revealed a causal relationship between gut microbiota composition and ITP risk, highlighting three inflammatory cytokines as potential causal mediators of this relationship. These findings provide potential targets and biomarkers for the prevention and treatment of ITP with significant clinical implications., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)