Causal role of gut microbiota in immune thrombocytopenia: A systematic review of mendelian randomization studies

Abstract

Abstract Background Gut dysbiosis has been repeatedly linked to immune thrombocytopenia (ITP), but confounding and reverse causation hamper interpretation. Mendelian randomization (MR) leverages germ-line variants as proxies for microbial abundance, offering quasi-experimental insight into causality. We systematically reviewed MR evidence probing the microbiota–ITP axis. Methods PubMed, Embase and Web of Science were searched from inception to 1 July 2025 for two-sample or multivariable MR studies that treated gut taxa (phylum–species) as exposures and ITP as outcomes. Three reviewers extracted exposure/outcome GWAS characteristics and synthesised findings narratively because taxonomic depth and analytic pipelines differed. Results Five eligible Mendelian-randomisation studies—Guo 2023, Jiang 2024, Li 2024, Hong 2024 and Ji Gan Wang 2024—each analysed 196–473 gut microbial traits in more than 600,000 MiBioGen (±Dutch Microbiome Project) participants and harmonised these with FinnGen or UK Biobank GWAS datasets that included 810–3,804 European immune-thrombocytopenia (ITP) cases; all instruments were strong (F > 10) and sensitivity analyses revealed negligible horizontal pleiotropy. Across studies, risk-enhancing taxa replicated in at least two analyses—Alcaligenaceae, methanogens, Alistipes, Gordonibacter and Coprococcus—with Guo first identifying Alcaligenaceae (odds ratio [OR] 2.40) and Gordonibacter (OR 1.64) as hazards. Protective taxa comprised the Bacteroidales S24-7 group, Actinobacteria, Porphyromonadaceae and the Eubacterium oxidoreducens group; Li confirmed a strong inverse association for Bacteroidales S24-7 (OR 0.46). Hong 2024 showed that three serum metabolite ratios—sphingomyelin, glucose-to-mannose and bilirubin—mediated 8–21 % of the total causal effects of Intestinimonas and Senegalimassilia on ITP, while Wang 2025 demonstrated that UBA1066, Treponema and Haloplasma transmitted risk via distinct cytokines (CXCL10, VEGF-A and CXCL5, respectively), accounting for 4–17 % of their total effects, and further established five cytokines (CXCL10, CXCL5, IL-12RA, TRAIL and VEGF-A) as directly causal for ITP. Reverse-direction MR consistently indicated that genetically predicted ITP does not modify gut composition, and leave-one-out tests across all studies confirmed the robustness of these estimates. Conclusions Convergent MR evidence now implicates distinct gut microbes in the modulation of ITP susceptibility. High-risk signatures (methanogens, Alistipes, UBA1066, Treponema, Haloplasma) and protective taxa (Bacteroidales S24-7, Porphyromonadaceae, Eubacterium spp.) elucidate mechanistic pathways, while cytokine-specific mediation indicates targeted anti-inflammatory strategies. Future metagenomic research on diverse ancestries, along with strain-level metagenomics and integrated multi-omics, is essential to enhance biomarkers and create microbiome-targeted interventions for ITP.