Introduction: Although extensive studies have revealed the critical role of immune cells in the pathogenesis of Familial Hypercholesterolemia (FH), the interplay between immune cells and gut microbiota and their potential mediating effects in developing this disease still lacks systematic investigation. This study aimed to investigate the potential causal effects of immune cells on FH and evaluate the mediating role of gut microbiota in this process. Methods: This study employed a two-sample Mendelian Randomization (MR) analysis to assess the causal relationships among immune cells, gut microbiota, and FH. Instrumental variables were selected as single-nucleotide polymorphisms significantly associated with exposures from relevant Genome-Wide Association Studies (GWAS). The Inverse-Variance Weighted (IVW) method was primarily used for causal effect estimation, supplemented by MR-Egger and weighted median methods to validate the robustness of the results. The validity of instrumental variables was ensured through heterogeneity tests (Cochran’s Q) and pleiotropy analysis (MR-Egger intercept). Data were sourced from public GWAS databases, ensuring sample independence. Results: This study identified 34 immune cell traits and 12 gut microbiota taxa significantly associated with FH. Among these, 19 immune cells were inversely associated with FH risk, while 15 showed positive associations; among the gut microbiota, six were inversely associated with FH risk, and the other six were positively associated. Mediation analysis results indicated that the associations between immune cells and FH were partially mediated by five gut microbial taxa (including two phyla, three families, and three genera). Specifically, CD39+ activated regulatory T cells (%CD4 Treg), CD39 on CD39+ secreting Treg, and CD39 on CD39+ CD4 exerted significant positive mediating effects on FH through Species Bifidobacterium kashiwanohense, with mediation proportions reaching 19.9%, 15.7%, and 14.3%, respectively; HLA DR on plasmacytoid DC and HLA DR on CD33- HLA DR exerted adverse mediating effects on FH through Family Fibrobacteraceae, with mediation proportions of -10.2% and -8.95%, respectively. Discussion: This study provides evidence linking specific immune cell phenotypes and gut microbial taxa to FH, with partial mediation through immune–microbiota interactions. Although FH is primarily a monogenic disorder, these findings suggest that immune and microbial factors may act as modifiers of lipid metabolism and inflammatory burden. The observed mediation effects were modest, indicating complementary rather than dominant roles, and highlight immune–microbial crosstalk as a relevant context for understanding systemic metabolic phenotypes. Conclusion: This study reveals potential causal links between immune cells and the gut microbiota in FH, providing novel perspectives on the pathogenesis of t
Liang et al. (2026) studied this question.