Abstract
Allergic rhinitis (AR) is a common immune-related disorder recently associated with gut microbiota (GM), though the underlying mechanisms remain unclear. This study employed Mendelian randomization (MR) to investigate causal relationships between GM and AR, combined with transcriptomic analyses, including both bulk and single-cell RNA sequencing (scRNA-seq), to explore molecular mechanisms at tissue and cellular resolutions. Data for AR and GM were sourced from public databases. MR identified causal microbial taxa, whose associated SNPs were mapped to genes. These were intersected with differentially expressed genes (DEGs) from transcriptomic data to identify candidate genes. Key genes were validated through expression analysis, immune infiltration, functional enrichment, regulatory network prediction, drug screening, and molecular docking. Single-cell RNA sequencing was used to identify key cell types and pseudotime trajectories. MR analysis identified 29 GM taxa causally linked to AR. For instance, family.Porphyromonadaceae.id.943 was protective, while genus.unknowngenus.id.1000006162 was a risk factor. SNP-based gene mapping yielded 246 genes, which overlapped with 1329 DEGs to identify INPP5D and KIF16B as key genes. These were enriched in pathways such as ribosome, peroxisome, and systemic lupus erythematosus. Immune infiltration revealed altered abundances of natural killer T cells and activated CD4 + T cells. Single-cell analysis highlighted Th1 cells as central to AR pathogenesis, with stable expression of INPP5D and KIF16B during Th1 differentiation. This study establishes a causal link between GM and AR and identifies INPP5D and KIF16B as potential key genes, with Th1 cells as a critical immune subset, providing new insights into AR's molecular mechanisms.