AUTHOR=Chai Xin , Wang Hongli , Wang Boxiang , Ma Yanchun , Zhang Xiaoyan , Guo Jing , Luo Shuping , Wang Yan , Hong Jinpeng , Ma Qiang , Chen Jiayu , Wang Biaomeng , Wang Yixuan 

TITLE=Mendelian randomization integrated with multi-omics analysis identifies TNIK as a key gene in gut microbiota-induced IBD development

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1678444

DOI=10.3389/fimmu.2025.1678444

ISSN=1664-3224

ABSTRACT=BackgroundDysbiosis of the gut microbiota (GM) has been linked to inflammatory bowel disease (IBD), yet its associated molecular mechanisms remain poorly defined. Identifying causal host genes mediating GM-IBD interactions is therefore of great importance.ObjectiveTo identify GM-associated causal genes for IBD and to prioritize key targets and cell types underlying GM-host crosstalk.MethodsWe integrated GWAS datasets of GM, UC, and CD using a two-sample Mendelian randomization (MR) framework with IVW as the primary estimator. Causal SNPs were mapped to genes for enrichment analyses. Candidate genes were refined by intersecting MR-derived genes with bulk RNA-seq DEGs (training: GSE87473, validation: GSE75214) and prioritized using nested cross-validated machine-learning models. Single-cell RNA-seq (GSE116222) was used to localize key genes to specific cell types. The functional role of TNIK was validated in IL-10-/- IBD mice via AAV9-mediated overexpression. Immunohistochemical staining of Ki67 and Cleaved caspase 3 was conducted to evaluate epithelial proliferation and apoptosis in colonic tissues.ResultsMR analysis identified 307 and 360 GM-associated causal genes for UC and CD, respectively. TNIK (TRAF2 and NCK-interacting kinase) was highlighted as a key candidate gene. Seven TNIK-associated immune cell subsets showed altered infiltration in UC. Single-cell transcriptomics revealed TNIK dysregulation in colonocytes, goblet cells. T/NK cells in UC. TNIK overexpression in IL-10-/- mice reduced disease severity and downregulated IL-1β, IL-6, and TNF-α. Immunohistochemistry confirmed that TNIK overexpression enhanced Ki67 expression and reduced Cleaved caspase 3 expression.ConclusionBy integrating MR with transcriptomics and single-cell seq results, we identified TNIK as a potential GM-associated host kinase linking dysbiosis to epithelial and immune dysfunction in IBD. TNIK emerges as a promising node for IBD prognosis through barrier maintenance and immune regulation.