Multi-cohort meta-analysis, single-cell and Mendelian randomization analyses with experimental validation identify RHBDF2 as a shared mediator of ulcerative colitis and blood–brain barrier disruption

Abstract

Ulcerative colitis (UC) is increasingly associated with central nervous system comorbidities, including cognitive decline and dementia, yet the molecular mechanisms linking intestinal inflammation to brain dysfunction remain unclear. Blood–brain barrier (BBB) disruption is a plausible convergence point, but the mediators involved are largely unknown. We performed random-effects meta-analyses of five human UC bulk-transcriptome cohorts (1,130 UC and 508 control samples) and three mouse BBB-disruption (BBBD) cohorts, followed by cross-species orthologue mapping to identify shared genes. The cellular context of candidate genes was resolved by single-cell RNA-sequencing analysis of human UC colonic mucosa (GSE214695) and paired human BBB-intact/BBB-opened brain samples (GSE208074), combined with scTenifoldKnk in-silico gene knockout. Summary-data-based Mendelian randomization (SMR) integrating whole-blood cis-eQTL and FinnGen GWAS data was used to assess causal relevance to dementia. Findings were validated in dextran sulfate sodium (DSS)-induced colitis in mice preventively treated with the ADAM17 inhibitor GW280264X, with Evans blue assessment of BBB permeability. Four genes—TNF, RHBDF2, PILRA and CXCL16—were significantly and concordantly up-regulated in both UC and BBBD, forming a protein–protein association module organized around the sheddase ADAM17. RHBDF2, the essential activating chaperone of ADAM17, was predominantly up-regulated in colonic epithelial cells in UC, whereas its strongest inferred regulatory impact at the human BBB mapped to endothelial cells, affecting complement, microglial and angiogenic programs. Genetically predicted higher expression of RHBDF2 and PILRA was associated with increased risk of all-cause and Alzheimer’s dementia. In DSS-induced colitis, preventive administration of GW280264X attenuated intestinal inflammation, reduced cerebral Evans blue extravasation and lowered brain Rhbdf2, Adam17 and Tnfα protein levels. Integrative transcriptomic, genetic and experimental evidence identifies an RHBDF2–ADAM17–TNFα axis as a plausible mechanistic bridge between ulcerative colitis and blood–brain barrier disruption and a candidate therapeutic target.