Frontiers in synaptic neuroscience
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
By Cheng J and Xu A.
Abstract
Background
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.
Methods
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.