Cross-species systems analysis distinguishes inflammatory remodeling from primary mucus secretory failure in...

Intestinal mucus and epithelial barrier dysfunction are central features of inflammatory bowel disease (IBD), yet the regulatory mechanisms underlying mucus disruption remain inconsistent across individual studies. Anterior gradient 2 (AGR2) is an endoplasmic reticulum chaperone required for mucin folding, and its loss in mice causes primary mucus secretory failure and spontaneous colitis. Here, we integrated cross-cohort human transcriptomics with a genetic model of mucus secretory collapse to determine whether mucus dysfunction in IBD reflects intrinsic mucin-folding defects or secondary inflammatory remodeling.

We performed a meta-analysis of 26 independent human colonic transcriptomic datasets comprising 1,302 active, untreated samples to derive a consensus mucus-barrier regulatory program in Crohn's disease (CD) and ulcerative colitis (UC). Random-effects modeling identified differentially expressed genes, which were evaluated using gene set enrichment for biological processes relevant to mucus regulation. To provide a mechanistic benchmark for primary secretory failure, we generated an orthogonal colon proteome from Agr2 ^-/- mice.

Across human cohorts, 3,129 genes in CD and 3,729 in UC were differentially expressed, with substantial overlap between diseases. Both conditions showed coordinated upregulation of pathways linked to goblet-cell differentiation, mucin transcription, post-translational glycosylation, secretion, microbial sensing, and endoplasmic reticulum quality control. MUC1, MUC4, MUC5AC, and MUC5B were consistently upregulated in active IBD relative to healthy controls. MUC2 was strongly elevated in CD. Glycosyltransferases, including ST3GAL1 and FUT8, were upregulated, and secretion-associated immune regulators, such as NOD2 and CASP1, increased, whereas the barrier lectin ZG16 decreased. ER stress components HSPA5, XBP1, and AGR2 were also upregulated compared with controls.

Cross-species comparison revealed convergence between IBD and Agr2 deficiency in unfolded-protein response and microbial sensing pathways, including lipopolysaccharide and Toll-like receptor signaling. However, cytokine-driven regulatory programs prominent in IBD, including IL-6-STAT3 and IL-17 pathways, were not recapitulated in Agr2 ^-/- mice. These findings indicate that mucus barrier dysfunction in human IBD reflects inflammatory remodeling of epithelial programs rather than primary secretory collapse alone, while sharing conserved ER-stress and microbial response signatures. Integrating human and murine datasets identifies candidate pathways that may stabilize mucin folding, refine glycan composition, and preserve host-microbe spatial segregation in intestinal disease.