{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T06:03:12Z","timestamp":1780984992957,"version":"3.54.1"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Introduction<\/jats:title>\n \n 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 (\n AGR2<\/jats:italic>\n ) 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.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n 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\u2019s 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\n Agr2<\/jats:italic>\n -\/-<\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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.\n MUC1<\/jats:italic>\n ,\n MUC4<\/jats:italic>\n ,\n MUC5AC<\/jats:italic>\n , and\n MUC5B<\/jats:italic>\n were consistently upregulated in active IBD relative to healthy controls.\n MUC2<\/jats:italic>\n was strongly elevated in CD. Glycosyltransferases, including\n ST3GAL1<\/jats:italic>\n and\n FUT8<\/jats:italic>\n , were upregulated, and secretion-associated immune regulators, such as\n NOD2<\/jats:italic>\n and\n CASP1<\/jats:italic>\n , increased, whereas the barrier lectin\n ZG16<\/jats:italic>\n decreased. ER stress components\n HSPA5<\/jats:italic>\n ,\n XBP1<\/jats:italic>\n , and\n AGR2<\/jats:italic>\n were also upregulated compared with controls.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n \n Cross-species comparison revealed convergence between IBD and\n Agr2<\/jats:italic>\n 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\u2013STAT3 and IL-17 pathways, were not recapitulated in\n Agr2<\/jats:italic>\n -\/-<\/jats:sup>\n 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.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1813019","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:41:57Z","timestamp":1780983717000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cross-species systems analysis distinguishes inflammatory remodeling from primary mucus secretory failure in inflammatory bowel disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Jessica","family":"Xhumari","sequence":"first","affiliation":[{"name":"Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida","place":["Gainesville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Ojeda","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida","place":["Gainesville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwamayowa S.","family":"Akinsuyi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida","place":["Gainesville, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz F. 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