Goblet Cell Loss Linked to NOD2 and Secondary Resection in Crohn's Disease Is Induced by Dysbiosis and Epithelial MyD88

Abstract

BACKGROUND & AIMS: The role of goblet cells in small intestinal inflammation in Crohn's disease (CD) is unknown. Polymorphisms of NOD2 confer risk for CD and associate with small intestinal disease location. We previously showed in mice that Nod2 deficiency leads to overexpansion of Phocaeicola vulgatus in the gut and downstream goblet cell defects, which preceded small intestinal inflammation. In this study, we ask whether goblet cell defects occur in patients with CD with NOD2 polymorphisms and investigate in mice how P vulgatus signals through the intestinal epithelium. METHODS: We performed a retrospective study of patients with CD to assess clinical outcomes and goblet cell histology by NOD2 status. We evaluated the contribution of microbiota and MyD88 signaling in the intestinal epithelium to goblet cell defects in the setting of Nod2 deficiency using genetic mouse models and germ-free mice. RESULTS: In patients with CD who have undergone ileocolic resection, NOD2 risk alleles confer a risk for reoperation (odds ratio, 8.12; P 1/4 .047) and for increased phosphorylated extra-cellular signal-regulated kinase and goblet cell defects in uninflamed ileal tissue. We show that patients with CD with ileal involvement harbor P vulgatus regardless of NOD2 risk allele status. We show that intestinal epithelial MyD88 and TLR4 are required for goblet cell defects in Nod2-/-mice harboring P vulgatus. Finally, we show that P vulgatus requires complex microbiota to exert its effects in Nod2-deficient mice. CONCLUSIONS: Goblet cell defects may be a harbinger of small intestinal inflammation in patients with CD, particularly in the postoperative setting. Our findings in mice show that small intestinal goblet cell loss associated with Nod2 mutation is induced by microbiome dysbiosis and epithelial MyD88, in part due to TLR4 signaling. (Cell Mol Gastroenterol Hepatol 2025; 19:101533; https://doi.org/10.1016/j.jcmgh.2025.101533)