IL-22-STAT3 Pathway Plays a Key Role in the Maintenance of Ileal Homeostasis in Mice Lacking Secreted Mucus Barrier

Background:Muc2-deficient mice show no signs of ileal pathology but the mechanisms remained unknown.Methods:Wild-type (WT), Muc2(+/-), and Muc2(-/-) mice were killed at 2, 4, and 8 weeks of age. Total RNA from ileum was used for full genome transcriptome analysis and qPCR. Microbiota composition was determined using a mouse intestinal chip (MITChip). Morphological and immunohistological studies were performed on segments of ileum.Results:The ileum was colonized by more diverse microbiota in young (week 4) WT than in Muc2(-/-) mice, and composition was influenced by genotype. Weaning was associated with major changes in the transcriptome of all mice, and the highest number of differentially expressed genes compared with adults, reflecting temporal changes in microbiota. Although the spatial compartmentalization of bacteria was compromised in Muc2(-/-) mice, gene set enrichment analysis revealed a downregulation of Toll-like receptor, immune, and chemokine signaling pathways compared to WT mice. The predicted effects of enhanced IL-22 signaling were identified in the Muc2(-/-) transcriptome as the upregulation of epithelial cell proliferation altered expression of mitosis and cell-cycle control pathways. This is consistent with increased villus length and number of Ki67(+) epithelial cells in Muc2(-/-) mice. Additionally, expression of the network of IL-22 regulated defense genes, including Fut2, Reg3, Reg3, Relmb, and the Defensin Defb46 were increased in Muc2(-/-) mice.Conclusions:These findings highlight a role for the IL-22-STAT3 pathway in maintaining ileal homeostasis when the mucus barrier is compromised and its potential as a target for novel therapeutic strategies in inflammatory bowel disease.