title: IL-22-STAT3 pathway plays a key role in the maintenance of ileal homeostasis in mice lacking secreted mucus barrier.
abstract: 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, Reg3β, Reg3γ, 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.
authors: *Top Institute Food and Nutrition, Wageningen, the Netherlands; †Host-Microbe Interactomics Group, Animal Sciences Department, Wageningen University and Research Center, Wageningen, the Netherlands; ‡Department of Pediatrics, Erasmus MC-Sophia, Rotterdam, the Netherlands; §Department of Pediatrics, Academic Medical Center, Amsterdam, the Netherlands; ‖Department of Agrotechnology and Food Sciences, Laboratory of Microbiology, Wageningen University and Research Center, Wageningen, the Netherlands; ¶Department of Agrotechnology and Food Sciences, Division of Human Nutrition, Wageningen University and Research Center, Wageningen, the Netherlands; **NIZO food research, Ede, the Netherlands; ††University Medical Center of Groningen, Groningen, the Netherlands; and ‡‡Nutricia Research, Utrecht, the Netherlands.
authors: Bruno
authors: B
authors: Sovran
authors: Linda M P
authors: LM
authors: Loonen
authors: Peng
authors: P
authors: Lu
authors: Floor
authors: F
authors: Hugenholtz
authors: Clara
authors: C
authors: Belzer
authors: Ellen H
authors: EH
authors: Stolte
authors: Mark V
authors: MV
authors: Boekschoten
authors: Peter
authors: P
authors: van Baarlen
authors: Michiel
authors: M
authors: Kleerebezem
authors: Paul
authors: P
authors: de Vos
authors: Jan
authors: J
authors: Dekker
authors: Ingrid B
authors: IB
authors: Renes
authors: Jerry M
authors: JM
authors: Wells
mesh_terms: D000818:Animals; D017209:Apoptosis; D001419:Bacteria / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006706:Homeostasis; D007082:Ileum / Q000502:physiology*; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota; D055262:Mucin-2 / Q000502:physiology*; D009093:Mucus / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D055262:Mucin-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C524626:Muc2 protein, mouse