Table 1.
Inflammatory bowel disease animal models with primary defects of intestinal epithelial origin.
| Animal model | Disease location/phenotype of inflammation | Histologic features | Identified gene(s) involved | Epithelial-specific dysfunction |
|---|---|---|---|---|
| CHEMICALLY INDUCED MODELS | ||||
| DSS-induced colitis (57) | Superficial colitis | Superficial ulcerations | Loci increasing susceptibility to the induced model found on Chr5 and Chr2 | Chemical destruction of mucosal barrier with consequent increase in luminal bacterial translocation |
| Infiltration of acute inflammatory cells | ||||
| Crypt distortion | ||||
| Loss of goblet cells | ||||
| TNBS-induced colitis (61) | Transmural colitis | Ulceration | N/A | Ethanol-induced destruction of mucosal barrier facilitating hapten penetration and contact with underlying mucosal immune system |
| Infiltration of acute/chronic inflammatory cells | ||||
| Crypt distortion | ||||
| Loss of goblet cells | ||||
| GENETICALLY ENGINEERED MODELS AFFECTING EPITHELIAL BARRIER INTEGRITY | ||||
| Mdr1a knockout (103) | Transmural colitis | Colonic thickening with crypt hyperplasia | Mdr1a deletion | Increased basal colonic ion transport |
| Focal ulcerations | Dysregulated epithelial cell growth | |||
| Crypt abscesses Leukocyte infiltration Increased number of granulocytes | Increased permeability (dependent on bacterial colonization | |||
| Decreased phosphorylation of TJ proteins (ZO-1 and occludin) | ||||
| Dominant negative N-cadherin transgenic (62) | Patchy foci of ileal inflammation | Cryptitis and crypt abscesses Epithelial hyperplasia Presence of lymphoid aggregates | Dominant negative N-cadherin expression in small intestinal IEC | Breakdown of intestinal epithelial apical junctional complexes |
| Aberrant cell migration, proliferation, and apoptosis in small intestinal crypts | ||||
| Gai2 knockout (64) | Superficial pancolitis; increased severity in distal colon | Cryptitis and crypt abscesses with crypt distortion | Gai2 deletion | Possible impairment of epithelial TJ assembly |
| Mucosal PMN infiltrates | ||||
| JAM-A knockout (66) | Colitis | Normal epithelial architecture Increased PMN infiltration Formation of large lymphoid aggregates | JAM-A deletion | Impaired TJ structure and consequent increase in epithelial permeability |
| Increase in the TJ proteins, claudin-10 and -15 | ||||
| GENETICALLY ENGINEERED MODELS AFFECTING EPITHELIAL INNATE RESPONSES | ||||
| TLR5 knockout (5) | Colitis; 10% incidence of rectal prolapse | Mononuclear infiltrates Epithelial hyperplasia Focal crypt loss Goblet cell depletion | TLR5 deletion | Increased epithelial permeability (secondary to inflammation) |
| Ineffective bacterial clearance | ||||
| NEMOIEC-KO (23) | Pancolitis | Mucosal thickening Enlarged crypts Loss of goblet cells Extensive epithelial destruction Marked infiltration of mononuclear cells in mucosa/submucosa | IEC-specific inhibition of NF-κB via conditional ablation of NEMO (IKKg) | Colonic epithelial cell apoptosis (via increased sensitivity to TNF) |
| Impaired expression of anti-microbial peptides | ||||
| Dysregulated epithelial barrier integrity | ||||
| TAK1IEC-KO (24) | Enterocolitis | Complete disruption of small intestine structure | IEC specific conditional ablation of TAK1 | Colonic epithelial cell apoptosis (via increased sensitivity to TNF) |
| Less severe alterations of colonic tissue | Impaired innate immune response | |||
| GENETICALLY ENGINEERED MODELS AFFECTING EPITHELIAL CELL INTEGRITY AND MUCUS PRODUCTION | ||||
| XBP1IEC-KO (100) | Focal non-granulomatous enteritis | Absence of Paneth cells Loss of goblet cells Lamina propria mononuclear infiltrate Crypt abscesses Mucosal ulcerations Villus shortening with a reduction of villus:crypt ratio | IEC specific conditional ablation of XBP1 | Impaired innate immune response due to Paneth cell loss by apoptosis |
| Endoplasmic reticulum (ER) stress secondary to the lack of XBP1 | ||||
| Increased proinflammatory signaling due to increased JNK/SAPK activation secondary to the lack of XBP1 | ||||
| AP1M2 knockout (98) | Transmural colitis | Epithelial hyperplasia | Epithelia-specific membrane trafficking factor AP-1B deficiency induced via AP1M2 deletion | Loss of IEC polarity |
| Crypt distorsion Loss of goblet cells Mucosal and submucosal inflammatory infiltrate | Impaired epithelial production of anti-microbial peptides | |||
| Defective luminal transport of secretory IgA | ||||
| GENETICALLY ENGINEERED MODELS AFFECTING EPITHELIAL CELL INTEGRITY AND MUCUS PRODUCTION | ||||
| RBP-JIEC-KO (99) | Colitis; rectal prolapse | Goblet cell hyperplasia | IEC-specific impairment of Notch signaling via conditional ablation of RBP-J | Retarded IEC turnover |
| Aberrant accumulation of mucus under the tunica serosa Neutrophilic infiltrate | Increased epithelial permeability | |||
| Impaired epithelial defense against bacteria | ||||
| MUC2 knockout (123) | Superficial colitis; more severe in the distal colon | Complete lack of goblet cells | MUC2 deletion | Altered bacterial stimulation of IECs due to a diminished mucus layer |
| Crypt hyperplasia | ||||
| Flattening of the epithelial layer and superficial erosions | ||||
| Mild inflammatory infiltration | ||||
| Lamina propria distorsion | ||||
| MUC2 mutant (Winnie and Eeyore strains) (124) | Superficial colitis; more severe in the distal colon | Focal epithelial erosions Crypt elongation | MUC2 missense mutations | Altered bacterial stimulation of IECs due to a diminished mucus layer |
| Increased endoplasmic reticulum (ER) stress due to mutated MUC2 protein misfolding and accumulation in ER | ||||
| Neutrophilic infiltrate | ||||
| Crypt abscesses | ||||
| Goblet cell loss | ||||
| POFUT1IEC-KO (128) | Enterocolitis | Crypt hyperplasia | IEC specific conditional ablation of POFUT1 | Notch signaling impairment with consequent goblet cell hyperplasia and mucus hypersecretion, leading to associated gut microbiota alterations |
| Dilated and mucus filled crypts | ||||
| Hyperplasia of Paneth cells and enteroendocrine cells | ||||
| Inflammatory infiltrate of the lamina propria | ||||
| Crypt abscesses | ||||
| Transmural inflammation | ||||
| SPONTANEOUS MODELS | ||||
| SAMP1/YitFc (74) | Segmental, discontinuous, transmural ileitis; increased severity in the terminal ileum with 2–3% incidence of perianal disease | Villous blunting/crypt hypertrophy Paneth cell/goblet cell hyperplasia PMN/mononuclear cell infiltration in lamina propria and submucosa Aphthous inflammatory lesions Granuloma formation Cryptitis/crypt microabscesses Basal plasmacytosis | Multigenic etiology; susceptibility found on Chr6, Chr8, Chr9, and ChrX | Primary non-hematopoietic (i.e., epithelial) dysfunction |
| Increased epithelial permeability independent of commensal bacterial colonization | ||||
| Altered TJ protein expression (increase in claudin-2, decrease in occludin) | ||||
| Dysregulated epithelial innate responses | ||||
| C3H/HeJBir (7) | Colitis; primary localization in the cecum | Acute and chronic inflammatory infiltrate | Multigenic etiology; susceptibility found on Chr3, Chr1, Chr2, Chr8, Chr17, and Chr18 | Dysregulated epithelial innate responses |
| Crypt abscesses | Ineffective bacterial clearance | |||
| Ulcerations Regenerative hyperplasia | Hyper-responsiveness to flagellin stimulation | |||