Table 1.

Experimental Models of IBD Due to Specific Genetic Defects

Model	Underlying Defect	Major Consequences	Significance
Muc2 colitis147,148	Deficiency of Muc2 (mucin 2), the main gastrointestinal mucin.	Spontaneous colitis (severe in the distal colon) that is enhanced by DSS administration and develops into colorectal cancer. Inflammation is associated with increases in intestinal lymphocytes, TNF-α and IL-1β.	Loss of epithelial barrier function resulting from Muc2 deficiency causes inflammation.
Related Muc2 models149,150	Lack of C3GnT (β1,3-N-acetylglucosamin-transferase), an enzyme involved in the synthesis of core 3-derived O-glycans that are components of colonic mucins149.	Increased susceptibility to DSS colitis and DSS/AOM-induced tumorigenesis; Th1 and Th7 pro-inflammatory cytokine production is elevated.	Enhanced intestinal permeability due to deficiency in core 3-derived O-glycans and reduced Muc2 levels increases susceptibility to colitis and colorectal cancer.
	Targeted deletion of core 1-derived O-glycans, also components of mucins150.	Spontaneous colitis (severe in the distal colon and rectum) driven by TNF-α-producing macrophages and granulocytes rather than lymphocytes. Inflammation is independent of TLR signaling.	Core 1-derived O-glycans deficiency leading to a reduced inner mucus layer and decreased Muc2 enhances intestinal permeability to both proteins and bacteria and causes inflammation, that is associated with epithelial cell expression of the Tn antigen, observed in some UC patients.
MDR1a colitis151	Lack of P-glycoprotein, the product of the MDR1a (multidrug resistance protein 1) gene alters epithelial barrier function.	Spontaneous colitis driven by Th1 cytokines.	A barrier defect arising from P-glycoprotein deficiency causes increased intestinal permeability and translocation of bacteria into the lamina propria, and the development of colitis152, 153
TRUC model122	Disruption of the transcriptional regulator T-bet in the innate immune system of RAG2−/− mice.	Spontaneous colitis driven by intestinal flora and increased production of TNF-α and IL-23. Co-housing of TRUC mice with wild type mice demonstrate transmission of colitis to a normal host and thus reveal the existence of a “colitogenic” microflora (such as Proteus mirabilis and Klebsiella pneumonia or Helicobacter typhlonius)154.	First and only demonstration of the existence of a colitogenic intestinal microflora. However, treatment of TRUC mice with anti-TNF-α therapy prevents inflammation and bacterial populations from becoming “colitogenic” indicating that the development of the latter requires an abnormal mucosal immune system.
NEMO colitis155	Intestinal epithelial cell-specific disruption of NF-κB function via targeted deletion of NEMO, an essential regulatory subunit of NF-κB also known as IKK-γ.	Spontaneous and severe chronic intestinal inflammation.	Lack of NF-κB signaling results in heightened TNF-α sensitivity and apoptosis of colonic epithelial cells followed by inflammation caused by translocation of bacteria into the mucosa. Highlights role of TNF-α in maintenance of epithelial cell barrier function.
Related NEMO model156	Specific deletion of the catalytic subunit of IKK-β in intestinal epithelial cells.	Severe intestinal inflammation after infection with the gut-dwelling parasite Trichuris muris and reduced expression of TSLP.	IKK-β in intestinal epithelial cells promotes Th2-cell dependent immunity and limits chronic inflammation.
SAMP1/Yit mouse157	The SAMP1/Yit strain was established by selective breading of SAM (senescence accelerated mouse derived from AKR/J mice) P1 strain mice showing spontaneous skin ulcerations.	Spontaneous inflammation of the terminal ileum and caecum driven by a Th1 response; however, a Th2 response may develop at later disease stages of disease. Exhibit “skip lesions.” Inflammation originates from epithelial barrier defect.	One of the few models exhibiting severe inflammation of the terminal ileum, the primary location of CD lesions.
XBP1 model158,159	Epithelial cell-specific deletion of the transcription factor, XBP1, an important component of the endoplasmic reticulum (ER) stress response.	Spontaneous enteritis and enhanced susceptibility to DSS colitis.	Induction of ER stress through disruption of XPB1 causes small intestinal inflammation possibly due to absence of Paneth cell anti-bacterial mediators and reduction of goblet cells.
STAT3-deficient colitis160,161	Macrophage/neutro phil-specific deficiency of the transcriptional regulator STAT3.	Spontaneous chronic enterocolitis associated with a polarized Th1 response dependent on overproduction of IL-12p40. Defective IL-10 signaling in macrophages.	IL-10 signaling in macrophages and neutrophils is necessary to prevent abnormal regulation of responses to the normal microflora.
Related STAT3 model (IL-22 deficiency)162	Targeted deletion of STAT3 in intestinal epithelial cells and associated IL-22 deficiency.	Enhanced susceptibility to DSS colitis.	In intestinal epithelial cells, STAT3 activity is critical for mucosal wound healing mediated by IL-22 during acute colitis.
IL-7 transgenic mice163	Systemic overexpression of IL-7.	Spontaneous chronic colitis associated with a Th1 response.	IL-7 acts as a critical survival factor for colitogenic CD4+ effector memory T cells164. Bone marrow is the main source of IL-7 and a substantial population of colitogenic CD4+ memory T cells reside in the bone marrow165–168