Table 1.

Synopsis of the major characteristics of individual animal models of intestinal fibrosis

Model of Intestinal Fibrosis	Advantages	Disadvantages	Site of Involvement	Relevance to Human Disease	Reference
Spontaneous
SAMP1/YitFc ileitis	Spontaneous inflammation and fibrosis No need for stimulus or additional manipulations Gut histology resembles Crohn's disease The natural history of the disease is chronic	Low breeding rate Few colonies in existence Long time needed to complete experiments Not commercially available	Primarily small bowel (terminal ileum) in early and late disease Colon involvement in late disease	High Disease location, histology, presence of granulomas, fistulas, perianal disease and chronic evolution bear close resemblance to human Crohn's disease	59, 82, 117
Gene Knockout and Transgenic
IL-10 deficiency	L-10 is a cytokine with a well recognized immunoregulatory and anti-inflammatory activity Mechanisms of inflammation resulting from its deficiency are well defined	The model requires genetically manipulated animals Appearance and severity of inflammation, and consequently of fibrosis, is variable depending on the breeding facility	Primarily colon and less commonly small bowel	Moderate Human infants with genetic IL-10 receptor deficiency and severe IBD have been described	4, 5, 61, 76, 111, 126
TGF-β1 overexpression	TGF-β1 is the most potent pro-fibrogenic factor and unquestionably linked to intestinal fibrosis Mechanisms of inflammation resulting from its deficiency are well defined	The model requires transfection with an adenoviral vector producing bioactive TGF-β1 Fibrosis is focal	Colonic fibrosis with obstruction	Moderate Patients with IBD have spontaneously high levels of TGF-β1 and fibrosis in the inflamed tissue	8, 17, 37, 62, 83, 96, 133
MCP-1 overexpression	MCP-1 is chemokine involved in intestinal inflammation Mechanisms of inflammation caused by its overproduction are well defined	The model requires transfection with an adenoviral vector producing bioactive MCP-1 Fibrosis is focal	Transmural fibrosis of colon and rectum	Moderate Patients with IBD have high levels of MCP-1 (and several other chemokines) and fibrosis in the inflamed tissue	39, 91
Chemically Induced
TNBS-induced	Colonic inflammation is clearly T cell dependent Appearance of fibrosis follows a logical Th1 to Th2 cytokine switch	The model requires repeated enemas for induction of intestinal fibrosis There is considerable variability in the induction of colitis depending on source and amount of TNBS Intensity of inflammation varies in different strains	Colon involvement in late disease	Moderate There is no evidence that haptens play a role in human IBD T cell dependency is important in human IBD, particularly Crohn's disease Transmural inflammation with fibrosis and granulomas are features of Crohn's disease	26, 58, 71, 81, 89, 96, 145, 148
DSS-induced	The easiest and most reproducible protocol to induce colonic inflammation with associated fibrosis	Initial insult is an acute chemical injury to the colonic epithelium Detailed mechanisms of colonic inflammation still not fully characterized	Colon involvement in late disease	Low There is no evidence that chemical damage causes IBD and fibrosis Injury can be useful to study epithelial inflammation and subepithelial fibrosis in ulcerative colitis	18, 54, 76, 79, 97
Peroxynitrite-induced	Straightforward induction of colitis by administration of peroxynitrite-containing enemas	The model has been described only in one report Reproducibility is unknown No direct link between NO and induction of fibrosis	Colon involvement in subacute stage	Potentially high NO is produced in large quantities in intestinal inflammation and IBD and induces tissue damage	108
Immune-Mediated
T cell transfer-induced	The mechanisms of induction of intestinal inflammation are well defined T cell abnormalities may indirectly modulate mesenchymal cell behavior	The model is laborious and artificial The degree to which intestinal fibrosis correlates with severity or duration of inflammation is unknown	Colon	Uncertain Studies in this model have been heavily oriented toward immune regulation No convincing evidence for T cell regulatory defects in IBD patients	72, 90, 92, 105
Bacteria-Induced
PG-PS-induced	The dependency of the model on bacteria-derived components is pathophysiologically relevant The model allows a time-dependent investigation of fibrogenesis	The model is laborious t requires a laparotomy and intramural injection of PG-PS into the bowel wall	Small and large bowel	Moderate-high Massive fibrosis with bowel thickening and adhesion are found in Crohn's disease, but bacterial components derive from the lumen in human patients	122, 125, 136, 149
Gut microbiota-induced	The dependency of the model on bacteria-derived components and activation of the TGF-β pathway are both pathophysiologically relevant events	The model is laborious It requires a laparotomy and intramural injection of fecal suspensions or extracts of selected anaerobic bacteria into the bowel wall	Colon	Very high Crohn's disease pathogenesis and complications, including fibrosis, are believed to be closely linked to an immune response to the gut microbiota	85, 93
Infection-induced	The induction of gut inflammation and fibrosis only requires oral administration of infectious agents Induction of increased levels of TGF-β, CTGF, and IGF-I is pathophysiologically relevant The model allows a time-dependent evaluation of the fibrogenic response and removal of the fibrogenic stimulus with antibiotic treatment	The intestinal fibrogenic process in this model and in humans may be pathophysiologically different	Colon	Low-moderate No evidence that infectious agents directly cause IBD Epidemiology studies show a correlation of acute bacterial infections and subsequent development of IBD, although not fibrosis	38, 40, 49
Radiation-Induced
Exteriorized bowel segment	Choice of bowel segment to be irradiated with sparing of remaining intestine	The model requires a surgical procedure	Colorectal fibrosis with radiation dose-dependent obstruction	Moderate Segmental bowel radiation mimics human situation	29, 42, 43
Scrotal hernia placement	Easy external access to bowel segment to be irradiated	The model requires surgical procedure Anatomical location of the irradiated bowel segment is not physiological	Small intestine	Moderate-low The irradiated area is extra-abdominal and does not reproduce the bowel anatomical position in humans	65, 67, 140–142
Postoperative
Anastomotic fibrosis	Results reproduce outcome of routine bowel resection	The model requires a surgical procedure and bowel resection	Model-dependent small bowel, colon or ileocolic anastomosis	High The surgical anastomosis uses the same procedure used for human bowel resection	60, 116
Intra-abdominal adhesions	Results reproduce outcome of intra-abdominal manipulation of bowel segments during surgery	The model requires a surgical procedure and bowel manipulation	Manipulation site-dependent small or large bowel	High Postsurgical adhesions mimic events developing after intra-abdominal procedures in humans	13, 46, 47, 132

CTGF, connective tissue growth factor; IBD, inflammatory bowel disease; MCP-1, monocyte chemoattractant protein 1; PG-PS, peptidoglycan-polysaccharide.