Chronic enteric salmonella infection in mice leads to severe and persistent intestinal fibrosis.
OBJECTIVE
Intestinal fibrosis and stricture formation are serious complications of Crohn's disease, often requiring surgical intervention. Unfortunately, the mechanisms underlying intestinal fibrosis development are poorly understood, in part because of the lack of relevant animal models. Here, we present a novel murine model of severe and persistent intestinal fibrosis caused by chronic bacterial-induced colitis.


METHODS
Mice were treated with streptomycin 24 hours prior to oral infection with Salmonella enterica serovar Typhimurium. Tissues were analyzed for bacterial colonization and inflammation, and fibrosis was assessed by Masson's trichrome staining and collagen quantification. Expression of the profibrotic cytokines transforming growth factor-beta1, connective tissue growth factor and insulin-like growth factor-I was determined, and the cell types present in fibrotic tissues were assessed by immunohistochemistry.


RESULTS
Infection led to chronic Salmonella colonization of the cecum and colon followed by edema, mucosal ulcerations, and severe transmural inflammation. This pathology was accompanied by significantly elevated expression of transforming growth factor-beta1, connective tissue growth factor, and insulin-like growth factor-I along with extensive type I collagen deposition in the cecal mucosa, submucosa, and muscularis mucosa of infected mice. Fibrosis was evident by 7 days postinfection, peaking at day 21 and still present at day 70. The fibrotic regions were found to be rich in fibroblasts and myofibroblasts.


CONCLUSIONS
These data demonstrate that chronic Salmonella infection of the murine gastrointestinal tract leads to severe tissue fibrosis. Because this model is highly reproducible and easy to perform, it provides great potential for investigating both host and bacterial contributions to intestinal fibrosis.
Grassl
Guntram A
GA
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
Valdez
Yanet
Y
Bergstrom
Kirk S B
KS
Vallance
Bruce A
BA
Finlay
B Brett
BB
D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics; D002432:Cecum / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D055513:Connective Tissue Growth Factor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D017874:Immediate-Early Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007410:Intestinal Diseases / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D009154:Mutation; D012480:Salmonella Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D012720:Severity of Illness Index; D013045:Species Specificity; D013307:Streptomycin / Q000008:administration & dosage; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D037521:Virulence Factors / Q000378:metabolism; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D016207:Cytokines; D017874:Immediate-Early Proteins; D007334:Insulin-Like Growth Factor I; D036341:Intercellular Signaling Peptides and Proteins; D013307:Streptomycin; D053773:Transforming Growth Factor beta1; D037521:Virulence Factors; D000099173:Natural Resistance-associated Macrophage Protein 1; C526318:CCN2 protein, mouse