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. 2008 Dec;58(6):534-41.

Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in IL10-deficient mice

Maciej Chichlowski  1 , Julie M Sharp, Deborah A Vanderford, Matthew H Myles, Laura P Hale
Affiliations

Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in IL10-deficient mice

Maciej Chichlowski et al. Comp Med. 2008 Dec.

Abstract

Infection with Helicobacter species is endemic in many animal facilities and may alter the penetrance of inflammatory bowel disease (IBD) phenotypes. However, little is known about the relative pathogenicity of H. typhlonius, H. rodentium, and combined infection in IBD models. We infected adult and neonatal IL10-/- mice with H. typhlonius, H. rodentium, or both bacteria. The severity of IBD and incidence of inflammation-associated colonic neoplasia were assessed in the presence and absence of antiHelicobacter therapy. Infected IL10-/- mice developed IBD with severity of noninfected (minimal to no inflammation) < H. rodentium < H. typhlonius VSports手机版. Inflammation-associated colonic neoplasia was common in infected mice and its incidence correlated with IBD severity. Combined treatment with amoxicillin, clarithromycin, metronidazole, and omeprazole eradicated Helicobacter in infected mice and ameliorated established IBD in both infected and noninfected mice. Infection of IL10-/- mice with H. rodentium, H. typhlonius, or both organisms can trigger development of severe IBD that eventually leads to colonic neoplasia. The high incidence and multiplicity of neoplastic lesions in infected mice make this model well-suited for future research related to the development and chemoprevention of inflammation-associated colon cancer. The similar antiinflammatory effect of antibiotic therapy in Helicobacter-infected and -noninfected IL10-/- mice with colitis indicates that unidentified microbiota in addition to Helicobacter drive the inflammatory process in this model. This finding suggests a complex role for both Helicobacter and other intestinal microbiota in the onset and perpetuation of IBD in these susceptible hosts. .

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Figures

Figure 1.
Figure 1.
Short-term survival and colitis severity in Helicobacter-infected adult IL10−/− mice. (A) Kaplan–Meier plot shows survival rate of adult IL10−/− mice infected with H. rodentium (H. rod), H. typhlonius (H. typh), or both (mixed) bacteria (short-term study). Control, H. rodentium-, H. typhlonius-, and mixed H. rodentium + H. typhlonius-infected groups contained 10, 10, 11, and 8 mice, respectively. Survival rates in H. typhlonius- and mixed infection groups were significantly decreased compared with the noninfected mice (P = 0.01 and 0.04, respectively). PI, postinfection. (B) Histologic scores (mean ± SEM) of mice infected at 7 to 8 wk of age and euthanized 11 wk after infection. Control, H. rodentium-, H. typhlonius-, and combined H. rodentium + H. typhlonius-infected groups contained 9, 10, 9, and 7 mice, respectively. Mice infected with H. typhlonius or both H. rodentium and H. typhlonius had significantly higher histologic scores than did the noninfected control group (P = 0.0005 and 0.0009, respectively, by Student t test).
Figure 2.
Figure 2.
Long-term survival and colitis severity in Helicobacter-infected adult IL10−/− mice. (A) Kaplan–Meier plot shows survival rate of adult IL10−/− mice (n = 10 for each group) infected with H. rodentium (H. rod) or H. typhlonius (H. typh) in long-term experiments. Survival was significantly decreased in mice infected with either H. rodentium or H. typhlonius compared with noninfected control mice (P < 0.01 and 0.0001, respectively). (B) Histologic scores (mean ± SEM) of mice (n = 10 for each group) infected at 7 to 8 wk of age. Mice infected with H. rodentium or H. typhlonius had significantly higher histologic scores compared with the control group (P = 0.02 and < 0.001, respectively, by Student t test).
Figure 3.
Figure 3.
Colon histology and neoplasia in Helicobacter-infected and noninfected IL10−/− adult mice. The histologic appearance of the cecum is shown for noninfected control mice (A, B), mice infected with H. rodentium (H. rod; C, D), H. typhlonius (H. typh; E, F, K), or both (Mixed; G, H, L) and noninfected mice with inflammatory bowel disease triggered by piroxicam (I, J) in the presence (Abx) and absence (no Rx) of treatment with a 4-drug antiHelicobacter regimen. Untreated IL10−/− mice infected with H. typhlonius or mixed H. rodentium plus H. typhlonius or noninfected mice exposed to piroxicam had marked mucosal hyperplasia with prominent inflammatory infiltrates that were totally abrogated by antiHelicobacter treatment. Inflammatory changes in mice infected with H. rodentium alone are not evident at this magnification. Examples of neoplastic lesions seen in long-term H. typhlonius-infected (K, proximal colon) IL10−/− mice and mice infected long-term with both H. typhlonius and H. rodentium (L, cecum) are shown. All photomicrographs were taken at the same magnification; bar, 200 μm.
Figure 4.
Figure 4.
Incidence of neoplasia in IL10−/− mice born to mothers infected with H. rodentium (H. rod), H. typhlonius (H. typh), or both (Mixed). Gray bars represent mice with only noninvasive gastrointestinal intraepithelial neoplasia (equivalent to dysplasia and carcinoma in situ), whereas black bars represent mice with at least 1 focus of invasive colonic adenocarcinoma. In pups born to H. typhlonius-infected mothers, neoplastic lesions were present in 24% mice examined, with invasive adenocarcinoma present in 18%. Neoplasia was present in 29% of pups born to mothers infected with H. rodentium, with 12% having invasive adenocarcinoma. Pups with H. typhlonius and mixed infection were significantly younger when examined than were control pups (P = 0.008 and 0.001, respectively). In adults, the incidence of colonic neoplasia in mice infected with H. typhlonius was 50% and 40% for total neoplasia and invasive adenocarcinoma, respectively. The incidence of colonic neoplasia in adults decreased as the severity of IBD decreased (compare with Figures 1 and 2), with 30% incidence of neoplasia in adult mice infected with H. rodentium alone. Invasive adenocarcinoma was not present in control (noninfected) or H. rodentium-infected adult mice.
Figure 5.
Figure 5.
Survival and colitis severity in IL10−/− mice infected as pups. (A) Kaplan–Meier plot showing survival rate of pups born to the mothers infected with H. rodentium (H. rod), H. typhlonius (H. typh), or both (Mixed). Control, H. rodentium-, H. typhlonius-, and combined H. rodentium- and H. typhlonius-infected groups contained 21, 18, 19 and 7 mice, respectively. Pups born to mothers infected with H. typhlonius had significantly (P < 0.01) lower survival rate at 18 wk compared with control pups. (B) Histologic scores (mean ± SEM) of pups born to infected mothers. Control, H. rodentium-, H. typhlonius-, and combined H. rodentium and H. typhlonius-infected groups contained 20, 17, 17 and 7 mice, respectively. Pups born to dams infected with H .rodentium, H. typhlonius, or both H. rodentium and H. typhlonius had significantly higher histologic scores compared with the control group (P = 0.04, 0.001, and 0.01, respectively, by Student t test).
Figure 6.
Figure 6.
Effect of antiHelicobacter therapy on Helicobacter-infected IL10−/− mice. Histologic scores (mean ± SEM) are shown for IL10−/− mice infected with H. rodentium or H.typhlonius at the age of 6 to 8 wk and treated with the 4-drug antiHelicobacter combination after day 30 of infection. Treated control, H. rodentium-, H. typhlonius-, and combined H. rodentium + H. typhlonius-infected groups contained 7, 9, 9 and 8 mice, respectively. Nontreated control, H. rodentium-, H. typhlonius-, and combined H. rodentium + H. typhlonius-infected groups contained 9, 10, 9, and 7 mice, respectively. Survival rates did not differ between the groups of antibiotic-treated mice. Mice were euthanized at 11 wk after infection.
Figure 7.
Figure 7.
Effect of antiHelicobacter therapy on noninfected IL10−/− mice with colitis. Inflammatory bowel disease was induced by exposure to 200 ppm piroxicam for 7 d, after which mice were treated with the 4-drug antiHelicobacter therapy combination for 16 d. Mice treated with antiHelicobacter therapy had significantly lower histologic scores (mean score ± SEM, 11 ± 3; n = 10) compared with mice not treated with antiHelicobacter drugs (31 ± 5; n = 8; P = 0.006).
Figure 8.
Figure 8.
Quantification of H. rodentium and H. typhlonius in intestinal tissue and stomach. Three IL10−/− mice inoculated with both bacterial strains were studied. Tissue was collected on day 82 of infection. Quantification of the bacterial genomes was based on the presence of Ni/Fe hydrogenase and cdtB gene for H. rodentium and H. typhlonius, respectively. The number of copies of the bacterial genome is expressed per gram of tissue.
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