Modeling Crohn’s Disease

Crohn’s disease usually presents in early adulthood.

Patients have a markedly reduced quality of life and a 5 to 7-fold increased risk for developing

colorectal cancer.

Currently no cure &

cause is poorly understood.

Canterbury

Prevalence of CD:

155 / 100 000

Incidence of CD:

16.5 / 100 000

Gearry et al. 2006

MAP is the causative agent of Johne’s disease in ruminants.

Johne’s disease is characterised by chronic intestinal inflammation.

Studies report increased molecular & microbiological evidence of MAP in Crohn’s disease patients.

Does MAP infection have a role in the aetiology of Crohn’s disease?

Mycobacterium avium subspecies paratuberculosis

(MAP)

Model: Interleukin-10 gene-deficient mice

Rationale for using this model

Normal intestinal epithelium provides a barrier relatively impermeable to luminal constituents.

Patients with IBD experience enhanced intestinal permeability that correlates with degree of injury.

IL10-/- mice develop a primary intestinal permeability defect in response to enteric microflora.

IL10 -/- mice

Uninfected (naïve)

(Mice 1-10)

Infected (challenged with MAP)

(Mice 11-20)

Specific pathogen free (SPF) mice

Housed in micro-isolator cages

Assessed weekly for 20 weeks

0

0.5

1

1.5

2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

WeekC

DA

I

Uninfected Infected

Crohn’s Disease Activity Index (CDAI)

Weight loss > 5%

Diarrhoea

Excreted perianal mucous

Rectal prolapse

Mouse Jejunum Asc. colon Caecum Desc. colon TOTAL Lymph node Liver

1 0 1 1 1 3 0 0

2 1 1 1 1 4 0 0

3 1 4 4 1 10 1 1

4 1 0 1 1 3 0 0

5 1 2 4 0 7 1 1

6 0 0 2 0 2 2 0

7 0 0 1 0 1 0 0

8 0 1 2 0 3 0 0

9 1 0 1 0 2 0 0

10 1 4 4 2 11 3 3

11 0 1 2 0 3 0 0

12 0 1   0 1 0 0

13 1 0 2 1 4 1 0

14 0 0 1 0 1 0 0

15 2 3 4 1 10 3 3

16 2 2 1 0 5 0 1

17 0 1 2 0 3 0 0

18 0 0 2 0 2 0 0

19 1 1 1 1 4 0 1

20 0 0 1 0 1 0 0

Inflammation score: 0 - 4

Un

infe

cted

Infe

tce

d

Mouse 15 Mouse 4

Potential model of inflammation-induced colon cancer.