OC-010 PhenotypingTrichuriscolitis reveals innate and adaptive immunological commonalities to human Crohn's disease

Abstract

Introduction Trichuris muris, an intestinal dwelling nematode, induces chronic colitis in susceptible mouse strains. Pathology is characterised by patchy, full thickness colonic inflammation, similar to Crohn9s disease (CD). Conversely, resistant mouse strains exhibit transient acute infection ( Aims (1) Characterise colonic mucosal gene expression in resistant and susceptible mouse strains following T muris infection. (2) Phenotype and compare the clinical and immunological profiles of T muris chronic colitis with available CD data. Method Susceptible (AKR) and resistant (BALB/c) mice were administered 300 T muris ova by oral gavage. Naive, resistant and susceptible mice were compared at day 35 post-infection. Wellbeing, body weight and stools were assessed throughout. Worm count, serum IgG, macroscopic and microscopic colonic changes were determined. Pooled colonic mRNA (n=5) was applied to Affymetrix GeneChip Mouse Exon 1.0 ST arrays. 3 replicate GeneChips were processed per study group. Bio-informatic and ANOVA statistical analysis, qPCR replication, and in silico data mining was performed. Results Resistant BALB/c exhibited “normal” macroscopic and microscopic appearances and a strong Th2 immune response post-infection. Diarrhoea, weight loss, and colonic shortening were seen in susceptible infected AKR, with moderate-to-severe focal, transmural colonic inflammation and fat hypertrophy. Consistent with clinical and histological findings, infected AKR demonstrated differentially upregulated innate pattern-recognition and autophagy transcripts (eg, TLR4, MyD88, Ripk2, NFkB, NOD2, IRGM) (>×1.2-fold upregulation cf. naive, p Conclusion With clinical, histological, and immunological commonalities with human Crohn9s disease, chronic Trichuriasis offers a validated, immuno-competent and reproducible tool for colitis research. The exploration and translation of resistance and susceptibility phenotypes/genotypes in this model of colonic inflammation may be far reaching.