Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation

Abstract

BackgroundGenetic susceptibility to colonic inflammation is poorly defined at the gene level. Although Genome Wide Association studies (GWAS) have identified loci in the human genome which confer susceptibility to Inflammatory Bowel Disease (Crohn’s and Ulcerative Colitis), it is not clear if precise loci exist which confer susceptibility to inflammation at specific locations within the gut e.g. small versus large intestine. Susceptibility loci for colitis in particular have been defined in the mouse, although specific candidate genes have not been identified to date. We have previously shown that infection with Trichuris muris (T. muris) induces chronic colitis in susceptible mouse strains with clinical, histological, and immunological homology to human colonic Crohn’s disease. We performed an integrative analysis of colitis susceptibility, using an F2 inter-cross of resistant (BALB/c) and susceptible (AKR) mice following T. muris infection. Quantitative Trait Loci (QTL), polymorphic and expression data were analysed alongside in silico workflow analyses to discover novel candidate genes central to the development and biology of chronic colitis.Results7 autosomal QTL regions were associated with the establishment of chronic colitis following infection. 144 QTL genes had parental strain SNPs and significant gene expression changes in chronic colitis (expression fold-change ≥ +/-1.4). The T. muris QTL on chromosome 3 (Tm3) mapped to published QTL in 3 unrelated experimental models of colitis and contained 33 significantly transcribed polymorphic genes. Phenotypic pathway analysis, text mining and time-course qPCR replication highlighted several potential cis-QTL candidate genes in colitis susceptibility, including FcgR1, Ptpn22, RORc, and Vav3.ConclusionGenetic susceptibility to induced colonic mucosal inflammation in the mouse is conserved at Tm3 and overlays Cdcs1.1. Genes central to the maintenance of intestinal homeostasis reside within this locus, implicating several candidates in susceptibility to colonic inflammation. Combined methodology incorporating genetic, transcriptional and pathway data allowed identification of biologically relevant candidate genes, with Vav3 newly implicated as a colitis susceptibility gene of functional relevance.

Differential expression of soluble receptor for advanced glycation end-products (sRAGE) in mice susceptible or resistant to chronic colitis

“…Representative images of haematoxylin and eosin stained proximal colon sections in naïve mice and at 31 days PI are shown in Figure 1C. Collectively, these results reproduce previously published research in the AKR/BALB/c infection model [4], where BALB/c mice initiate an acute, resolving inflammation after T. muris challenge and AKR mice show delayed immune response that results in a chronic inflammatory phenotype due to a failure to expel worms.…”

“…It is impossible to reliably predict onset, relapse or remission of IBD [3] and currently, only animal models provide a means of studying the perturbations in the gut that precede colitis. Infecting susceptible mouse strains with the enteric nematode parasite Trichuris muris closely parallels human Crohn’s disease in both the pathological and transcriptional changes induced [4] and has been established as a model for the study of the initiation of immune responses in the colon [5]. T. muris resistant BALB/c and C57BL6 mice mount an early immune response against the worms within 24 hours of infection, with large numbers of dendritic cells (DCs) migrating to the lamina propria, whereas AKR mice or C57BL/6 mice with a low dose infection mount a delayed immune response, resulting in chronic intestinal inflammation and a failure to expel the worms [5, 6].…”

Immunity to gastrointestinal nematode infections

“…Indeed, chronic T. muris infection results in the accumulation of interferon-g þ T cells in the bone marrow, 213 and does not appear to protect against the development of colitis. 214,215 Furthermore, depending on the strain, chronically infected mice gain less weight than their uninfected counterparts, 216 and in some cases even acquire colitis-like symptoms, thus losing weight, 217 mirroring the malnutrition and wasting of some infected humans. In contrast, lung pathology appears to be decreased in response to papain challenge, 218 illustrating that worm-induced protection against inflammatory disorders is highly context specific.…”

The role of mouse strain differences in the susceptibility to fibrosis: a systematic review

“…They identified seven potential QTL and four candidate genes for susceptibility to colitis, FCgR1 , Ptpn22 , RoRc and Vav3 [80]. However, these data have not yet been mapped to the human condition of intestinal fibrosis.…”