Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis

Abstract

Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract in which alterations to the bacterial community contribute to disease. Adherent-invasive E. coli (AIEC) are associated with human Crohn’s disease, however their role in intestinal immunopathology is unclear due to the lack of an animal model compatible with chronic timescales. Here we establish chronic AIEC infection in streptomycin-treated conventional mice (CD-1, DBA/2, C3HeN, 129e, C57BL/6), enabling the study of host response and immunopathology. AIEC induces an active Th17 response, heightened levels of proinflammatory cytokines and fibrotic growth factors, with transmural inflammation and fibrosis. Depletion of CD8+ T cells increases cecal bacterial load, pathology and intestinal fibrosis in C57BL/6 mice suggesting a protective role. Our findings provide evidence that chronic AIEC infections result in immunopathology similar to that seen in Crohn’s disease. With this model, research into the host and bacterial genetics associated with AIEC-induced disease becomes more widely accessible.

Host Defense Peptide Resistance Contributes to Colonization and Maximal Intestinal Pathology by Crohn's Disease-Associated Adherent-Invasive Escherichia coli

“…Six-to 8-week-old female CD-1 mice were obtained from Charles River. Twenty-four hours before infection, mice received 20 mg of streptomycin via orogastric gavage as described previously (35). For competitive infections, equal volumes of overnight cultures of wild-type NRG857c strain and the kanamycin-resistant mutant were mixed, and the bacteria were washed in PBS and resuspended to ϳ2 ϫ 10 10 CFU/ml.…”

“…At the indicated times (indicated in the figures), the ilea, ceca, and colons of infected mice were removed, fixed in buffered 10% formalin, embedded in paraffin, sectioned into 5-m slices, and then stained with hematoxylin and eosin (H&E) by Histology Services at McMaster University. Multiple sections from the same tissue from several animals at each time point were scored according to a published pathology scoring matrix (36) with minor modifications (35).…”

“…In order to quantify the in vivo fitness benefit of ompT, PI-6, and the individual genes therein, we competed mutant strains against the wild-type strain NRG857c using a model of chronic infection in female CD-1 mice (35). The PI-6 mutant was rapidly outcompeted by wild-type NRG857c, beginning on day 2 postinfection and reaching undetectable levels in fecal output by day 7 (Fig.…”

Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin

“…This is supported by epidemiologic studies linking prior enteric infection with increased IBD risk 36 and in a AIEC-induced murine colitis model where inflammation persisted beyond times when viable AIEC could be detected. 37,38 Although we did not formally measure mucin levels, glycosylation patterns, or barrier leakiness in our study of MDX-supplemented mice, we postulate that similar defects in mucosal barrier integrity would occur in these mice and that they would be more prone to expansion of pathobionts, such as AIEC. It may be that a diet rich in MDX leads to alterations in the commensal microbiome and cellular glycome which leads to increased susceptibility to enteric pathogen infection and IBD development.…”

Microbiote intestinal et développement des maladies inflammatoires chroniques de l’intestin

“…Des anticorps anti-levures, mis en évidence par des tests utilisant des antigènes glycaniques isolés de la levure Saccharomyces cerevisiae (ASCA), sont détectés chez 50 à 60 % des patients présentant une MC et, de façon intéressante, chez 20 à 25 % des membres sains devenir pathogène sous différentes formes appelées pathovars 4 [21]. Les patients atteints de MICI sont colonisés avec une fréquence anormale par des souches d'E.…”