Project Details
Projekt
Functional dynamics of dysbiosis in a gnotobiotic transfer model of Crohn`s disease-like ileitis: Impact of diet and inflammation
Applicant
Professor Dr. Dirk Haller
Subject Area
Nutritional Sciences
Gastroenterology
Gastroenterology
Term
from 2013 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 237119533
The increasing incidence of inflammatory bowel diseases (IBD) is considered to be the consequence of environmental and individual risk factors. A major focus of research into disease mechanisms underlying chronic inflammation is the gut microbial ecosystem and its interaction with the intestinal mucosa. Crohn’s disease is one of the two major IBD phenotypes mostly affecting the terminal ileum. Despite the fact that a variety of susceptibility genes suggest a role for microbial triggers in the pathogenesis of Crohn’s disease, numerous IBD-related mouse models target chronic inflammation only in the colon and functional evidence for the intestinal microbiota in shaping a spontaneously developing, chronic inflammatory process of the small intestine is still lacking. The aim of the present project is to identify and mechanistically characterize a disease-relevant microbiota in a unique murine model for Crohn’s disease-like ileitis (heterozygous Tnf ΔARE/+ mice). First experiments showed that antibiotic treatment (vancomycin/metronidazole) of Tnf ΔARE/+ mice inhibited ileal inflammation, supporting the hypothesis that microbial factors play an essential role in the disease pathogenesis of the small intestine. Improvement of ileal pathology was associated with marked changes in mucosa-associated and luminal bacterial diversity, but not cell density, as measured by high-throughput sequence analysis of 16S rRNA gene amplicons. Based on these findings, we will use isolated bacterial strains of the endogenous microbiota to initiate (Objective 1) or prevent (Objective 2) recurrent pathology in germ-free and antibiotic-treated Tnf ΔARE/+ mice. The interplay of selected microbiota with the disease-susceptible host will be analyzed at the epithelial (ileum) and T cell level targeting innate and antigen-specific mechanisms. In summary, we propose to use one of the few model systems for Crohn’s disease-like ileitis to study the functional role of the non-infectious intestinal microbiota in initiating chronic inflammation of the small intestine.
DFG Programme
Priority Programmes
