Project Details
Projekt
Mechanisms of microbiota induced IL-23/Th17 immune responses in chronic colitis
Subject Area
Gastroenterology
Term
from 2013 to 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 237734245
Complex regulatory mechanisms work together to maintain intestinal homeostasis, and a breakdown in these pathways may finally result in inflammatory bowel disease (IBD). Much of our present understanding of intestinal homeostasis is built around the concept that the microbiota continuously interacts with the intestinal immune system and that the microbiota composition regulates the fine equilibrium between pro-inflammatory and tolerogenic immune responses. However, whether disease related shifts in microbiota composition that were shown to occur in IBD directly cause disease or reflect the adaptation of bacterial communities to inflammation or host genotype related changes in the intestinal environment is still incompletely understood. Genetic polymorphisms in the IL-23R gene and other regions that encode proteins implicated in the IL-23/TH17 pathway in IBD as well as murine studies suggest that appropriate regulation of IL-23 dependent immune responses is critical for intestinal immune homeostasis. On the other hand the IL-23/TH17 axis may play a central role in protective immunity to gastrointestinal infections. In this project, we will mechanistically investigate the crosstalk between IL-23 producing cells, IL-23R+ immune cell populations, their effector cytokines and the commensal flora. An IL-23 reporter mouse strain will be used to analyze the spatiotemporal expression of IL-23 under germfree conditions and after re-colonization with conventional or defined microflora. Using a mouse model of IL-23 dependent spontaneous colitis, we will characterize the intestinal T cell and innate lymphoid cell (ILC) pool in intestinal tissues before and after onset of colitis; these results will be compared to the situation in IBD patients. In parallel, the compositional analysis of the intestinal microbiota by 16S rRNA metagenomic studies will help to characterize the microbiota/immune system interactions in the transition phase from healthy to inflammatory settings. Moreover, as the cytokines IL-17 and IL-22 that are particularly produced by TH17 cells and RORγt+ ILC in an IL-23 dependent manner are important regulators of antimicrobial peptide production in intestinal epithelial cells (IEC), we will determine how cytokine induced antimicrobial peptide production affects microbial composition and diversity in the gut. In line with this, we will analyze in models of infectious colitis, how IL-23 dependent production of antimicrobial factors in IEC contribute to physiological host responses to intestinal pathogens.
DFG Programme
Priority Programmes
Subproject of
SPP 1656:
Intestinal Microbiota - A Microbial Ecosystem at the Edge between Immune Homeostasis and Inflammation
Participating Person
Professor Dr. André Bleich
