TLR-mediated microbiota-host interaction in the regulation of intestinal homeostasis and nflammation

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The intestinal lumen is colonised by trillions of commensal bacteria that provide essential digestive support but also influence the regulation of mucosal and systemic immune responses. The cross talk between host cells and the microbiota is now believed to be the major determinant of health and disease in the gastrointestinal tract. Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the intestine with unclear aetiology. Deregulation of the cross talk between the intestinal microbiota and the host immune system is currently believed to be the main factor contributing to IBD. The single-layered intestinal epithelium forms a mechanical barrier separating the luminal contents from the mucosa but also provides an active immunological barrier directly regulating and interacting with both the microbiota and the host immune system. The cross-talk of intestinal epithelial cells with the microbiota and with the host immune system is believed to be critical for the regulation of intestinal homeostasis, however the mechanisms regulating epithelial responses to intestinal bacteria and mucosal immune cells remain poorly understood. We showed previously that inhibition of NF-κB signalling in the intestinal epithelium by epithelial specific knockout of NEMO/IKKgamma triggered the spontaneous development of severe chronic colon inflammation. The development of colitis in these epithelial-specific NEMO knockout mice depends on MyD88-mediated TLR signalling and on the presence of intestinal bacteria. In this project we aim to address the role of the TLR-mediated cross talk between the host and the microbiota in the regulation of intestinal homeostasis and inflammation. In the first part of the project we will use genetic mouse models to address the mechanisms by which TLR signalling induces the pathogenesis of chronic colon inflammation in mice with epithelial-specific NEMO knockout. In the second part of the project we will use mouse models allowing the inducible inhibition of TLR signalling specifically in the intestinal epithelium in order to address the role of epithelial TLR signalling in the regulation of the composition of the intestinal microbial communities. Together, these studies will provide important information that will advance the current state of the art in understanding the TLR-mediated mechanisms controlling the cross-talk between the host and the microbiota and their impact in the regulation of epithelial homeostasis and inflammation.