Bitter taste receptors in Inflammatory Bowel Diseases: possible new drug targets

Bitter taste receptors (TAS2R) have been found expressed primarily in the oral cavity and represent the second largest group of chemosensory G-protein coupled receptors. However, in the last decade, several studies have investigated the extra chemoreceptive roles of TAS2Rs in selected tissues and organs of the body in vitro and in vivo, as well as their possible clinical implications. In 2002, Wu et al. demonstrated the gene expression of several TAS2Rs in both murine stomach and duodenum, followed by several evidence demonstrating their expression on different cell types in the gut epithelium, suggesting a role of bitter ligands in the gut both in hormonal secretion and in the protective immunity. Ulcerative Colitis and Crohn’s disease represent the two major clinically defined forms of inflammatory bowel disease (IBD) that may affect the whole gastrointestinal tract and the colonic mucosa and represent an urgent need of new pharmacological approaches in the management of these diseases. In fact, therapies for IBD include chronic administration of glucocorticosteroids, sulfasalazine derivatives and anti-TNF monoclonal antibodies but all of them have long term toxicity. In this perspective, the identification and characterization of new therapeutic targets for the development of innovative anti-IBD drugs appear to be crucial. Therefore, the project aims to provide significant advancement of knowledge related to the progression of IBD concentrating the research on subtypes 10, 38 and 46 of hTAS2R. We intend to evaluate the role of bitter taste signalling at different level of intestinal activity, that is its involvement in peristalsis and in the inflammatory process, both heavily involved in the pathogenesis of IBD. Moreover, we aim to evaluate the role of hTAS2R in different blood mononuclear cells in the inflammatory pathway in periphery as a biomarkers and targets of IBD. Two units participate in a tight collaboration, the University of Pavia (UNIPV) and University of Piemonte Orientale (UNIUPO) that will approach the pathologies directly on human models, in vitro studies and murine models. Briefly, the project will develop to study: i) the expression of hTAS2Rs in ex vivo gut samples from IBD patients and HC, and in human smooth muscle intestinal primary cell line and human epithelial cell line; ii) the expression of hTAS2Rs in peripheral mononuclear cells isolated from blood of IBD patients and HC; iii) the downstream bitter signalling on calcium homeostasis, oxidative stress and cytokine release and (iv) study the role of modulating TAS2Rs signalling in vivo murine models of IBD.