The gut, which is the key interface between food and the human body, “tastes” what we eat in much the same way as the lingual system. Indeed, taste receptors are expressed on epithelial cells and monitor the presence of nutrients but also of non-nutrients such as bitter compounds to elicit appropriate physiological processes. During this talk, I will focus on the role of bitter taste receptors (TAS2R) in the gut as metabolic regulators in patients with obesity that affect the release of appetite regulating gut hormones and a stress regulated cytokine that acts as a defense signal. Further, the role of TAS2Rs in the regulation of innate immune factors (mucins, defensins) that affect E. coli growth and thus shape the gut microbiota, will be elucidated as well. The role of TAS2R deletion polymorphisms as a tool to predict therapeutic responses will be illustrated. These studies should elucidate whether targeting of extra-oral bitter receptors with specific agonists may represent a relevant strategy to control energy homeostasis and innate immune responses.