Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity

Bitter taste receptors (TAS2R) serve as warning sensors in the lingual system against ingestion of potential poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially from obese subjects, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and REG3A) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. The effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 amino acid/deletion polymorphisms and thus confirmed a role for TAS2R43. RNA sequencing uncovered that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and the LDLR, genes that are involved in anorectic signaling and lipid homeostasis. To conclude, TAS2Rs in the intestine provide a promising target for treating diseases that involve disturbances in the innate immune system and in body weight control. Polymorphisms in TAS2Rs may be valuable genetic markers to predict therapeutic responses.