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

• DOI: 10.1172/jci144828
• Publication Date: 2021-11-17T15:26:13Z
• Authors: Kathrin I. Liszt; Qiaoling Wang; Mona Farhadipour; Anneleen Segers; Theo Thijs; Linda Nys; Ellen Deleus; Bart Van der Schu...; Christopher Gerner; Benjamin Neuditschko; Laurens J. Ceulemans; Matthias Lannoo; Jan Tack; Inge Depoortere
• Keywords: EXPRESSION; Male; 0301 basic medicine; Growth Differentiation Factor 15; Peptide Hormones; Pancreatitis-Associated Proteins; Pancreatitis-Associated Proteins/immunology; COMPREHENSIVE ANALYSIS; Receptors, G-Protein-Coupled; 03 medical and health sciences; SDG 3 - Good Health and Well-being; REVEALS; Receptors; Innate; Humans; Intestinal Mucosa/immunology; Obesity; RNA-Seq; G proteincoupled receptors; Intestinal Mucosa; 301305 Medizinische Chemie; G-Protein-Coupled/immunology; Innate immunity; Peptide Hormones/immunology; 2. Zero hunger; 301303 Medizinische Biochemie; RANGES; Obesity/immunology; UNFOLDED PROTEIN RESPONSE; 301305 Medical chemistry; Immunity; Gastroenterology; R; Growth Differentiation Factor 15/immunology; Middle Aged; Immunity, Innate; 3. Good health; Metabolism; Receptors, LDL; SDG 3 – Gesundheit und Wohlergehen; DEFENSINS; LDL/immunology; PROTEOMICS; Medicine; 301303 Medical biochemistry; PANETH CELLS; TUFT CELLS; Research Article

Bitter taste receptors (taste 2 receptors, TAS2Rs) serve as warning sensors in the lingual system against the ingestion of potentially 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 those from individuals with obesity, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and regenerating islet-derived protein 3 α [REG3A]) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. We found that the effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 deletion polymorphisms and thus confirmed a role for TAS2R43. RNA-Seq revealed 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 LDLR, genes that are involved in anorectic signaling and lipid homeostasis. In conclusion, TAS2Rs in the intestine constitute a promising target for treating diseases that involve disturbances in the innate immune system and body weight control. TAS2R polymorphisms may be valuable genetic markers to predict therapeutic responses.