Human intestinal bitter taste receptors regulate innate immune responses and metabolic regulators in obesity
Kathrin I. Liszt, … , Jan Tack, Inge Depoortere
Kathrin I. Liszt, … , Jan Tack, Inge Depoortere
Published November 16, 2021
Citation Information: J Clin Invest. 2022;132(3):e144828. https://doi.org/10.1172/JCI144828.
View: Text | PDF
Research Article Gastroenterology Metabolism

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

Abstract

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.

Authors

Kathrin I. Liszt, Qiaoling Wang, Mona Farhadipour, Anneleen Segers, Theo Thijs, Linda Nys, Ellen Deleus, Bart Van der Schueren, Christopher Gerner, Benjamin Neuditschko, Laurens J. Ceulemans, Matthias Lannoo, Jan Tack, Inge Depoortere

×

Figure 4

Role of TAS2R43 in the effect on E. coli growth of CSNs from patients with obesity coli growth of CSNs from patients with obesity stimulated with bitter compounds.

Options: View larger image (or click on image) Download as PowerPoint
Role of TAS2R43 in the effect on E. coli growth of CSNs from patients wi...
(A) E. coli CFU following treatment with the supernatant of obese patients’ jejunal crypts (n = 5–14) stimulated for 30 minutes with bitter compounds (compound-CSN) or Krebs (Krebs-CSN). Crypt-independent effects of bitter agonists are shown as well (bacteriostatic control). All results are expressed as the percentage of Krebs-CSN with or without vehicle. Compounds were grouped by their TAS2R activation profile: generalists (>5 TAS2Rs); intermediates (3 or 4 TAS2Rs), and specialists (1 or 2 TAS2Rs). Test concentrations and abbreviations are given in Table 1. (B) Western blots showing expression of α-defensin 5 or REG3A in lysates from crypts from obese individuals. Crypts were treated for 30 minutes with bitter agonists or Krebs. Vertical line indicates that the lanes were run on the same gel but were noncontiguous. Summary of Western blot analyses for the effect on (C) α-defensin 5 or (D) REG3A protein expression (n = 6–8). (E and F) Effect of TAS2R43 deletion/amino acid polymorphisms. (E) Effect on E. coli growth of the supernatant of crypts from TAS2R43+ and TAS2R43– patients with obesity. Crypts were stimulated for 30 minutes with the TAS2R43 agonists aloin (30 μM, n = 11 TAS2R43+, n = 4 TAS2R43–); quinine (0.1 mM, n = 4 TAS2R43+, n = 2 TAS2R43–); or DB (0.1 mM, n = 4 TAS2R43+, n = 3 TAS2R43–). (F) Effect on E. coli growth of the supernatant of crypts from obese patients with a TAS2R43 genotype that is highly sensitive (n = 5 TAS2R43+ W); mildly sensitive (n = 5 TAS2R43+ S); or not sensitive (n = 4 TAS2R43–) to aloin. Data represent the mean ± SEM, and single values are plotted. Statistical significance was determined using a mixed model with patient as the random effect and, for Western blot analysis, a paired Student’s t test with Bonferroni-Holm adjustment. *P < 0.05, **P < 0.01, and ***P < 0.001, versus Krebs-CSN or the vehicle control (100% control); #P < 0.05 and ##P < 0.01, versus the bacteriostatic control.