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.
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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

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Figure 2

Intracellular Ca2+ changes in response to DB and immunostaining identification of cells in primary crypts from patients with obesity.

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Intracellular Ca2+ changes in response to DB and immunostaining identifi...
(A) Percentage of 30 mM KCl-responsive primary jejunal cells from patients with obesity that responded to 0.1 mM or 1 mM DB administration with either a decrease or increase in intracellular Ca2+ levels. (B) Relative rise in fluorescence intensity in single cells from crypts of individuals with obesity treated with DB or KCl. Data represent the mean ± SEM. n = 3–4 subjects. (C–E) Images show the cells in bright-field, as well as immunofluorescence staining for α-defensin 5 (red) and mucin 2 (green). Nuclei were stained with DAPI (blue). Ca2+ changes in the regions of interest from the images in C–E are shown in the tracings. (C) Tracing of a Paneth cell responding to 1 mM DB with a Ca2+ rise and another unidentified, nonresponding cell. (D) Tracing of a Paneth cell responding to 0.5 mM DB with a Ca2+ increase and another unidentified, nonresponding cell. (E) Tracing of a goblet cell responding to 0.5 mM DB with a Ca2+ decrease and an unidentified, nonresponding cell. Scale bars: 20 μM.