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 7

Transcriptomics analysis of jejunal crypts from patients with obesity stimulated with DB or aloin.

Options: View larger image (or click on image) Download as PowerPoint
Transcriptomics analysis of jejunal crypts from patients with obesity st...
Significantly DEGs revealed by transcriptomics analysis of human primary jejunal crypts from patients with obesity (n = 5–13) after 4 hours of treatment with the bitter compounds DB or aloin. (A) Volcano plot showing the log2 FCs of the detected genes after treatment of crypts with 1 mM DB versus DMEM (n = 13). Significantly DEGs are indicated in red. (B) Selected DEGs of Paneth cell markers (antimicrobial peptides), cytokines, and goblet cell markers (mucus proteins) after treatment with 1 mM DB. (C) Canonical pathways affected by 1 mM DB treatment, identified by analyzing the RNA-Seq data with IPA. Diff reg, differential regulation; Mechan., mechanism. (D) Venn Diagram comparing the amount of significantly DEGs identified in the data sets that included either all TAS2R43+ and TAS2R43– or only TAS2R43+ or only TAS2R43– genotypes. (E) Volcano plot showing the log2 FCs of the detected genes after treatment of crypts with 30 μM aloin or DMEM (n = 6–8). Significantly DEGs are indicated in red. (F) DEGs after treatment with 30 μM aloin in crypts from TAS2R43+ (n = 6) compared with TAS2R43– (n = 4) patients with obesity. (G) IPA identification of the canonical pathways that were affected in jejunal crypts after treatment with 30 μM aloin. Antiproli., antiproliferative.