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Jalševac F, Segú H, Balaguer F, Ocaña T, Moreira R, Abad-Jordà L, Gràcia-Sancho J, Fernández-Iglesias A, Andres-Lacueva C, Martínez-Huélamo M, Beltran-Debon R, Rodríguez-Gallego E, Terra X, Ardévol A, Pinent M. TAS2R5 and TAS2R38 are bitter taste receptors whose colonic expressions could play important roles in age-associated processes. J Nutr Biochem 2025; 140:109872. [PMID: 39986633 DOI: 10.1016/j.jnutbio.2025.109872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/09/2024] [Accepted: 02/13/2025] [Indexed: 02/24/2025]
Abstract
Ageing disrupts how our bodies process nutrients, leading to deregulation of nutrient-sensing and increased inflammation. Dietary interventions can promote healthy ageing, which demonstrates the importance of both metabolism and the gastrointestinal tract for our health. Bitter taste receptors (TAS2R) present in the intestine are key members of metabolic regulation. TAS2R are involved in controlling enterohormonal secretion, detect phenolic compounds in our diet, and potentially have a great impact on the ageing process. Here, we aimed to analyze the potential role of intestinal TAS2R on the ageing process and establish potential impact of these receptors on the biomarkers. Healthy subjects were divided into two age cohorts: young (38.9±6) and aged (63.6±6). TAS2R expression was analyzed in the colon. Analyses of metabolomics and of phenolic markers were performed in plasma. Best discriminatory parameters were obtained using three machine-learning methods. Finally, Spearman's rank correlation was performed. The best separators of the age cohorts were docosahexaenoic acid and multiple lipoprotein fractions. Two TAS2R were also identified: TAS2R5 and TAS2R38. TAS2R5 correlated with multiple lipoprotein-derived fractions, inflammatory marker IL-6 and polyunsaturated fatty acids. TAS2R38 was much more selective, correlating with a few parameters, including membrane lipid sphingomyelin, ketone body acetone, and omega acids. Both TAS2R5 and TAS2R38 correlated with β-hydroxybutyrate. The parameters that correlated with TAS2R have known effects on the ageing process. This suggests that TAS2R5 and TAS2R38 are the bitter receptors most likely to play a role in the development and progress of ageing.
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Affiliation(s)
- Florijan Jalševac
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Helena Segú
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Francesc Balaguer
- Gastroenterology department, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Teresa Ocaña
- Gastroenterology department, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Rebeca Moreira
- Gastroenterology department, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Laia Abad-Jordà
- Liver Vascular Biology, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Jordi Gràcia-Sancho
- Liver Vascular Biology, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology, Hospital Clinic Barcelona, IDIBAPS (Institut d´Investigacions Biomédiques August Pi i Sunyer), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Cristina Andres-Lacueva
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Miriam Martínez-Huélamo
- Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Raul Beltran-Debon
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain; IISPV, Hospital Joan XXIII, Tarragona, Spain
| | - Esther Rodríguez-Gallego
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain; IISPV, Hospital Joan XXIII, Tarragona, Spain
| | - Ximena Terra
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain; IISPV, Hospital Joan XXIII, Tarragona, Spain
| | - Anna Ardévol
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain; IISPV, Hospital Joan XXIII, Tarragona, Spain.
| | - Montserrat Pinent
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain; IISPV, Hospital Joan XXIII, Tarragona, Spain
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Lan X, Ma L, Ma J, Huang Z, Liu L, Li F, Wang M, Hu Y. Tas2r105 ameliorates gut inflammation, possibly through influencing the gut microbiota and metabolites. mSystems 2025; 10:e0155624. [PMID: 40079578 PMCID: PMC12013267 DOI: 10.1128/msystems.01556-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated gastrointestinal disorder that significantly impacts the life quality of people worldwide. Genetic factors play crucial roles in the development of IBD. Tas2rs, members of the G protein-coupled receptor (GPCR) superfamily, are known for their roles in bitter taste perception. However, Tas2rs have also been identified in the gut, where they help sense luminal contents and regulate gastrointestinal hormones. Periodontal Tas2r105 has been shown to modulate innate immunity by interacting with metabolites produced by oral bacteria. In this study, we observed increased Tas2r105 in the inflammatory colons induced by dextran sulfate sodium salt (DSS). We also noted that α-gustducin, the α-subunit of GPCRs, is present in the intestine, and that α-gustducin knockout mice exhibit aggravated colitis. Based on these findings, we hypothesize that Tas2r105 may play a role in immune regulation during IBD pathogenesis. To test this hypothesis, we used Tas2r105 knockout (KO) mice in a colitis model. Our results show that the KO mice had significantly shorter colon length, more severe colon inflammation, and greater destruction of the gut barrier compared with control mice. We also observed increased recruitment of macrophages to the lamina propria mucosa in the KO mice. Microbiological analysis revealed a significant increase in Proteobacteria and Bacteroidota, with a concomitant decrease in Firmicutes after Tas2r105 knockout. Metabolomic analysis showed a significant reduction in lysophosphatidylethanolamine (LPE) levels in the KO mice, which is known to have anti-inflammatory effects. Based on these findings, we speculate that Tas2r105 may help protect the intestine from inflammation by influencing the gut microbiota composition and LPE production.IMPORTANCEIncreased Tas2r105 was detected in the inflamed colon of mice outside the tongue. Tas2r105 deletion aggravated mice colon colitis. Tas2r105 might alleviate mice colitis by downregulating the Proteobacteria and the Bacteroidota abundance in the colon. Lysophosphatidylethanolamine (LPE) might be the key metabolite that mediated the intestinal protection of Tas2r105.
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Affiliation(s)
- Xiucai Lan
- Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Liang Ma
- Department of Radiology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jiaming Ma
- Department of Health-Related Product Assessment, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Zhipeng Huang
- Departments of Gastroenterology, First Hospital of Quanzhou affiliated to Fujian Medical University, Quanzhou, China
| | - Lingling Liu
- Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Shanghai, China
| | - Feng Li
- Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Shanghai, China
| | - Mingbang Wang
- Department of Neonatology, Affiliated Shenzhen Women and Children's Hospital (Longgang) of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, Shenzhen, Guangdong, China
- Department of Experiment & Research, South China Hospital, Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Yaomin Hu
- Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Sternini C, Rozengurt E. Bitter taste receptors as sensors of gut luminal contents. Nat Rev Gastroenterol Hepatol 2025; 22:39-53. [PMID: 39468215 DOI: 10.1038/s41575-024-01005-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/03/2024] [Indexed: 10/30/2024]
Abstract
Taste is important in the selection of food and is orchestrated by a group of distinct receptors, the taste G protein-coupled receptors (GPCRs). Taste 1 receptors (Tas1rs in mice and TAS1Rs in humans; also known as T1Rs) detect sweet and umami tastes, and taste 2 receptors (Tas2rs in mice and TAS2Rs in humans; also known as T2Rs) detect bitterness. These receptors are also expressed in extraoral sites, including the gastrointestinal mucosa. Tas2rs/TAS2Rs have gained interest as potential targets to prevent or treat metabolic disorders. These bitter taste receptors are expressed in functionally distinct types of gastrointestinal mucosal cells, including enteroendocrine cells, which, upon stimulation, increase intracellular Ca2+ and release signalling molecules that regulate gut chemosensory processes critical for digestion and absorption of nutrients, for neutralization and expulsion of harmful substances, and for metabolic regulation. Expression of Tas2rs/TAS2Rs in gut mucosa is upregulated by high-fat diets, and intraluminal bitter 'tastants' affect gastrointestinal functions and ingestive behaviour through local and gut-brain axis signalling. Tas2rs/TAS2Rs are also found in Paneth and goblet cells, which release antimicrobial peptides and glycoproteins, and in tuft cells, which trigger type 2 immune response against parasites, thus providing a direct line of defence against pathogens. This Review will focus on gut Tas2r/TAS2R distribution, signalling and regulation in enteroendocrine cells, supporting their role as chemosensors of luminal content that serve distinct functions as regulators of body homeostasis and immune response.
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Affiliation(s)
- Catia Sternini
- Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
- Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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Behrens M. International Union of Basic and Clinical Pharmacology. CXVII: Taste 2 receptors-Structures, functions, activators, and blockers. Pharmacol Rev 2025; 77:100001. [PMID: 39952694 DOI: 10.1124/pharmrev.123.001140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 06/20/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
For most vertebrates, bitter perception plays a critical role in the detection of potentially harmful substances in food items. The detection of bitter compounds is facilitated by specialized receptors located in the taste buds of the oral cavity. This work focuses on these receptors, including their sensitivities, structure-function relationships, agonists, and antagonists. The existence of numerous bitter taste receptor variants in the human population and the fact that several of them profoundly affect individual perceptions of bitter tastes are discussed as well. Moreover, the identification of bitter taste receptors in numerous tissues outside the oral cavity and their multiple proposed roles in these tissues are described briefly. Although this work is mainly focused on human bitter taste receptors, it is imperative to compare human bitter taste with bitter taste of other animals to understand which forces might have shaped the evolution of bitter taste receptors and their functions and to distinguish apparently typical human features from rather general ones. For readers who are not very familiar with the gustatory system, short descriptions of taste anatomy, signal transduction, and oral bitter taste receptor expression are included in the beginning of this article. SIGNIFICANCE STATEMENT: Apart from their role as sensors for potentially harmful substances in the oral cavity, the numerous additional roles of bitter taste receptors in tissues outside the gustatory system have recently received much attention. For careful assessment of their functions inside and outside the taste system, a solid knowledge of the specific and general pharmacological features of these receptors and the growing toolbox available for studying them is imperative and provided in this work.
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Affiliation(s)
- Maik Behrens
- Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.
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Araj-Khodaei M, Ayati MH, Azizi Zeinalhajlou A, Novinbahador T, Yousefi M, Shiri M, Mahmoodpoor A, Shamekh A, Namazi N, Sanaie S. Berberine-induced glucagon-like peptide-1 and its mechanism for controlling type 2 diabetes mellitus: a comprehensive pathway review. Arch Physiol Biochem 2024; 130:678-685. [PMID: 37921026 DOI: 10.1080/13813455.2023.2258559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/05/2023] [Indexed: 11/04/2023]
Abstract
INTRODUCTION A growing number of studies have thus far showed the association between type 2 diabetes mellitus (DM) and the intestinal microbiome homoeostasis. As reported, the gut microflora can be significantly different in patients with type 2 DM (T2DM) compared to those in healthy individuals. METHODS The authors collected the relevant articles published until 2022 and these are carefully selected from three scientific databases based on keywords. DISCUSSION This review highlights research on the anti-diabetic properties of berberine (BBR)-induced glucagon-like peptide-1 (GLP-1), as a glucose-lowering factor and a balance regulator in the microbial flora of the intestines, which plays an important role in adjusting the signalling pathways affecting insulin secretion. RESULTS Considering the anti-diabetic characteristics of the BBR-induced GLP-1, BBR makes a promising complementary treatment for reducing the clinical symptoms of DM by reducing the hyperglycaemia. Berberin might be a safe and effective drug for T2DM with little or no adverse effects.
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Affiliation(s)
| | - Mohammad Hossein Ayati
- Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Akbar Azizi Zeinalhajlou
- Department of Geriatric Health, Faculty of Health Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tannaz Novinbahador
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Shiri
- Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shamekh
- Student Research Committee, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazli Namazi
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sarvin Sanaie
- Research Center of Psychiatry and Behavioral Sciences, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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Shimizu T, Fushimi T, Ohno R, Yasuyuki F, Aso K, Jacobs UM, Nureki O, Suhara Y, Calabrese V, Osakabe N. Verification of the interaction between human bitter taste receptor T2R46 and polyphenols; Computational chemistry approach. Curr Res Food Sci 2024; 9:100914. [PMID: 39687422 PMCID: PMC11647170 DOI: 10.1016/j.crfs.2024.100914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/23/2024] [Accepted: 11/02/2024] [Indexed: 12/18/2024] Open
Abstract
Recent studies have indicated that the activation of bitter taste receptors (T2R) expressed in gastrointestinal secretory cells has a regulatory effect on the secretion of gastrointestinal hormones. Polyphenols are known to be ingested at a daily intake of 5 g or more and commonly have a bitter taste. Consequently, the interaction between the bitter taste receptor T2R46 and 490 polyphenols was investigated using in silico simulation techniques. It was demonstrated that W883.32 and E2657.39 play a pivotal role in the recognition of polyphenols and known ligands by T2R46, with frequent interactions observed, particularly with flavonoids. The results of the quantitative structure-activity relationship (QSAR) analysis demonstrated a high degree of correlation (R2 = 0.9359) between polyphenols and T2R46 in a model that incorporated molecular interaction field regions and branching scales. Furthermore, known ligands were also found to fit this model (R2 = 0.9155). These findings suggest that polyphenols may act as T2R46 ligands.
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Affiliation(s)
- Takafumi Shimizu
- Systems Engineering and Science, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
| | - Taiki Fushimi
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
| | - Rio Ohno
- Department of Bioscience and Engineering, Faculty of System Science and Engineering, Shibaura Institute of Technology, Japan
| | - Fujii Yasuyuki
- SIT Research Laboratories, Shibaura Institute of Technology, Japan
| | - Kenta Aso
- Central Research Institute, ITO EN, Ltd., Japan
| | | | - Osamu Nureki
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Japan
| | - Yoshitomo Suhara
- Systems Engineering and Science, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
- Department of Bioscience and Engineering, Faculty of System Science and Engineering, Shibaura Institute of Technology, Japan
| | - Vittorio Calabrese
- Department of Biomedical and Biotechnological Sciences, University of Catania, Italy
| | - Naomi Osakabe
- Systems Engineering and Science, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
- Functional Control Systems, Graduate School of Engineering and Science, Shibaura Institute of Technology, Japan
- Department of Bioscience and Engineering, Faculty of System Science and Engineering, Shibaura Institute of Technology, Japan
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Jalševac F, Descamps-Solà M, Grau-Bové C, Segú H, Auguet T, Avilés-Jurado FX, Balaguer F, Jorba R, Beltrán-Debón R, Blay MT, Terra Barbadora X, Pinent M, Ardévol A. Profiling bitter taste receptors (TAS2R) along the gastrointestinal tract and their influence on enterohormone secretion. Gender- and age-related effects in the colon. Front Endocrinol (Lausanne) 2024; 15:1436580. [PMID: 39512758 PMCID: PMC11541047 DOI: 10.3389/fendo.2024.1436580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 09/25/2024] [Indexed: 11/15/2024] Open
Abstract
Extraoral bitter taste receptors offer intriguing potential for modulating metabolism and the gut-brain axis through dietary interventions. Our understanding of these receptors is limited, and data on their effects on ageing are scarce. The complexity conveyed by their high diversity, low expression levels and species-dependent variability challenges our comprehension. We used real-time PCR to examine the relative abundance of multiple TAS2R across different segments of gastrointestinal mucosa in four human cohorts and related them to enteroendocrine secretions at the colon site. TAS2R14 exhibited the highest expression levels in all analyzed tissues. In contrast, TAS2R39, -38 and -42 consistently exhibited lower expression levels. Ageing was found to upregulate TAS2R4, -5, -13, -20 and GLP-1 mRNA in the descending colon. Stimulating TAS2R14 in Hutu-80 cells induced GLP-1 secretion, while stimulating TAS2R5 modulated GLP-1 and PYY secretion. Given the modifications TAS2R agonists may undergo along the GIT, as well as the distinctive expression patterns and possible functional roles of TAS2R receptors along the intestinal tract, our findings suggest the viability of a targeted strategy aimed at enhancing specific functions to improve health outcomes. This study offers valuable insights into the intricate interplay between bitter taste receptors, gut physiology and potential dietary interventions.
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Affiliation(s)
- Florijan Jalševac
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Maria Descamps-Solà
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Carme Grau-Bové
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Helena Segú
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
| | - Teresa Auguet
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, GEMMAIR Research Group, Tarragona, Spain
| | - Francesc Xavier Avilés-Jurado
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, Tarragona, Spain
- Head Neck Tumors Unit, Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Rosa Jorba
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, Tarragona, Spain
| | - Raúl Beltrán-Debón
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, MoBioFood Research Group, Tarragona, Spain
| | - Maria Teresa Blay
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, MoBioFood Research Group, Tarragona, Spain
| | - Ximena Terra Barbadora
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, MoBioFood Research Group, Tarragona, Spain
| | - Montserrat Pinent
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, MoBioFood Research Group, Tarragona, Spain
| | - Anna Ardévol
- Universitat Rovira i Virgili, Department of Biochemistry and Biotechnology, MoBioFood Research Group, Tarragona, Spain
- Institut d’Investigació Sanitària Pere Virgili (IISPV), Hospital Joan XXIII, MoBioFood Research Group, Tarragona, Spain
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8
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Dontamsetti KD, Pedrosa‐Suarez LC, Aktar R, Peiris M. Sensing of luminal contents and downstream modulation of GI function. JGH Open 2024; 8:e13083. [PMID: 38779131 PMCID: PMC11109814 DOI: 10.1002/jgh3.13083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024]
Abstract
The luminal environment is rich in macronutrients coming from our diet and resident microbial populations including their metabolites. Together, they have the capacity to modulate unique cell surface receptors, known as G-protein coupled receptors (GPCRs). Along the entire length of the gut epithelium, enteroendocrine cells express GPCRs to interact with luminal contents, such as GPR93 and the calcium sensing receptor to sense proteins, FFA2 and GPR84 to sense fatty acids, and SGLT1 and T1R to sense carbohydrates. Nutrient-receptor interaction causes the release of hormonal stores such as glucagon-like peptide 1, peptide YY, and cholecystokinin, which further regulate gut function. Existing data show the role of luminal components and microbial fermentation products on gut function. However, there is a lack of understanding in the mechanistic interactions between diet-derived luminal components and microbial products and nutrient-sensing receptors and downstream gastrointestinal modulation. This review summarizes current knowledge on various luminal components and describes in detail the range of nutrients and metabolites and their interaction with nutrient receptors in the gut epithelium and the emerging impact on immune cells.
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Affiliation(s)
- Kiran Devi Dontamsetti
- Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Laura Camila Pedrosa‐Suarez
- Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Rubina Aktar
- Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Madusha Peiris
- Centre for Neuroscience, Surgery & Trauma, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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Bloxham CJ, Hulme KD, Fierro F, Fercher C, Pegg CL, O'Brien SL, Foster SR, Short KR, Furness SGB, Reichelt ME, Niv MY, Thomas WG. Cardiac human bitter taste receptors contain naturally occurring variants that alter function. Biochem Pharmacol 2024; 219:115932. [PMID: 37989413 DOI: 10.1016/j.bcp.2023.115932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/26/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023]
Abstract
Bitter taste receptors (T2R) are a subfamily of G protein-coupled receptors that enable humans to detect aversive and toxic substances. The ability to discern bitter compounds varies between individuals and is attributed mainly to naturally occurring T2R polymorphisms. T2Rs are also expressed in numerous non-gustatory tissues, including the heart, indicating potential contributions to cardiovascular physiology. In this study. T2Rs that have previously been identified in human cardiac tissues (T2Rs - 10, 14, 30, 31, 46 and 50) and their naturally occurring polymorphisms were functionally characterised. The ligand-dependent signaling responses of some T2R variants were completely abolished (T2R30 Leu252 and T2R46 Met228), whereas other receptor variants had moderate changes in their maximal response, but not potency, relative to wild type. Using a cAMP fluorescent biosensor, we reveal the productive coupling of T2R14, but not the T2R14 Phe201 variant, to endogenous Gαi. Modeling revealed that these variants resulted in altered interactions that generally affected ligand binding (T2R30 Leu252) or Gα protein interactions (T2R46 Met228 and T2R14 Phe201), rather than receptor structural stability. Interestingly, this study is the first to show a difference in signaling for T2R50 Tyr203 (rs1376251) which has been associated with cardiovascular disease. The observation of naturally occurring functional variation in the T2Rs with the greatest expression in the heart is important, as their discovery should prove useful in deciphering the role of T2Rs within the cardiovascular system.
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Affiliation(s)
- Conor J Bloxham
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, QLD, Australia; Regenerative Medicine in Cardiovascular Diseases, First Department of Medicine, Klinikum rechts der Isar, Technical University of Munich, Germany
| | - Katina D Hulme
- School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, QLD, Australia; Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Fabrizio Fierro
- Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Israel
| | - Christian Fercher
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, QLD, Australia
| | - Cassandra L Pegg
- School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, QLD, Australia
| | - Shannon L O'Brien
- Institute of Metabolism and Systems Research, University of Birmingham, United Kingdom; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, United Kingdom
| | - Simon R Foster
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, QLD, Australia; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Kirsty R Short
- School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, QLD, Australia
| | - Sebastian G B Furness
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, QLD, Australia; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Melissa E Reichelt
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, QLD, Australia
| | - Masha Y Niv
- Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Israel
| | - Walter G Thomas
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, QLD, Australia.
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Caremoli F, Huynh J, Lagishetty V, Markovic D, Braun J, Dong TS, Jacobs JP, Sternini C. Microbiota-Dependent Upregulation of Bitter Taste Receptor Subtypes in the Mouse Large Intestine in High-Fat Diet-Induced Obesity. Nutrients 2023; 15:4145. [PMID: 37836428 PMCID: PMC10574285 DOI: 10.3390/nu15194145] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Bitter taste receptors (Tas2rs in mice) detect bitterness, a warning signal for toxins and poisons, and are expressed in enteroendocrine cells. We tested the hypothesis that Tas2r138 and Tas2r116 mRNAs are modulated by microbiota alterations induced by a long-term high-fat diet (HFD) and antibiotics (ABX) (ampicillin and neomycin) administered in drinking water. Cecum and colon specimens and luminal contents were collected from C57BL/6 female and male mice for qRT-PCR and microbial luminal 16S sequencing. HFD with/without ABX significantly increased body weight and fat mass at 4, 6, and 8 weeks. Tas2r138 and Tas2r116 mRNAs were significantly increased in mice fed HFD for 8 weeks vs. normal diet, and this increase was prevented by ABX. There was a distinct microbiota separation in each experimental group and significant changes in the composition and diversity of microbiome in mice fed a HFD with/without ABX. Tas2r mRNA expression in HFD was associated with several genera, particularly with Akkermansia, a Gram-negative mucus-resident bacterium. These studies indicate that luminal bacterial composition is affected by sex, diet, and ABX and support a microbial dependent upregulation of Tas2rs in HFD-induced obesity, suggesting an adaptive host response to specific diet-induced dysbiosis.
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Affiliation(s)
- Filippo Caremoli
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Jennifer Huynh
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
- Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Venu Lagishetty
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Daniela Markovic
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Jonathan Braun
- Inflammatory Bowel and Immunobiology Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
| | - Tien S. Dong
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Jonathan P. Jacobs
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Catia Sternini
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (F.C.); (J.H.); (V.L.); (T.S.D.); (J.P.J.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
- Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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11
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Atanga R, Singh V, In JG. Intestinal Enteroendocrine Cells: Present and Future Druggable Targets. Int J Mol Sci 2023; 24:ijms24108836. [PMID: 37240181 DOI: 10.3390/ijms24108836] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/03/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
Enteroendocrine cells are specialized secretory lineage cells in the small and large intestines that secrete hormones and peptides in response to luminal contents. The various hormones and peptides can act upon neighboring cells and as part of the endocrine system, circulate systemically via immune cells and the enteric nervous system. Locally, enteroendocrine cells have a major role in gastrointestinal motility, nutrient sensing, and glucose metabolism. Targeting the intestinal enteroendocrine cells or mimicking hormone secretion has been an important field of study in obesity and other metabolic diseases. Studies on the importance of these cells in inflammatory and auto-immune diseases have only recently been reported. The rapid global increase in metabolic and inflammatory diseases suggests that increased understanding and novel therapies are needed. This review will focus on the association between enteroendocrine changes and metabolic and inflammatory disease progression and conclude with the future of enteroendocrine cells as potential druggable targets.
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Affiliation(s)
- Roger Atanga
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
| | - Varsha Singh
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Julie G In
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
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12
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Wang Y, Geng R, Zhao Y, Fang J, Li M, Kang SG, Huang K, Tong T. The gut odorant receptor and taste receptor make sense of dietary components: A focus on gut hormone secretion. Crit Rev Food Sci Nutr 2023; 64:6975-6989. [PMID: 36785901 DOI: 10.1080/10408398.2023.2177610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Odorant receptors (ORs) and taste receptors (TRs) are expressed primarily in the nose and tongue in which they transduce electrical signals to the brain. Advances in deciphering the dietary component-sensing mechanisms in the nose and tongue prompted research on the role of gut chemosensory cells. Acting as the pivotal interface between the body and dietary cues, gut cells "smell" and "taste" dietary components and metabolites by taking advantage of chemoreceptors-ORs and TRs, to maintain physiological homeostasis. Here, we reviewed this novel field, highlighting the latest discoveries pertinent to gut ORs and TRs responding to dietary components, their impacts on gut hormone secretion, and the mechanisms involved. Recent studies indicate that gut cells sense dietary components including fatty acid, carbohydrate, and phytochemical by activating relevant ORs, thereby modulating GLP-1, PYY, CCK, and 5-HT secretion. Similarly, gut sweet, umami, and bitter receptors can regulate the gut hormone secretion and maintain homeostasis in response to dietary components. A deeper understanding of the favorable influence of dietary components on gut hormone secretion via gut ORs and TRs, coupled with the facts that gut hormones are involved in diverse physiological or pathophysiological phenomena, may ultimately lead to a promising treatment for various human diseases.
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Affiliation(s)
- Yanan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Ruixuan Geng
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yuhan Zhao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Jingjing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Mengjie Li
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Seong-Gook Kang
- Department of Food Engineering, Mokpo National University, Muangun, Korea
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
| | - Tao Tong
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
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13
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Brubaker PL. The Molecular Determinants of Glucagon-like Peptide Secretion by the Intestinal L cell. Endocrinology 2022; 163:6717959. [PMID: 36156130 DOI: 10.1210/endocr/bqac159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Indexed: 11/19/2022]
Abstract
The intestinal L cell secretes a diversity of biologically active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L cell demonstrates complex relationships with not only circulating, paracrine, and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L cell secretion, ranging from minutes to 24 hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L cell and its secreted peptides, GLP-1 and GLP-2.
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Affiliation(s)
- Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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14
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Savulescu-Fiedler I, Gurghean AL, Siliste RN. The complex involvement of the digestive tract in human defense behavior - structural and functional arguments. J Med Life 2022; 15:1081-1089. [PMID: 36415517 PMCID: PMC9635236 DOI: 10.25122/jml-2022-0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 08/12/2022] [Indexed: 11/21/2022] Open
Abstract
The digestive system has an innate monitoring and defense capacity, which allows the recognition and elimination of different dangerous substances. The complex analysis of the intestinal content comprises the cross-interactions between the epithelial cells, the enteroendocrine cells, the neural tissue and the cellular defense mechanisms. The enteric nervous system, also called "the enteric brain" or "the second brain" is the only neuronal network outside the central nervous system capable of autonomous reflex activity. The enteric nervous system activity is mostly independent of the central nervous system, but not in all aspects. In fact, even the enteral reflexes are a consequence of the bidirectional intestine-brain relation. The central nervous and enteric nervous systems are coupled through the sympathetic and parasympathetic branches of the autonomic nervous system. The gastrointestinal functions are regulated due to the interaction between the intrinsic neurons within the gastrointestinal wall and the extrinsic neurons outside the gastrointestinal tract. Here we provide an overview of the important role of the enteric brain in defensive behavior, as well as its structural and functional particularities that make it a special organ.
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Affiliation(s)
- Ilinca Savulescu-Fiedler
- Internal Medicine and Cardiology Department, Coltea Clinical Hospital, Bucharest, Romania
- Department 1 Medical Semiology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Adriana Luminita Gurghean
- Internal Medicine and Cardiology Department, Coltea Clinical Hospital, Bucharest, Romania
- Department 1 Medical Semiology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
| | - Roxana-Nicoleta Siliste
- Internal Medicine and Cardiology Department, Coltea Clinical Hospital, Bucharest, Romania
- Department 1 Medical Semiology, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
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15
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Mori Y, Aoki A, Okamoto Y, Isobe T, Ohkawara S, Hanioka N, Tanaka-Kagawa T, Jinno H. Isoform-Specific Quantification of Human Bitter Taste Receptor Transcripts Using Real-Time PCR Analysis. Biol Pharm Bull 2022; 45:1185-1190. [DOI: 10.1248/bpb.b22-00292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yoko Mori
- Faculty of Pharmacy, Meijo University
| | | | | | - Takashi Isobe
- Faculty of Pharmacy, Yokohama University of Pharmacy
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16
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Jeruzal-Świątecka J, Borkowska E, Łaszczych M, Nowicka Z, Pietruszewska W. TAS2R38 Bitter Taste Receptor Expression in Chronic Rhinosinusitis with Nasal Polyps: New Data on Polypoid Tissue. Int J Mol Sci 2022; 23:ijms23137345. [PMID: 35806350 PMCID: PMC9266535 DOI: 10.3390/ijms23137345] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 06/24/2022] [Accepted: 06/30/2022] [Indexed: 02/04/2023] Open
Abstract
Studies have shown differences in TAS2R38 receptor expression in patients with chronic rhinosinusitis (CRS) compared to healthy controls. Known agonists of TAS2R38 stimulate epithelial cells, leading to robust intracellular nitric oxide (NO) production, which damages bacterial membranes, enzymes, and DNA, but also increases ciliary beat frequency. In this study we examined, using qRT-PCR, the expression of TAS2R38 receptor in nasal polyps (NP) of patients with CRS (N = 107) and in inferior turbinate mucosa (ITM) of patients with CRS and controls (N = 39), and confronted it with clinical features and the severity of the disease. The expression was shown in 43 (50.00%) samples of ITM in the study group (N = 107), in 28 (71.79%) in the control group (N = 39) (p = 0.037), and in 43 (46.24%) of NP. There were no differences in levels of the expression in all analyzed tissues. Patients who rated their symptoms at 0–3 showed higher TAS2R38 expression in ITM in comparison to the patients with 8–10 points on the VAS scale (p = 0.020). A noticeable, however not significant, correlation between the TAS2R38 expression in ITM and the Lund–Mackay CT score was shown (p = 0.068; R = −0.28). Patients with coexisting asthma had significantly higher receptor expression in the NP (p = 0.012). Our study is the first to confirm the presence of the TAS2R38 receptor in NP. Expression of the TAS2R38 receptor is reduced in the sinonasal mucosa in patients with more advanced CRS with NP.
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Affiliation(s)
- Joanna Jeruzal-Świątecka
- Department of Otolaryngology, Head and Neck Oncology, Medical University of Lodz, 90-419 Lodz, Poland;
- Correspondence: ; Tel.: +48-501-785470
| | - Edyta Borkowska
- Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Mateusz Łaszczych
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 90-419 Lodz, Poland; (M.Ł.); (Z.N.)
| | - Zuzanna Nowicka
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 90-419 Lodz, Poland; (M.Ł.); (Z.N.)
| | - Wioletta Pietruszewska
- Department of Otolaryngology, Head and Neck Oncology, Medical University of Lodz, 90-419 Lodz, Poland;
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17
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Walker EG, Lo KR, Pahl MC, Shin HS, Lang C, Wohlers MW, Poppitt SD, Sutton KH, Ingram JR. An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: a randomized, crossover clinical trial. Am J Clin Nutr 2022; 115:925-940. [PMID: 35102364 DOI: 10.1093/ajcn/nqab418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 12/20/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Gastrointestinal enteroendocrine cells express chemosensory bitter taste receptors that may play an important role in regulating energy intake (EI) and gut function. OBJECTIVES To determine the effect of a bitter hop extract (Humulus lupulus L.) on acute EI, appetite, and hormonal responses. METHODS Nineteen healthy-weight men completed a randomized 3-treatment, double-blind, crossover study with a 1-wk washout between treatments. Treatments comprised either placebo or 500 mg of hop extract administered in delayed-release capsules (duodenal) at 11:00 h or quick-release capsules (gastric) at 11:30 h. Ad libitum EI was recorded at the lunch (12:00 h) and afternoon snack (14:00 h), with blood samples taken and subjective ratings of appetite, gastrointestinal (GI) discomfort, vitality, meal palatability, and mood assessed throughout the day. RESULTS Total ad libitum EI was reduced following both the gastric (4473 kJ; 95% CI: 3811, 5134; P = 0.006) and duodenal (4439 kJ; 95% CI: 3777, 5102; P = 0.004) hop treatments compared with the placebo (5383 kJ; 95% CI: 4722, 6045). Gastric and duodenal treatments stimulated prelunch ghrelin secretion and postprandial cholecystokinin, glucagon-like peptide 1, and peptide YY responses compared with placebo. In contrast, postprandial insulin, glucose-dependent insulinotropic peptide, and pancreatic polypeptide responses were reduced in gastric and duodenal treatments without affecting glycemia. In addition, gastric and duodenal treatments produced small but significant increases in subjective measures of GI discomfort (e.g., nausea, bloating, abdominal discomfort) with mild to severe adverse GI symptoms reported in the gastric treatment only. However, no significant treatment effects were observed for any subjective measures of appetite or meal palatability. CONCLUSIONS Both gastric and duodenal delivery of a hop extract modulates the release of hormones involved in appetite and glycemic regulation, providing a potential "bitter brake" on EI in healthy-weight men.
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Affiliation(s)
- Edward G Walker
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Kim R Lo
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Malcolm C Pahl
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Hyun S Shin
- Human Nutrition Unit; School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Claudia Lang
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Mark W Wohlers
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
| | - Sally D Poppitt
- Human Nutrition Unit; School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Kevin H Sutton
- The New Zealand Institute for Plant and Food Research Limited, Lincoln, New Zealand
| | - John R Ingram
- The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand
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18
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Hendel SK, Kellermann L, Hausmann A, Bindslev N, Jensen KB, Nielsen OH. Tuft Cells and Their Role in Intestinal Diseases. Front Immunol 2022; 13:822867. [PMID: 35237268 PMCID: PMC8884241 DOI: 10.3389/fimmu.2022.822867] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/25/2022] [Indexed: 12/11/2022] Open
Abstract
The interests in intestinal epithelial tuft cells, their basic physiology, involvement in immune responses and relevance for gut diseases, have increased dramatically over the last fifteen years. A key discovery in 2016 of their close connection to helminthic and protozoan infection has further spurred the exploration of these rare chemosensory epithelial cells. Although very sparse in number, tuft cells are now known as important sentinels in the gastrointestinal tract as they monitor intestinal content using succinate as well as sweet and bitter taste receptors. Upon stimulation, tuft cells secrete a broad palette of effector molecules, including interleukin-25, prostaglandin E2 and D2, cysteinyl leukotriene C4, acetylcholine, thymic stromal lymphopoietin, and β-endorphins, some of which with immunomodulatory functions. Tuft cells have proven indispensable in anti-helminthic and anti-protozoan immunity. Most studies on tuft cells are based on murine experiments using double cortin-like kinase 1 (DCLK1) as a marker, while human intestinal tuft cells can be identified by their expression of the cyclooxygenase-1 enzyme. So far, only few studies have examined tuft cells in humans and their relation to gut disease. Here, we present an updated view on intestinal epithelial tuft cells, their physiology, immunological hub function, and their involvement in human disease. We close with a discussion on how tuft cells may have potential therapeutic value in a clinical context.
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Affiliation(s)
- Sebastian Kjærgaard Hendel
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
- *Correspondence: Sebastian Kjærgaard Hendel,
| | - Lauge Kellermann
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Annika Hausmann
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niels Bindslev
- Department of Biomedical Sciences , University of Copenhagen, Copenhagen, Denmark
| | - Kim Bak Jensen
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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19
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Jalševac F, Terra X, Rodríguez-Gallego E, Beltran-Debón R, Blay MT, Pinent M, Ardévol A. The Hidden One: What We Know About Bitter Taste Receptor 39. Front Endocrinol (Lausanne) 2022; 13:854718. [PMID: 35345470 PMCID: PMC8957101 DOI: 10.3389/fendo.2022.854718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/04/2022] [Indexed: 12/21/2022] Open
Abstract
Over thousands of years of evolution, animals have developed many ways to protect themselves. One of the most protective ways to avoid disease is to prevent the absorption of harmful components. This protective function is a basic role of bitter taste receptors (TAS2Rs), a G protein-coupled receptor family, whose presence in extraoral tissues has intrigued many researchers. In humans, there are 25 TAS2Rs, and although we know a great deal about some of them, others are still shrouded in mystery. One in this latter category is bitter taste receptor 39 (TAS2R39). Besides the oral cavity, it has also been found in the gastrointestinal tract and the respiratory, nervous and reproductive systems. TAS2R39 is a relatively non-selective receptor, which means that it can be activated by a range of mostly plant-derived compounds such as theaflavins, catechins and isoflavones. On the other hand, few antagonists for this receptor are available, since only some flavones have antagonistic properties (all of them detailed in the document). The primary role of TAS2R39 is to sense the bitter components of food and protect the organism from harmful compounds. There is also some indication that this bitter taste receptor regulates enterohormones and in turn, regulates food intake. In the respiratory system, it may be involved in the congestion process of allergic rhinitis and may stimulate inflammatory cytokines. However, more thorough research is needed to determine the precise role of TAS2R39 in these and other tissues.
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Le Gléau L, Rouault C, Osinski C, Prifti E, Soula HA, Debédat J, Busieau P, Amouyal C, Clément K, Andreelli F, Ribeiro A, Serradas P. Intestinal alteration of α-gustducin and sweet taste signaling pathway in metabolic diseases is partly rescued after weight loss and diabetes remission. Am J Physiol Endocrinol Metab 2021; 321:E417-E432. [PMID: 34338041 DOI: 10.1152/ajpendo.00071.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 07/20/2021] [Indexed: 12/15/2022]
Abstract
Carbohydrates and sweeteners are detected by the sweet taste receptor in enteroendocrine cells (EECs). This receptor is coupled to the gustducin G-protein, which α-subunit is encoded by GNAT3 gene. In intestine, the activation of sweet taste receptor triggers a signaling pathway leading to GLP-1 secretion, an incretin hormone. In metabolic diseases, GLP-1 concentration and incretin effect are reduced while partly restored after Roux-en-Y gastric bypass (RYGB). We wondered if the decreased GLP-1 secretion in metabolic diseases is caused by an intestinal defect in sweet taste transduction pathway. In our RNA-sequencing of EECs, GNAT3 expression is decreased in patients with obesity and type 2 diabetes compared with normoglycemic obese patients. This prompted us to explore sweet taste signaling pathway in mice with metabolic deteriorations. During obesity onset in mice, Gnat3 expression was downregulated in EECs. After metabolic improvement with enterogastro anastomosis surgery in mice (a surrogate of the RYGB in humans), the expression of Gnat3 increased in the new alimentary tract and glucose-induced GLP-1 secretion was improved. To evaluate if high-fat diet-induced dysbiotic intestinal microbiota could explain the changes in the expression of sweet taste α-subunit G-protein, we performed a fecal microbiota transfer in mice. However, we could not conclude if dysbiotic microbiota impacted or not intestinal Gnat3 expression. Our data highlight that metabolic disorders were associated with altered gene expression of sweet taste signaling in intestine. This could contribute to impaired GLP-1 secretion that is partly rescued after metabolic improvement.NEW & NOTEWORTHY Our data highlighted 1) the sweet taste transduction pathway in EECs plays pivotal role for glucose homeostasis at least at gene expression level; 2) metabolic disorders lead to altered gene expression of sweet taste signaling pathway in intestine contributing to impaired GLP-1 secretion; and 3) after surgical intestinal modifications, increased expression of GNAT3, encoding α-gustducin contributed to metabolic improvement.
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Affiliation(s)
- Léa Le Gléau
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Christine Rouault
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Céline Osinski
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Edi Prifti
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
- IRD, Sorbonne University, UMMISCO, Bondy, France
| | - Hédi Antoine Soula
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Jean Debédat
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Pauline Busieau
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Chloé Amouyal
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
- Assistance Publique/Hôpitaux de Paris, APHP, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France
- Assistance Publique-Hôpitaux de Paris, APHP, Diabetology-Metabolisms Department, Pitié-Salpêtrière Hospital, Paris, France
| | - Karine Clément
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
- Assistance Publique/Hôpitaux de Paris, APHP, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France
| | - Fabrizio Andreelli
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
- Assistance Publique/Hôpitaux de Paris, APHP, Nutrition Department, Pitié-Salpêtrière Hospital, Paris, France
- Assistance Publique-Hôpitaux de Paris, APHP, Diabetology-Metabolisms Department, Pitié-Salpêtrière Hospital, Paris, France
| | - Agnès Ribeiro
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
| | - Patricia Serradas
- Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics), Paris, France
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21
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Sung WW, Tu JH, Yu JS, Ulfa MZ, Chang JH, Cheng HL. Bacillus amyloliquefaciens exopolysaccharide preparation induces glucagon-like peptide 1 secretion through the activation of bitter taste receptors. Int J Biol Macromol 2021; 185:562-571. [PMID: 34216658 DOI: 10.1016/j.ijbiomac.2021.06.187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 12/23/2022]
Abstract
The exopolysaccharide preparation of Bacillus amyloliquefaciens amy-1 (EPS) regulates glycemic levels and promotes glucagon-like peptide 1 (GLP-1) secretion in vivo and in vitro. This study aimed to identify the molecular mechanism underlying EPS-induced GLP-1 secretion. HEK293T cells stably expressing human Gα-gustducin were used as a heterologous system for expressing the genes of human bitter taste receptor (T2R) 10, 14, 30, 38 (PAV), 38 (AVI), 43, and 46, which were expressed as recombinant proteins with an N-terminal tag composed of a Lucy peptide and a human somatostatin receptor subtype 3 fragment for membrane targeting and a C-terminal red fluorescent protein for expression monitoring. EPS induced a dose-dependent calcium response from the human NCI-H716 enteroendocrine cell line revealed by fluorescent calcium imaging, but inhibitors of the G protein-coupled receptor pathway suppressed the response. EPS activated heterologously expressed T2R14 and T2R38 (PAV). shRNAs of T2R14 effectively inhibited EPS-induced calcium response and GLP-1 secretion in NCI-H716 cells, suggesting the involvement of T2R14 in these effects. The involvement of T2R38 was not characterized because NCI-H716 cells express T2R38 (AVI). In conclusion, the activation of T2Rs mediates EPS-induced GLP-1 secretion from enteroendocrine cells, and T2R14 is a critical target activated by EPS in these cells.
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Affiliation(s)
- Wei-Wen Sung
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan
| | - Jing-Hong Tu
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan
| | - Jyun-Sian Yu
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan
| | - Marisa Zakiya Ulfa
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan; Department of Agroindustrial Biotechnology, Brawijaya University, Jalan Veteran, Malang 65145, Indonesia
| | - Jia-Hong Chang
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan
| | - Hsueh-Ling Cheng
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, No. 1, Shuehfu Rd., Neipu Township, Pingtung 912301, Taiwan.
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22
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von Molitor E, Riedel K, Krohn M, Hafner M, Rudolf R, Cesetti T. Sweet Taste Is Complex: Signaling Cascades and Circuits Involved in Sweet Sensation. Front Hum Neurosci 2021; 15:667709. [PMID: 34239428 PMCID: PMC8258107 DOI: 10.3389/fnhum.2021.667709] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
Sweetness is the preferred taste of humans and many animals, likely because sugars are a primary source of energy. In many mammals, sweet compounds are sensed in the tongue by the gustatory organ, the taste buds. Here, a group of taste bud cells expresses a canonical sweet taste receptor, whose activation induces Ca2+ rise, cell depolarization and ATP release to communicate with afferent gustatory nerves. The discovery of the sweet taste receptor, 20 years ago, was a milestone in the understanding of sweet signal transduction and is described here from a historical perspective. Our review briefly summarizes the major findings of the canonical sweet taste pathway, and then focuses on molecular details, about the related downstream signaling, that are still elusive or have been neglected. In this context, we discuss evidence supporting the existence of an alternative pathway, independent of the sweet taste receptor, to sense sugars and its proposed role in glucose homeostasis. Further, given that sweet taste receptor expression has been reported in many other organs, the physiological role of these extraoral receptors is addressed. Finally, and along these lines, we expand on the multiple direct and indirect effects of sugars on the brain. In summary, the review tries to stimulate a comprehensive understanding of how sweet compounds signal to the brain upon taste bud cells activation, and how this gustatory process is integrated with gastro-intestinal sugar sensing to create a hedonic and metabolic representation of sugars, which finally drives our behavior. Understanding of this is indeed a crucial step in developing new strategies to prevent obesity and associated diseases.
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Affiliation(s)
- Elena von Molitor
- Institute of Molecular and Cell Biology, Hochschule Mannheim, Mannheim, Germany
| | | | | | - Mathias Hafner
- Institute of Molecular and Cell Biology, Hochschule Mannheim, Mannheim, Germany
| | - Rüdiger Rudolf
- Institute of Molecular and Cell Biology, Hochschule Mannheim, Mannheim, Germany.,Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Tiziana Cesetti
- Institute of Molecular and Cell Biology, Hochschule Mannheim, Mannheim, Germany
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23
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Therapeutic potential of targeting intestinal bitter taste receptors in diabetes associated with dyslipidemia. Pharmacol Res 2021; 170:105693. [PMID: 34048925 DOI: 10.1016/j.phrs.2021.105693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/23/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022]
Abstract
Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.
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24
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Nakagita T, Taketani C, Narukawa M, Hirokawa T, Kobayashi T, Misaka T. Ibuprofen, a Nonsteroidal Anti-Inflammatory Drug, is a Potent Inhibitor of the Human Sweet Taste Receptor. Chem Senses 2021; 45:667-673. [PMID: 32832995 DOI: 10.1093/chemse/bjaa057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
A sweet taste receptor is composed of heterodimeric G-protein-coupled receptors T1R2 and T1R3. Although there are many sweet tastants, only a few compounds have been reported as negative allosteric modulators (NAMs), such as lactisole, its structural derivative 2,4-DP, and gymnemic acid. In this study, candidates for NAMs of the sweet taste receptor were explored, focusing on the structural motif of lactisole. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has an α-methylacetic acid moiety, and this structure is also shared by lactisole and 2,4-DP. When ibuprofen was applied together with 1 mM aspartame to the cells that stably expressed the sweet taste receptor, it inhibited the receptor activity in a dose-dependent manner. The IC50 value of ibuprofen against the human sweet taste receptor was calculated as approximately 12 μM, and it was almost equal to that of 2,4-DP, which is known as the most potent NAM for the receptor to date. On the other hand, when the inhibitory activities of other profens were examined, naproxen also showed relatively potent NAM activity against the receptor. The results from both mutant analysis for the transmembrane domain (TMD) of T1R3 and docking simulation strongly suggest that ibuprofen and naproxen interact with T1R3-TMD, similar to lactisole and 2,4-DP. However, although 2,4-DP and ibuprofen had almost the same inhibitory activities, these activities were acquired by filling different spaces of the ligand pocket of T1R3-TMD; this knowledge could lead to the rational design of a novel NAM against the sweet taste receptor.
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Affiliation(s)
- Tomoya Nakagita
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan.,Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.,Proteo-Science Center, Ehime University, Bunkyo-cho, Matsuyama, Ehime, Japan
| | - Chiaki Taketani
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Masataka Narukawa
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Takatsugu Hirokawa
- Molecular Profiling Research Center for Drug Discovery, National Institutes of Advanced Industrial Science and Technology, Aomi, Koto-ku, Tokyo, Japan.,Department of Chemical Biology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan
| | - Takuya Kobayashi
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan
| | - Takumi Misaka
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
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25
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Lu VB, Gribble FM, Reimann F. Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion. Nutrients 2021; 13:nu13030883. [PMID: 33803183 PMCID: PMC8000029 DOI: 10.3390/nu13030883] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
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26
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Effects of gastrointestinal delivery of non-caloric tastants on energy intake: a systematic review and meta-analysis. Eur J Nutr 2021; 60:2923-2947. [PMID: 33559026 PMCID: PMC8354866 DOI: 10.1007/s00394-021-02485-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/08/2021] [Indexed: 12/17/2022]
Abstract
Purpose Taste receptors are expressed throughout the gastrointestinal tract. The activation of post-oral taste receptors using tastants could provide a non-invasive treatment option in combating the obesity epidemic. The aim of this review was to examine the effect of post-oral delivery of non-caloric tastants on eating behavior reflected by primary outcome energy intake and secondary outcomes GI symptoms and perceptions and potential underlying mechanisms. This review was conducted according to the PRISMA guidelines for systematic reviews. Methods A systematic literature search of the Cochrane, PubMed, Embase, and Medline databases was performed. This systematic review and meta-analysis was registered in the PROSPERO database on 26 February 2020 (ID: CRD42020171182). Two researchers independently screened 11,912 articles and extracted information from 19 articles. If at least two studies investigated the effect of the same taste compound on primary outcome energy intake, a meta-analysis was performed to determine pooled effect sizes. Results Nineteen papers including healthy volunteers were included. In the 19 papers analyzed, effects of various tastants were investigated in healthy volunteers. Most extensively investigated were bitter tastants. The meta-analysis of effects of bitter tastants showed a significant reduction in energy intake of 54.62 kcal (95% CI − 78.54 to − 30.69, p = 0.0014). Conclusions Bitter stimuli are most potent to influence eating behavior. Energy intake decreased after post-oral delivery of bitter tastants. This highlights the potential of a preventive role of bitter tastants in battling the obesity epidemic. Supplementary Information The online version contains supplementary material available at 10.1007/s00394-021-02485-4.
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27
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Wang Y, Alkhalidy H, Liu D. The Emerging Role of Polyphenols in the Management of Type 2 Diabetes. Molecules 2021; 26:molecules26030703. [PMID: 33572808 PMCID: PMC7866283 DOI: 10.3390/molecules26030703] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.
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Affiliation(s)
- Yao Wang
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
| | - Hana Alkhalidy
- Department of Nutrition and Food Technology, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Dongmin Liu
- Department of Human Nutrition, Foods and Exercise, College of Agricultural and Life Sciences, Virginia Tech, Blacksburg, VA 24060, USA;
- Correspondence: ; Tel.: +1-540-231-3402; Fax: +1-540-231-3916
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28
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Effect of oral or intragastric delivery of the bitter tastant quinine on food intake and appetite sensations: a randomised crossover trial. Br J Nutr 2021; 125:92-100. [PMID: 32660667 DOI: 10.1017/s0007114520002536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Stimulation of gastrointestinal taste receptors affects eating behaviour. Intraduodenal infusion of tastants leads to increased satiation and reduced food intake, whereas intraileal infusion of tastants does not affect eating behaviour. Currently, it is unknown whether oral- or intragastric administration of tastants induces a larger effect on eating behaviour. This study investigated the effects of oral- and/or intragastric administration of quinine on food intake, appetite sensations and heart rate variability (HRV). In a blinded randomised crossover trial, thirty-two healthy volunteers participated in four interventions with a 1-week washout: oral placebo and intragastric placebo (OPGP), oral quinine and intragastric placebo (OQGP), oral placebo and intragastric quinine (OPGQ) and oral quinine and intragastric quinine (OQGQ). On test days, 150 min after a standardised breakfast, subjects ingested a capsule containing quinine or placebo and were sham-fed a mixture of quinine or placebo orally. At 50 min after intervention, subjects received an ad libitum meal to measure food intake. Visual analogue scales for appetite sensations were collected, and HRV measurements were performed at regular intervals. Oral and/or intragastric delivery of the bitter tastant quinine did not affect food intake (OPGP: 3273·6 (sem 131·8) kJ, OQGP: 3072·7 (sem 132·2) kJ, OPGQ: 3289·0 (sem 132·6) kJ and OQGQ: 3204·1 (sem 133·1) kJ, P = 0·069). Desire to eat and hunger decreased after OQGP and OPGQ compared with OPGP (P < 0·001 and P < 0·05, respectively), whereas satiation, fullness and HRV did not differ between interventions. In conclusion, sole oral sham feeding with and sole intragastric delivery of quinine decreased desire to eat and hunger, without affecting food intake, satiation, fullness or HRV.
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29
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An alternative pathway for sweet sensation: possible mechanisms and physiological relevance. Pflugers Arch 2020; 472:1667-1691. [PMID: 33030576 DOI: 10.1007/s00424-020-02467-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/14/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor. In addition, experiments with mouse models lacking the sweet-taste receptor or its downstream signaling components led to the proposal of a parallel "alternative pathway" that may serve as metabolic sensor and energy regulator. Indeed, these mice showed residual nerve responses and behavioral attraction to sugars and oligosaccharides but not to artificial sweeteners. In analogy to pancreatic β cells, such alternative mechanism, to sense glucose in sweet-sensitive taste cells, might involve glucose transporters and KATP channels. Their activation may induce depolarization-dependent Ca2+ signals and release of GLP-1, which binds to its receptors on intragemmal nerve fibers. Via unknown neuronal and/or endocrine mechanisms, this pathway may contribute to both, behavioral attraction and/or induction of cephalic-phase insulin release upon oral sweet stimulation. Here, we critically review the evidence for a parallel sweet-sensitive pathway, involved signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and its sensitivity to different stimuli. Finally, we propose its physiological role in detecting the energy content of food and preparing for digestion.
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30
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TAS2R expression profile in brown adipose, white adipose, skeletal muscle, small intestine, liver and common cell lines derived from mice. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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31
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Jeruzal-Świątecka J, Fendler W, Pietruszewska W. Clinical Role of Extraoral Bitter Taste Receptors. Int J Mol Sci 2020; 21:E5156. [PMID: 32708215 PMCID: PMC7404188 DOI: 10.3390/ijms21145156] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/15/2022] Open
Abstract
Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two main types of GPCRs that transmit information about sweet, umami and bitter tastes-the Tas1r and TAS2R families. There are about 25 functional TAS2R genes coding bitter taste receptor proteins. They are found not only in the mouth and throat, but also in the intestines, brain, bladder and lower and upper respiratory tract. The determination of their purpose in these locations has become an inspiration for much research. Their presence has also been confirmed in breast cancer cells, ovarian cancer cells and neuroblastoma, revealing a promising new oncological marker. Polymorphisms of TAS2R38 have been proven to have an influence on the course of chronic rhinosinusitis and upper airway defensive mechanisms. TAS2R receptors mediate the bronchodilatory effect in human airway smooth muscle, which may lead to the creation of another medicine group used in asthma or chronic obstructive pulmonary disease. The discovery that functionally compromised TAS2R receptors negatively impact glucose homeostasis has produced a new area of diabetes research. In this article, we would like to focus on what facts have been already established in the matter of extraoral TAS2R receptors in humans.
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Affiliation(s)
- Joanna Jeruzal-Świątecka
- Department of Otolaryngology, Head and Neck Oncology, Medical University of Lodz, 90-419 Lodz, Poland;
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 90-419 Lodz, Poland;
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Wioletta Pietruszewska
- Department of Otolaryngology, Head and Neck Oncology, Medical University of Lodz, 90-419 Lodz, Poland;
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Huang WK, Xie C, Young RL, Zhao JB, Ebendorff-Heidepriem H, Jones KL, Rayner CK, Wu TZ. Development of innovative tools for investigation of nutrient-gut interaction. World J Gastroenterol 2020; 26:3562-3576. [PMID: 32742126 PMCID: PMC7366065 DOI: 10.3748/wjg.v26.i25.3562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract is the key interface between the ingesta and the human body. There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds, particularly the secretion of numerous hormones, is critical to the regulation of appetite, body weight and blood glucose. This concept has led to an increasing focus on "gut-based" strategies for the management of metabolic disorders, including type 2 diabetes and obesity. Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice. To this end, an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells. This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.
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Affiliation(s)
- Wei-Kun Huang
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Cong Xie
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Richard L Young
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Diabetes, Nutrition and Gut Health, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, SA 5005, Australia
| | - Jiang-Bo Zhao
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Heike Ebendorff-Heidepriem
- Institute for Photonics and Advanced Sensing, School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
- The ARC Centre of Excellence for Nanoscale BioPhotonics, Adelaide, SA 5005, Australia
| | - Karen L Jones
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
| | - Christopher K Rayner
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia
| | - Tong-Zhi Wu
- Adelaide Medical School, Centre of Research Excellence in Translating Nutritional Science to Good Health, the University of Adelaide, Adelaide, SA 5005, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
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Papacocea T, Papacocea R, Rădoi M, Pițuru S, Balan DG. Stomach 'tastes' the food and adjusts its emptying: A neurophysiological hypothesis (Review). Exp Ther Med 2020; 20:2392-2395. [PMID: 32765721 DOI: 10.3892/etm.2020.8874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023] Open
Abstract
The presence of taste receptors and their secondary messengers in stomach raised the possibility that the stomach might play a role in food 'tasting' and consequently, it might initiate specific adaptations of its secretory and motor function. Furthermore, activated taste receptors release a variety of chemical mediators able to modulate the activity of the enteric nervous system (ENS), and also to influence both secretory and motor functions of the stomach. Based on the physiological fundamental structure of a reflex arch, the stimulation of the gastric taste receptors activates sensory neurons of the gastric wall, continues with motor neurons which initiate the contraction of the local smooth muscle fibers. Beyond this, compounds which act on different taste receptors initiate different responses, stimulatory or inhibitory. These interactions may be translated in the gastric ability to selectively evacuate different nutritive compounds into the duodenum. Consequently, sugars could be favored to the detriment of other compounds.
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Affiliation(s)
- Toma Papacocea
- Department of Neurosurgery, 'St. Pantelimon' Emergency Hospital, 021659 Bucharest, Romania
| | - Raluca Papacocea
- Department of Physiology I, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Mugurel Rădoi
- Department of Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 041914 Bucharest, Romania
| | - Silviu Pițuru
- Department of Dental Medicine II, 'Carol Davila' University of Medicine and Pharmacy, 010221 Bucharest, Romania
| | - Daniela Gabriela Balan
- Department of Physiology III, 'Carol Davila' University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Bloxham CJ, Foster SR, Thomas WG. A Bitter Taste in Your Heart. Front Physiol 2020; 11:431. [PMID: 32457649 PMCID: PMC7225360 DOI: 10.3389/fphys.2020.00431] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/08/2020] [Indexed: 12/11/2022] Open
Abstract
The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart. Though the precise role of T2Rs in the heart remains unclear, evidence points toward a role in cardiac contractility and overall vascular tone. In this review, we summarize the extra-oral expression of T2Rs, focusing on evidence for expression in heart; we speculate on the range of potential ligands that may activate them; we define the possible signaling pathways they activate; and we argue that their discovery in heart predicts an, as yet, unappreciated cardiac physiology.
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Affiliation(s)
- Conor J Bloxham
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
| | - Simon R Foster
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Walter G Thomas
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD, Australia
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Widmayer P, Partsch V, Pospiech J, Kusumakshi S, Boehm U, Breer H. Distinct Cell Types With the Bitter Receptor Tas2r126 in Different Compartments of the Stomach. Front Physiol 2020; 11:32. [PMID: 32116750 PMCID: PMC7019106 DOI: 10.3389/fphys.2020.00032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 01/15/2020] [Indexed: 12/16/2022] Open
Abstract
Cells expressing bitter taste receptors (T2Rs or Tas2rs) in extraoral tissues are considered to be chemosensory cells mediating protective responses to potentially harmful or even antiinflammatory or antimicrobial compounds. In a previous study the activity of the Tas2R143/Tas2R135/Tas2r126 cluster promoter in the stomach was monitored using a Cre-reporter mouse line. Reporter gene expression and Tas2r126 mRNA were found in brush cells located at the distal wall of the gastric groove. In this study, we explored whether brush cells and epithelial cells of the stomach in fact contain the Tas2r126 receptor protein. Using immunohistochemistry, we demonstrate the presence of Tas2r126 immunoreactivity in different cell populations in the glandular stomach, in a subset of brush cells at the gastric groove and in unique glandular units as well as in certain enteroendocrine cells. In brush cells at the gastric groove, a strong immunofluorescence signal for the Tas2r126 receptor was observed at the most apical region of the cells, i.e., the microvillar tuft. In addition, we found a high density of Tas2r126-positive brush cells in the unique glandular units. These invaginations are located distally to the groove, open directly into the furrow and are enwrapped by smoothelin-immunoreactive muscles. In the corpus, Tas2r126 immunoreactivity was found in histamine-producing ECL cells and in ghrelin-producing X/A-like cells, the main enteroendcrine cells of this compartment. In the antrum, Tas2r126 labeling was observed in serotonin-storing EC cells and ghrelin cells, both representing only minor populations of enteroendocrine cells in this compartment. In conclusion, our data provide evidence for the presence of the Tas2r126 receptor protein in distinct cell types in the epithelium lining the mouse stomach which render the stomach responsive to agonists for bitter receptors.
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Affiliation(s)
- Patricia Widmayer
- Institute of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Vanessa Partsch
- Institute of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Jonas Pospiech
- Institute of Physiology, University of Hohenheim, Stuttgart, Germany
| | - Soumya Kusumakshi
- Experimental Pharmacology, Center for Molecular Signaling, School of Medicine, Saarland University, Homburg, Germany
| | - Ulrich Boehm
- Experimental Pharmacology, Center for Molecular Signaling, School of Medicine, Saarland University, Homburg, Germany
| | - Heinz Breer
- Institute of Physiology, University of Hohenheim, Stuttgart, Germany
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Sansome DJ, Xie C, Veedfald S, Horowitz M, Rayner CK, Wu T. Mechanism of glucose-lowering by metformin in type 2 diabetes: Role of bile acids. Diabetes Obes Metab 2020; 22:141-148. [PMID: 31468642 DOI: 10.1111/dom.13869] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/07/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent chronic condition, characterized by abnormally elevated blood glucose concentrations and, as a consequence, increased risk of micro- and macrovascular complications. Metformin is usually the first-line glucose-lowering medication in T2DM; however, despite being used for more than 60 years, the mechanism underlying the glucose-lowering action of metformin remains incompletely understood. Although metformin reduces hepatic glucose production, there is persuasive evidence that the gastrointestinal tract is crucial in mediating this effect, particularly via secretion of the incretin hormone glucagon-like peptide 1 (GLP-1). It is now well recognized that bile acids, in addition to their established function in fat digestion and absorption, are important regulators of glucose metabolism. Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM. Metformin reduces intestinal bile acid resorption substantially, such that intraluminal bile acids may, at least in part, account for its glucose-lowering effect. The present review focuses on the conceptual shift in our understanding as to how metformin lowers blood glucose in T2DM, with a particular emphasis on the role of intestinal bile acids.
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Affiliation(s)
- Daniel J Sansome
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Simon Veedfald
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Christopher K Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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Roura E, Depoortere I, Navarro M. Review: Chemosensing of nutrients and non-nutrients in the human and porcine gastrointestinal tract. Animal 2019; 13:2714-2726. [PMID: 31387651 DOI: 10.1017/s1751731119001794] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal tract (GIT) is an interface between the external and internal milieus that requires continuous monitoring for nutrients or pathogens and toxic chemicals. The study of the physiological/molecular mechanisms, mediating the responses to the monitoring of the GIT contents, has been referred to as chemosensory science. While most of the progress in this area of research has been obtained in laboratory rodents and humans, significant steps forward have also been reported in pigs. The objective of this review was to update the current knowledge on nutrient chemosensing in pigs in light of recent advances in humans and laboratory rodents. A second objective relates to informing the existence of nutrient sensors with their functionality, particularly linked to the gut peptides relevant to the onset/offset of appetite. Several cell types of the intestinal epithelium such as Paneth, goblet, tuft and enteroendocrine cells (EECs) contain subsets of chemosensory receptors also found on the tongue as part of the taste system. In particular, EECs show specific co-expression patterns between nutrient sensors and/or transceptors (transport proteins with sensing functions) and anorexigenic hormones such as cholecystokinin (CCK), peptide tyrosine tyrosine (PYY) or glucagon-like peptide-1 (GLP-1), amongst others. In addition, the administration of bitter compounds has an inhibitory effect on GIT motility and on appetite through GLP-1-, CCK-, ghrelin- and PYY-labelled EECs in the human small intestine and colon. Furthermore, the mammalian chemosensory system is the target of some bacterial metabolites. Recent studies on the human microbiome have discovered that commensal bacteria have developed strategies to stimulate chemosensory receptors and trigger host cellular functions. Finally, the study of gene polymorphisms related to nutrient sensors explains differences in food choices, food intake and appetite between individuals.
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Affiliation(s)
- E Roura
- Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St Lucia, Queensland, Australia
| | - I Depoortere
- Translational Research Center for Gastrointestinal Disorders, Gut Peptide Research Lab, University of Leuven, Belgium
| | - M Navarro
- Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, St Lucia, Queensland, Australia
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Presence of carbohydrate binding modules in extracellular region of class C G-protein coupled receptors (C GPCR): An in silico investigation on sweet taste receptor. J Biosci 2019. [DOI: 10.1007/s12038-019-9944-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Raka F, Farr S, Kelly J, Stoianov A, Adeli K. Metabolic control via nutrient-sensing mechanisms: role of taste receptors and the gut-brain neuroendocrine axis. Am J Physiol Endocrinol Metab 2019; 317:E559-E572. [PMID: 31310579 DOI: 10.1152/ajpendo.00036.2019] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Nutrient sensing plays an important role in ensuring that appropriate digestive or hormonal responses are elicited following the ingestion of fuel substrates. Mechanisms of nutrient sensing in the oral cavity have been fairly well characterized and involve lingual taste receptors. These include heterodimers of G protein-coupled receptors (GPCRs) of the taste receptor type 1 (T1R) family for sensing sweet (T1R2-T1R3) and umami (T1R1-T1R3) stimuli, the T2R family for sensing bitter stimuli, and ion channels for conferring sour and salty tastes. In recent years, several studies have revealed the existence of additional nutrient-sensing mechanisms along the gastrointestinal tract. Glucose sensing is achieved by the T1R2-T1R3 heterodimer on enteroendocrine cells, which plays a role in triggering the secretion of incretin hormones for improved glycemic and lipemic control. Protein hydrolysates are detected by Ca2+-sensing receptor, the T1R1-T1R3 heterodimer, and G protein-coupled receptor 92/93 (GPR92/93), which leads to the release of the gut-derived satiety factor cholecystokinin. Furthermore, several GPCRs have been implicated in fatty acid sensing: GPR40 and GPR120 respond to medium- and long-chain fatty acids, GPR41 and GPR43 to short-chain fatty acids, and GPR119 to endogenous lipid derivatives. Aside from the recognition of fuel substrates, both the oral cavity and the gastrointestinal tract also possess T2R-mediated mechanisms of recognizing nonnutrients such as environmental contaminants, bacterial toxins, and secondary plant metabolites that evoke a bitter taste. These gastrointestinal sensing mechanisms result in the transmission of neuronal signals to the brain through the release of gastrointestinal hormones that act on vagal and enteric afferents to modulate the physiological response to nutrients, particularly satiety and energy homeostasis. Modulating these orally accessible nutrient-sensing pathways using particular foods, dietary supplements, or pharmaceutical compounds may have therapeutic potential for treating obesity and metabolic diseases.
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Affiliation(s)
- Fitore Raka
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Sarah Farr
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Jacalyn Kelly
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Alexandra Stoianov
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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40
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Carey RM, Lee RJ. Taste Receptors in Upper Airway Innate Immunity. Nutrients 2019; 11:nu11092017. [PMID: 31466230 PMCID: PMC6770031 DOI: 10.3390/nu11092017] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.
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Affiliation(s)
- Ryan M Carey
- Department of Otorhinolaryngology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology and Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Sarnelli G, Annunziata G, Magno S, Oriolo C, Savastano S, Colao A. Taste and the Gastrointestinal tract: from physiology to potential therapeutic target for obesity. INTERNATIONAL JOURNAL OF OBESITY SUPPLEMENTS 2019; 9:1-9. [PMID: 31391920 DOI: 10.1038/s41367-019-0012-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Flavor is the combination of gustatory, olfactory and trigeminal sensations, representing the three main sensory pathways that allow detecting environmental chemical substances. Taste, in particular, is a complex chemosensory path that allows identification of substances present in ingested foods and beverages. In this manuscript, we propose a conceptual roadmap from aspects related to the evolution and the physiological role of taste, up to the current knowledge about its implication in the modulation of a healthy state, or obesity. More specifically, we focused on the role of stimulation of taste receptors in releasing gut hormones (also known as enterohormones), and their effects on the regulation of food intake, by inducing satiety, either by locally acting (in the gastrointestinal tract), or centrally (in the brain). Recent evidence demonstrated that some enterohormones are able to modulate gastrointestinal motility, thus affecting an orexigenic responses in the central nervous system. In keeping with this, we discuss the ability of the gustatory system to be a final checkpoint control for food intake regulation, and we speculate about taste perception manipulation in the management of obesity.
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Affiliation(s)
- Giovanni Sarnelli
- 1Department of Clinical Medicine and Surgery, Division of Gastroenterology, University of Naples Federico II, Naples, Italy
| | | | - Silvia Magno
- Obesity Center at the Endocrinology Unit, Department of Clinical and Experimental Medicine, Pisa, Italy
| | - Claudia Oriolo
- 4Endocrinology Unit, Medical Department of Care Continuity and Disability, University of Bologna, Bologna, Italy
| | - Silvia Savastano
- 5Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Napoli, Italy
| | - Annamaria Colao
- 5Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Napoli, Italy
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GI inflammation Increases Sodium-Glucose Cotransporter Sglt1. Int J Mol Sci 2019; 20:ijms20102537. [PMID: 31126070 PMCID: PMC6566487 DOI: 10.3390/ijms20102537] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/20/2019] [Accepted: 05/21/2019] [Indexed: 12/12/2022] Open
Abstract
A correlation between gastrointestinal (GI) inflammation and gut hormones has reported that inflammatory stimuli including bacterial endotoxins, lipopolysaccharides (LPS), TNFα, IL-1β, and IL-6 induces high levels of incretin hormone leading to glucose dysregulation. Although incretin hormones are immediately secreted in response to environmental stimuli, such as nutrients, cytokines, and LPS, but studies of glucose-induced incretin secretion in an inflamed state are limited. We hypothesized that GI inflammatory conditions induce over-stimulated incretin secretion via an increase of glucose-sensing receptors. To confirm our hypothesis, we observed the alteration of glucose-induced incretin secretion and glucose-sensing receptors in a GI inflammatory mouse model, and we treated a conditioned media (Mϕ 30%) containing inflammatory cytokines in intestinal epithelium cells and enteroendocrine L-like NCI-H716 cells. In GI-inflamed mice, we observed that over-stimulated incretin secretion and insulin release in response to glucose and sodium glucose cotransporter (Sglt1) was increased. Incubation with Mϕ 30% increases Sglt1 and induces glucose-induced GLP-1 secretion with increasing intracellular calcium influx. Phloridzin, an sglt1 inhibitor, inhibits glucose-induced GLP-1 secretion, ERK activation, and calcium influx. These findings suggest that the abnormalities of incretin secretion leading to metabolic disturbances in GI inflammatory disease by an increase of Sglt1.
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Behrens M, Meyerhof W. A role for taste receptors in (neuro)endocrinology? J Neuroendocrinol 2019; 31:e12691. [PMID: 30712315 DOI: 10.1111/jne.12691] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/14/2019] [Accepted: 01/29/2019] [Indexed: 12/12/2022]
Abstract
The sense of taste is positioned at the forefront when it comes to the interaction of our body with foodborne chemicals. However, the role of our taste system, and in particular its associated taste receptors, is not limited to driving food preferences leading to ingestion or rejection before other organs take over responsibility for nutrient digestion, absorption and metabolic regulation. Taste sensory elements do much more. On the one hand, extra-oral taste receptors from the brain to the gut continue to sense nutrients and noxious substances after ingestion and, on the other hand, the nutritional state feeds back on the taste system. This intricate regulatory network is orchestrated by endocrine factors that are secreted in response to taste receptor signalling and, in turn regulate the taste receptor cells themselves. The present review summarises current knowledge on the endocrine regulation of the taste perceptual system and the release of hunger/satiety regulating factors by gastrointestinal taste receptors. Furthermore, the regulation of blood glucose levels via the activation of pancreatic sweet taste receptors and subsequent insulin secretion, as well as the influence of bitter compounds on thyroid hormone release, is addressed. Finally, the central effects of tastants are discussed briefly.
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Affiliation(s)
- Maik Behrens
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany
| | - Wolfgang Meyerhof
- Center for Integrative Physiology and Molecular Medicine, Saarland University, Homburg, Germany
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Klaassen T, Alleleyn AME, van Avesaat M, Troost FJ, Keszthelyi D, Masclee AAM. Intraintestinal Delivery of Tastants Using a Naso-Duodenal-Ileal Catheter Does Not Influence Food Intake or Satiety. Nutrients 2019; 11:nu11020472. [PMID: 30813412 PMCID: PMC6412712 DOI: 10.3390/nu11020472] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/20/2019] [Accepted: 02/20/2019] [Indexed: 12/21/2022] Open
Abstract
Intraduodenal activity of taste receptors reduces food intake. Taste receptors are expressed throughout the entire gastrointestinal tract. Currently, there are no data available on the effects of distal taste receptor activation. In this study, we investigate the effect of intraduodenal and/or intraileal activation of taste receptors on food intake and satiety. In a single-blind randomized crossover trial, fourteen participants were intubated with a naso-duodenal-ileal catheter and received four infusion regimens: duodenal placebo and ileal placebo (DPIP), duodenal tastants and ileal placebo (DTIP), duodenal placebo and ileal tastants (DPIT), duodenal tastants and ileal tastants (DTIT). Fifteen minutes after cessation of infusion, subjects received an ad libitum meal to measure food intake. Visual analog scale scores for satiety feelings were collected at regular intervals. No differences in food intake were observed between the various interventions (DPIP: 786.6 ± 79.2 Kcal, DTIP: 803.3 ± 69.0 Kcal, DPIT: 814.7 ± 77.3 Kcal, DTIT: 834.8 ± 59.2 Kcal, p = 0.59). No differences in satiety feelings were observed. Intestinal infusion of tastants using a naso-duodenal-ileal catheter did not influence food intake or satiety feelings. Possibly, the burden of the four-day naso-duodenal-ileal intubation masked a small effect that tastants might have on food intake and satiety.
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Affiliation(s)
- Tim Klaassen
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
- Food Innovation and Health, Center for Healthy Eating and Food Innovation, Maastricht University, 5911 AA Venlo, The Netherlands.
| | - Annick M E Alleleyn
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Mark van Avesaat
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Freddy J Troost
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
- Food Innovation and Health, Center for Healthy Eating and Food Innovation, Maastricht University, 5911 AA Venlo, The Netherlands.
| | - Daniel Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
| | - Adrian A M Masclee
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
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45
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Wang F, Song X, Zhou L, Liang G, Huang F, Jiang G, Zhang L. The downregulation of sweet taste receptor signaling in enteroendocrine L-cells mediates 3-deoxyglucosone-induced attenuation of high glucose-stimulated GLP-1 secretion. Arch Physiol Biochem 2018; 124:430-435. [PMID: 29277113 DOI: 10.1080/13813455.2017.1419366] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
CONTEXT Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion. OBJECTIVE This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion. METHODS STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels. RESULTS Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reduction of intracellular cAMP levels. CONCLUSION 3DG attenuates high glucose-stimulated GLP-1 secretion by reducing STR subunit expression and downstream signaling components.
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Affiliation(s)
- Fei Wang
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Xiudao Song
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Liang Zhou
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Guoqiang Liang
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Fei Huang
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Guorong Jiang
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
| | - Lurong Zhang
- a Suzhou Academy of Wumen Chinese Medicine , Suzhou Hospital of Traditional Chinese Medicine , Suzhou , P. R. China
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46
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Dalesio NM, Barreto Ortiz SF, Pluznick JL, Berkowitz DE. Olfactory, Taste, and Photo Sensory Receptors in Non-sensory Organs: It Just Makes Sense. Front Physiol 2018; 9:1673. [PMID: 30542293 PMCID: PMC6278613 DOI: 10.3389/fphys.2018.01673] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/07/2018] [Indexed: 01/28/2023] Open
Abstract
Sensory receptors that detect and respond to light, taste, and smell primarily belong to the G-protein-coupled receptor (GPCR) superfamily. In addition to their established roles in the nose, tongue, and eyes, these sensory GPCRs have been found in many ‘non-sensory' organs where they respond to different physicochemical stimuli, initiating signaling cascades in these extrasensory systems. For example, taste receptors in the airway, and photoreceptors in vascular smooth muscle cells, both cause smooth muscle relaxation when activated. In addition, olfactory receptors are present within the vascular system, where they play roles in angiogenesis as well as in modulating vascular tone. By better understanding the physiological and pathophysiological roles of sensory receptors in non-sensory organs, novel therapeutic agents can be developed targeting these receptors, ultimately leading to treatments for pathological conditions and potential cures for various disease states.
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Affiliation(s)
- Nicholas M Dalesio
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States.,Department of Otolaryngology/Head & Neck Surgery, Johns Hopkins University, Baltimore, MD, United States
| | - Sebastian F Barreto Ortiz
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Jennifer L Pluznick
- Department of Physiology, Johns Hopkins University, Baltimore, MD, United States
| | - Dan E Berkowitz
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
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47
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Mazzoni M, Karunaratne TB, Sirri F, Petracci M, De Giorgio R, Sternini C, Clavenzani P. Enteroendocrine profile of α-transducin and α-gustducin immunoreactive cells in the chicken (Gallus domesticus) gastrointestinal tract. Poult Sci 2018; 97:4063-4072. [PMID: 29955800 PMCID: PMC6162362 DOI: 10.3382/ps/pey279] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/12/2018] [Indexed: 11/20/2022] Open
Abstract
The enteroendocrine profile and distribution patterns of the taste signaling molecules, α-gustducin (Gαgust) and α-transducin (Gαtran) protein subunits, were studied in the gastrointestinal (GI) tract of the chicken (Gallus domesticus) using double labeling immunohistochemistry. Gαtran or Gαgust immunoreactivity was observed in enteroendocrine cells (EEC) expressing different peptides throughout the entire GI tract with different density. In the proventriculus tubular gland, Gαtran or Gαgust/gastrin (GAS) immunoreactive (-IR) cells were more abundant than Gαtran/or Gαgust containing glucagon-like peptide-1 (GLP-1) or peptide YY (PYY), whereas only few Gαtran or Gαgust cells co-stored ghrelin (GHR) or 5-hydroxytryptamine (5-HT). In the pyloric mucosa, many Gαtran or Gαgust-IR cells co-expressed GAS or GHR, with less Gαtran or Gαgust cells containing GLP-1, PYY, or 5-HT. In the small intestine, a considerable subset of Gαtran or Gαgust-IR cells co-expressed 5-HT in the villi of the duodenum and ileum, PYY in the villi of the jejunum, CCK or GLP-1 in the villi of the ileum, and GHR in the duodenum crypts. In the large intestine, many Gαtran or Gαgust-IR cells contained 5-HT or GLP-1 in the villi of the rectum, whereas some Gαtran/Gαgust-IR cells co-expressed PYY- or CCK-, and few Gαtran/Gαgust-IR cells were positive for GHR-IR. In the cecum, several Gαtran or Gαgust-IR cells were IR for 5-HT. Finally, many Gαtran/Gαgust cells containing 5-HT were observed in the villi and crypts of the cloaca, whereas there were few Gαtran or Gαgust/CCK-IR cells. The demonstration that Gα-subunits are expressed in the chicken GI enteroendocrine system supports the involvement of taste signaling machinery in the chicken chemosensing processes.
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Affiliation(s)
- M Mazzoni
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, 40064 Bologna, Italy
| | - T B Karunaratne
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Italy
| | - F Sirri
- Department of Agricultural and Food Sciences, University of Bologna, Ozzano Emilia, 40064 Bologna, Italy
| | - M Petracci
- Department of Agricultural and Food Sciences, University of Bologna, Ozzano Emilia, 40064 Bologna, Italy
| | - R De Giorgio
- Department of Medical Sciences, University of Ferrara, Nuovo Arcispedale S.Anna, in Cona, 44121 Ferrara, Italy
| | - C Sternini
- CURE/DDRC, Division of Digestive Diseases, Departments Medicine and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
| | - P Clavenzani
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, 40064 Bologna, Italy
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48
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Xie C, Wang X, Young RL, Horowitz M, Rayner CK, Wu T. Role of Intestinal Bitter Sensing in Enteroendocrine Hormone Secretion and Metabolic Control. Front Endocrinol (Lausanne) 2018; 9:576. [PMID: 30319553 PMCID: PMC6171477 DOI: 10.3389/fendo.2018.00576] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/10/2018] [Indexed: 02/05/2023] Open
Abstract
The gastrointestinal tract stores ingested nutrients in the stomach which are then delivered to the small intestine at a controlled rate to optimize their digestion and absorption. The interaction of nutrients with the small and large intestine generates feedback that slows gastric emptying, induces satiation, and reduces postprandial glycemic excursions. The mechanisms underlying these nutrient-gut interactions are complex; it has only recently been appreciated that the gut has the capacity to detect intraluminal contents in much the same way as the tongue, via activation of specific G-protein-coupled receptors, and that ensuing signaling mechanisms modulate the release of an array of gut hormones that influence gastrointestinal motility, appetite and glycemia. Interestingly, evidence from preclinical models supports a functional link between intestinal bitter taste receptor (BTRs) and gastrointestinal hormone secretion, and the outcomes of recent studies indicate that stimulation of intestinal BTRs may be used to modulate gastrointestinal function, to diminish energy intake and limit postprandial blood glucose excursions in humans. This review summarizes current evidence about the expression and function of intestinal BTRs in relation to enteroendocrine hormone release and discusses the clinical implications of this pathway for the management of obesity and type 2 diabetes.
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Affiliation(s)
- Cong Xie
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Xuyi Wang
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Richard L. Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Michael Horowitz
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Christopher K. Rayner
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Tongzhi Wu
- Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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49
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Jaggupilli A, Singh N, De Jesus VC, Gounni MS, Dhanaraj P, Chelikani P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics. FASEB J 2018; 33:501-517. [PMID: 30011231 DOI: 10.1096/fj.201800521rr] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Many medications including antibiotics taste bitter. The potency of these antibiotics on the 25 bitter taste receptors (T2Rs) in humans remains poorly understood. Here we characterize by sensory and structure-function analyses how antibiotics frequently used to treat airway infections in cystic fibrosis activate multiple human T2Rs. The potency of the broad-spectrum antibiotics, tobramycin, levofloxacin, and azithromycin on the highly expressed T2Rs in airways, T2R4, T2R14, and T2R20 was pursued. The amino acids and structural features of T2R4, T2R14, and T2R20 important for antibiotic binding were characterized by mutational analysis in heterologous cell-based assays. Strikingly, extracellular loop 2 in T2Rs performs a key function in binding to antibiotics with contribution from residues in transmembrane helices. Our results suggest that different antibiotics activate multiple T2Rs with different potencies. An understanding of the nonantibiotic and physiologic effects mediated through T2Rs on the host cells is much needed.-Jaggupilli, A., Singh, N., De Jesus, V. C., Gounni, M. S., Dhanaraj, P., Chelikani, P. Chemosensory bitter taste receptors (T2Rs) are activated by multiple antibiotics.
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Affiliation(s)
- Appalaraju Jaggupilli
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Nisha Singh
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Vivianne Cruz De Jesus
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Mohamed Soussi Gounni
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Premnath Dhanaraj
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
| | - Prashen Chelikani
- Manitoba Chemosensory Biology Research Group and Department of Oral Biology, University of Manitoba, Children's Hospital Research Institute of Manitoba (CHRIM), Winnipeg, Manitoba, Canada
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50
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Freund JR, Lee RJ. Taste receptors in the upper airway. World J Otorhinolaryngol Head Neck Surg 2018; 4:67-76. [PMID: 30035264 PMCID: PMC6051256 DOI: 10.1016/j.wjorl.2018.02.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 02/08/2023] Open
Abstract
Taste receptors were named for their originally-identified expression on the tongue and role in the sensation of taste (gustation). They are now known to be involved in many chemosensory processes outside the tongue. Expression of the receptors for bitter, sweet, and umami was recently identified in many organs, including the brain, airway, gastrointestinal tract, and reproductive systems. We do not yet know the full roles of these receptors in all of these tissues, nor do we know all of the endogenous ligands that activate them. However, taste receptors are emerging as potentially important therapeutic targets. Moreover, they may mediate some off target effects of drugs, as many medications in common clinical use are known to be bitter. The focus of this review is on recent basic and clinical data describing the expression of bitter (T2R) and sweet (T1R) receptors in the airway and their activation by secreted bacterial compounds. These receptors play important roles in innate immune nitric oxide production and antimicrobial peptide secretion, and may be useful targets for stimulating immune responses in the upper respiratory tract via topical therapies. Moreover, genetic variation in these receptors may play a role in the differential susceptibility of patients to certain types of respiratory infections as well as to differential outcomes in patients with chronic rhinosinusitis (CRS). CRS is a syndrome of chronic upper respiratory infection and inflammation and has a significant detrimental impact on patient quality of life. CRS treatment accounts for approximately 20% of adult antibiotic prescriptions and is thus a large driver of the public health crisis of antibiotic resistance. Taste receptors represent a novel class of therapeutic target to potentially stimulate endogenous immune responses and treat CRS patients without conventional antibiotics.
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Affiliation(s)
- Jenna R Freund
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert J Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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