Natural Bitter Compounds, Intestinal TAS2Rs, and GLP-1 Secretion: Mechanistic Evidence and Translational Challenges

Bitter taste receptors (TAS2Rs) are expressed beyond the oral cavity, and those in the intestine have been implicated in metabolic regulation. Selected natural bitter compounds (NBCs) increase glucagon-like peptide-1 (GLP-1) release in experimental enteroendocrine models, but predicted ligand binding, functional receptor activation, and receptor-dependent hormone secretion do not provide equivalent evidence. Intestinal TAS2Rs may thus provide a route to endogenous GLP-1 modulation distinct from receptor agonist therapy. Unlike broader reviews of extraoral chemosensing, this review maps these distinct endpoints for individual NBC-TAS2R pairs and separates measured GLP-1 release from changes in proglucagon expression. We define a receptor-supported enteroendocrine core and distinguish it from indirect evidence and testable hypotheses concerning microbiota-associated, immune–endocrine, and gut–brain interfaces. Receptor-directed perturbation supports selected compound-specific secretory responses, whereas the three proposed interfaces lack complete NBC-TAS2R-GLP-1 causal chains. We critically compare human-derived cell lines, animal models, primary tissues, and organoids, and summarize the experimental concentrations and GLP-1 assay endpoints where reported. Finally, we identify priorities for receptor-selective validation, measurement of intestinal target-site exposure, and prospective human studies. This evidence map clarifies what is experimentally supported and what must be demonstrated before intestinal TAS2Rs can be considered reliable targets for endogenous GLP-1 modulation.