Beyond the tongue: The emerging role of system bias and biased signaling in bitter taste receptor (TAS2R) function and nutrition

Background Bitter taste perception is a critical determinant of consumer food choice, dietary compliance, and nutrition-related health outcomes. While classical chemosensory research heavily focuses on the canonical, Gα gustducin -dependent signaling axis, accumulating evidence reveals that bitter taste receptors (TAS2Rs) can couple with alternative G-proteins and β-arrestins to regulate complex cellular responses, particularly in extra-oral tissues. Scope and approach This critical review delineates the emerging diversity of TAS2R signaling and evaluates ligand-induced biased signaling as a fundamental mechanism driving pathway-selective receptor responses. We analyze how structurally diverse food-derived agonists can preferentially induce specific intracellular cascades, modulating signaling kinetics, desensitization, and trafficking, and evaluate whether these extra-oral paradigms translate into human taste receptor cells. Key findings and conclusions Current evidence supports the concept that TAS2Rs can signal beyond the canonical Gα gustducin -dependent pathway in a cell- and context-dependent manner as a system bias, with emerging evidence for ligand-dependent signaling bias. Elucidating how specific dietary bitter compounds and endogenous metabolites selectively engage distinct downstream pathways will fundamentally enhance our understanding of chemosensory physiology and nutrition, establishing a rigorous molecular foundation for future functional food development and targeted flavor modulation.