Gut microbiota-derived small molecules, peptides, and proteins in GPCR signaling: current evidence for β-arrestin...

Gut microbiota modulate host metabolism, immunity, barrier integrity, and neural function through diverse classes of molecules, including small molecules such as short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and microbe-derived peptides and proteins. G protein-coupled receptors (GPCRs) constitute a major receptor system through which the host senses microbiota-derived signals. However, current research has largely focused on ligand recognition, G protein pathways and functional phenotypes, leaving an insufficient understanding of how signals are reorganized after receptor activation to generate functional selectivity. In addition to mediating GPCR desensitization and endocytosis, β-arrestin regulates receptor trafficking, sustains endosomal signaling, and orchestrates signaling scaffold assembly, thereby providing a key mechanistic framework for understanding the spatiotemporal reprogramming of microbiota-derived signaling. This review summarizes both canonical and non-canonical GPCR signaling mechanisms, delineates the roles of β-arrestin in regulating receptor fate, biased signaling, and functional outputs. By integrating the PRESTO-Tango system and the PubMed literature, we analyzed the microbiome-related evidence for the near-complete non-olfactory GPCRome (314 conventional GPCRs) in order to assess the association between distinct classes of microbiota-derived molecules and GPCR-β-arrestin signaling. Current evidence indicates that existing studies are dominated by small-molecule signals, whereas evidence for peptides and proteins remains relatively limited. Moreover, most functional studies cannot be directly interpreted as evidence for β-arrestin-dependent mechanisms. A β-arrestin-centered conceptual framework for GPCR signaling regulation may provide a basis forunderstanding how gut microbiota-associated molecules influence host physiological functions through thespatiotemporal modulation of receptor signaling.