Gut microbiota-derived small molecules, peptides, and proteins in GPCR signaling: current evidence for β-arrestin involvement
- 1Shandong Key Lab of Complex Medical Intelligence and Aging, The Second School of Clinical Medicine, Research and Translational Center for Immunological Disorders, Shandong Medical and Pharmaceutical University
Abstract
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.
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BibTeX
@article{hu2026microbiotaderived,
title = {{Gut microbiota-derived small molecules, peptides, and proteins in GPCR signaling: current evidence for β-arrestin involvement}},
author = {Yushan Hu and Yiru Liu and Haiyan Yao and Siteng Wang and Yice Gao and Ruixue Li and Hui Sun},
journal = {Frontiers in Microbiology},
year = {2026},
month = oct,
doi = {10.3389/fmicb.2026.1979411},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2026.1979411/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Gut microbiota-derived small molecules, peptides, and proteins in GPCR signaling: current evidence for β-arrestin involvement
AU - Yushan Hu
AU - Yiru Liu
AU - Haiyan Yao
AU - Siteng Wang
AU - Yice Gao
AU - Ruixue Li
AU - Hui Sun
PY - 2026
DA - 2026/10/08
JO - Frontiers in Microbiology
DO - 10.3389/fmicb.2026.1979411
UR - https://www.frontiersin.org/articles/10.3389/fmicb.2026.1979411/full
AB - 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.
SN - 1664-302X
ER -