Microbiota-Gpcr Interactome Reveals Bacteroides Regulate Oral Cancer Via Bdkrb2

The oral environment contains thousands of metabolites derived from different type cells, the microbiota, food, and medical drugs. Oral microbiota dysbiosis might promotes oral squamous cell carcinoma (OSCC) progression through bioactive metabolite-driven GPCR (G protein-coupled receptor) activation; however, current technological limitations hinder mechanistic interrogation of the oral microbiota-metabolite-GPCR interactions in OSCC progression. Our study aims to investigate how oral microbiota-derived metabolites modulate GPCR signaling through multi-omics approaches, thereby regulating OSCC progression and its underlying mechanisms. Here, we employ PRESTO-Salsa, a highly multiplexed screening technology that enables simultaneous profiling of ligand-receptor interactions across canonical GPCRs, integrated with salivary metagenomic sequencing and untargeted metabolomic profiling, to systematically analyze 314 GPCR activation patterns in OSCC patient-derived versus healthy control saliva specimens. This integrated approach revealed previously uncharacterized GPCR activation signatures associated with OSCC progression, while identifying specific microbial compositional alterations and their cognate metabolites driving receptor agonism. We found that saliva from healthy individuals strongly activated BDKRB2 signaling, whereas this agonistic activity was significantly suppressed in OSCC patients. This attenuation paralleled a marked decrease in the relative abundance of Bacteroides species within the oral microbiota of cancer patients compared to healthy controls. Next, functional validation of over 50 Bacteroides-derived small molecules identified a panel of BDKRB2-activating compounds that subsequently remodel the tumor immune microenvironment to promote OSCC pathogenesis. These studies thus establish a multi-omics integrative analytical framework and delineate the functional interplay between bacterial metabolites and the GPCRome in OSCC pathogenesis.