Gut Microbiome Alterations in TAAR5 Knockout Mice and In Silico Ligand Prediction

Trace amine-associated receptors (TAARs) are a class of G protein-coupled receptors with roles in olfaction, behaviour, and immunity. Known best as an olfactory receptor, TAAR5 has been linked to emotional behaviour and hippocampal neurogenesis, yet its peripheral mechanisms remain poorly understood. Given bidirectional influences between the gut microbiota and the host, we investigated whether TAAR5 deletion alters the gut microbiome in mice. Using 16S rRNA sequencing, we compared the gut microbiota of TAAR5-knockout (TAAR5-KO) and wild-type mice. While alpha-diversity remained unchanged, beta-diversity analysis revealed significant separation between genotypes, with TAAR5-KO mice exhibiting markedly increased inter-individual variability. Taxonomically, KO mice showed a significant reduction in Ruminococcus and ASF356, alongside an enrichment of specific Lachnospiraceae and Prevotellaceae lineages. Functional metagenomic prediction (PICRUSt2) implied a reduction in the metagenomic capacity for central metabolic pathways (glycolysis, TCA cycle, fatty acid β-oxidation) and an increase in the capacity for guanosine nucleotide degradation pathways; these hypotheses remain untested. Molecular docking identified candidate microbial metabolites, including small amines (2-aminophenol, aminoacetone, butan-1-amine), with ligand efficiencies comparable to the known TAAR5 agonist trimethylamine. These findings suggest that TAAR5 may influence gut microbiome composition and function, with particular impact on Ruminococcus—a genus linked to intestinal inflammation. The increased compositional variability in TAAR5-KO mice suggests that TAAR5 may act as a homeostatic gatekeeper in gut microbial ecology. Our in silico results offer testable hypotheses for future validation of microbial metabolites as novel TAAR5 ligands.