Linking intestinal bitter taste receptors and GSPE-induced long-lasting benefits in ageing rats: an integrative analysis

Ageing is associated with attenuated type-2 bitter-taste receptor (TAS2R) signalling and contributes to metabolic, inflammatory and barrier decline, but its system-wide impact along the gut remains undefined. We combined transcription analysis, physiology, metabolomics and microbiota profiling to test whether a brief grape-seed proanthocyanidin extract (GSPE) intervention can counter age-related dysfunction by long-term modulation of intestinal <i>Tas2r</i> expression. Female Wistar rats were distributed into young (2 months, <i>n</i> = 10) or aged (21 months, <i>n</i> = 24) groups; eleven aged animals received GSPE (500 mg kg^-1, oral gavage) for 10 days, followed by a 75-day wash-out. After sacrifice, we quantified Tas2r mRNA in five gut segments, assessed <i>ex vivo</i> permeability, enteroendocrine outputs, systemic metabolites, inflammatory markers, 16S microbiota and the untargeted plasma metabolome. An elastic-net/PLS-DA/random-forest pipeline ranked variables discriminating age and GSPE effects, and GeneNet partial correlations generated an integrated network. Ageing suppressed Tas2r gene expression across the small intestine and the distal colon, while the proximal colon was largely unchanged. Despite the long wash-out, the brief GSPE treatment restored small-intestinal Tas2r transcription of some receptors while paradoxically down-regulating a subset in the distal colon. Consensus variable selection highlighted enterohormone expression and its <i>ex vivo</i> secretion, intestinal barrier dysfunction indices, some microbiota genera and several Tas2r transcripts among the 34 strongest discriminators. Tas2rs formed high-betweenness hubs linking epithelial integrity, inflammatory tone and butyrate-producing taxa. These findings indicate that intestinal type-2 bitter taste receptors (Tas2rs) may integrate multisystem regulatory networks fundamental to healthy ageing. Brief administration of grape-seed proanthocyanidin extract (GSPE) is sufficient to durably reprogramme Tas2r expression and the surrounding microbiota-endocrine-barrier landscape in aged rats.