Resveratrol alleviates functional dyspepsia-like pathology by modulating chemokine- and cytokine-related immune-epithelial signaling in the duodenal mucosa.

OBJECTIVE

Resveratrol is a dietary polyphenol found in grapes, peanuts, and berries, with reported anti-inflammatory, immunomodulatory, barrier-protective, and microbiota-regulating properties. Functional dyspepsia (FD) is associated with duodenal immune dysregulation, epithelial barrier impairment, and microbial imbalance, suggesting an active mucosal microenvironment. This study therefore examined whether resveratrol could alleviate FD-like pathological changes. We also examined its links with epithelial homeostasis, gut microbiota, and chemokine- or cytokine-related ligand-receptor signaling.

METHODS

An FD-like mouse model was established and treated with resveratrol. Gastric emptying was assessed, and duodenal histopathology was examined by hematoxylin-eosin staining, including epithelial injury, goblet cell alterations, crypt disorganization, and inflammatory cell infiltration. Toluidine blue staining assessed mast cell accumulation. RNA sequencing, GO/KEGG enrichment, and protein-protein interaction analyses characterized immune-related pathways, hub genes, and potential signaling networks. qPCR validated genes related to mucosal metabolism and epithelial function, chemokine- and cytokine-related ligand-receptor signaling genes, mast cell markers, and epithelial barrier genes. 16S rRNA sequencing assessed gut microbial changes.

RESULTS

FD-like mice showed delayed gastric emptying, duodenal mucosal injury, inflammatory cell infiltration, goblet cell alterations, crypt disorganization, and mast cell accumulation, indicating low-grade mucosal immune activation and epithelial barrier disturbance. Resveratrol improved gastric emptying, alleviated duodenal injury, and reduced mast cell infiltration. Transcriptomic analysis showed broad changes in immune-related programs, particularly those associated with antigen presentation, adaptive immune responses, pro-inflammatory signaling, chemokine and cytokine activity, and mucosal immune regulation. PPI and qPCR analyses further supported the regulation of mucosal homeostasis, candidate Ccl2-Ccr2, Il6-Il6ra/Il6st, and Tnf-Tnfrsf1a signaling, mast cell-associated immune activation, and epithelial barrier gene expression. Resveratrol also altered gut microbial β-diversity, community composition, ecological assembly, and predicted functions.

CONCLUSION

Resveratrol attenuates FD-like gastric dysmotility and duodenal inflammatory injury, potentially by reducing mast cell-associated mucosal immune activation, modulating chemokine- and cytokine-related immune-epithelial signaling, supporting epithelial barrier homeostasis, and reshaping gut microbiota.