Resveratrol alleviates IBD-associated neuropsychiatric comorbidities via microbiota-dependent arginine metabolism reprogramming and microglial M2 polarization through gut-brain axis

Abstract Inflammatory bowel disease (IBD) is intricately linked to neuropsychiatric comorbidities through gut-brain axis dysregulation. This study demonstrates that resveratrol (RSV), a natural polyphenol, alleviates DSS-induced colitis-associated anxiety and depression by reprogramming the microbiota─metabolite-barrier network. RSV (100 mg/kg/day) ameliorated DSS-associated anxiety-like behaviors in open field tests (peripheral zone time ↓12.6%, P< 0.0001) and depression-like phenotypes (TST immobility ↓31.0%, P = 0.0004). It restored colonic barrier integrity via ZO-1 mRNA upregulation (↑80.4%, P < 0.0001) and PAS score recovery (↑29.6%, P < 0.0001), while reducing systemic inflammation (serum LPS ↓31.9%, TNF-α ↓29.9%; P < 0.0001) vs. DSS. Crucially, RSV attenuated neuroinflammation by enhancing brain ZO-1 protein expression (↑146.1%, P = 0.0016), suppressing TLR4/MyD88/NF-κB signaling (TLR4 mRNA ↓68.8%, MyD88 protein ↓48.8%; P < 0.05), and promoting M2 microglial polarization (CD206 protein ↑171.9%, P = 0.0003) vs. DSS. Multi-omics integration revealed RSV’s dual regulatory mechanism: ① Suppression of the pro-inflammatory Turicibacter 4-guanidinobutanoic acid axis (↓42% and ↓37%, respectively; P < 0.01), disrupting LPS─TLR4─MyD88 cascades; ② Enrichment of barrier-protective Muribaculum (↑419%) and Dubosiella (↑208%), driving polyamine synthesis (spermidine ↑92%, spermine ↑38%) vs. DSS to reinforce gut-brain barriers. Spearman correlations confirmed Turicibacter-4-guanidinobutanoic acid-LPS-MyD88 interactions(r = 0.658-0.865) and Dubosiella-spermine-ZO-1 associations (r = 0.539-0.725). Conclusions: These findings establish RSV as a microbiota-metabolite modulator that redirects arginine metabolism from a pro-inflammatory bypass to polyamine-mediated barrier repair, offering novel therapeutic strategies for IBD-related neuropsychiatric complications. The integrated "microbe-metabolite-neuroimmune" axis provides mechanistic insights into gut-brain crosstalk, emphasizing dual-barrier restoration as a critical intervention node. Graphical abstract Resveratrol (RSV) alleviates psychiatric comorbidities in dextran sulfate sodium (DSS)-induced colitis mice by inhibiting the "Turicibacter-4-Guanidinobutanoic Acid-MyD88" axis and activating the "Muribaculum/Dubosiella-polyamine-ZO-1" repair axis. This results in the restoration of gut-brain barrier integrity, reduction of inflammation, and regulation of microglial M2 polarization.