Guava Polysaccharide Interventions Ameliorate Delayed Neurocognitive Recovery by Modulating the Gut Microbiota–Arachidonic Acid Metabolism Axis and Attenuating Aβ/Tau Pathology

Abstract Delayed neurocognitive recovery (dNCR) is the most common complication after anesthesia and surgery (A/S) with unclear mechanisms and no effective therapy. Here, we purified a pectin polysaccharide (GP) from guava fruits (Mw 94.516 kDa), featuring a backbone of HG and RG-I domains with side chains of →3,6)-β-d-Galp-(1→ and →5)-α-l-Araf -(1→, and evaluated its neuroprotective effects in a dNCR mouse model. Our results demonstrated that GP ameliorates cognitive impairment, pathological damage, neuroinflammation, and oxidative stress injury, while inhibiting the pGSK-3β/pTau signaling pathway and Aβ deposition. Findings further reveal that GP ameliorates gut microbiota (GM) dysbiosis, enhances the production of short-chain fatty acids (SCFAs), and suppresses the key enzymes and metabolites in the AA metabolic pathway in dNCR mice. However, antibiotic treatment abolished the effects of GP, indicating that GP modulates the GM–AA metabolism axis to suppress Aβ/Tau pathology, thereby mitigating the progression of dNCR.