Resveratrol's Therapeutic Role in Sepsis-Associated Encephalopathy.

Abstract

Introduction/objective: Sepsis-Associated Encephalopathy (SAE) represents a lifethreatening complication of sepsis, whose pathogenesis is driven by intestinal dysbiosis through bidirectional gut-brain axis signaling. Resveratrol, a neuroprotective natural polyphenol, exerts anti-SAE effects in a microbiota-dependent manner; nevertheless, existing mechanistic evidence has not been systematically integrated. This review comprehensively summarizes its multitiered protective signaling cascades centered on gut-brain crosstalk.

Methods: We systematically retrieved relevant literature published between January 2006 and July 2026 from mainstream databases in accordance with the PRISMA-S reporting standard. We integrated CLP/LPS septic animal and cellular data, and compared auxiliary evidence from non-septic models without direct extrapolation.

Results: Preclinical septic animal studies confirmed four core protective axes of resveratrol centered on gut microbiota remodeling: (1) reshaping intestinal flora to limit LPS translocation; (2) stabilizing intestinal and cerebral tight junctions via SIRT1/NF-κB signaling; (3) elevating gut-derived shortchain fatty acids to inhibit glial pro-inflammatory activation; (4) activating Nrf2/HO-1 to relieve cerebral mitochondrial oxidative injury. Reciprocal fecal microbiota transplantation, germ-free and antibiotic depletion assays verified gut flora as an indispensable intermediate mediator linking oral resveratrol to neurological recovery. Non-septic model data provided auxiliary molecular references but cannot be extrapolated to SAE without septic-specific validation. Major translational obstacles include low oral bioavailability, narrow therapeutic window, and conflicting efficacy under combined ICU routine medications.

Discussion: All cerebral pathological lesions (neuroinflammation, glial polarization, oxidative stress, BBB damage) originate from gut dysbiosis and endotoxin translocation in SAE, which establishes the gut-brain axis as the core therapeutic target of resveratrol. Repeated redundant mechanistic descriptions across pathways were condensed and overlapping glial sections merged in this revised minireview to meet journal word limits. Indirect non-septic evidence lacks the systemic endotoxin storm characteristic of SAE, thus only serves as supplementary reference. Novel microbiota-targeted delivery formulations are promising solutions to overcome resveratrol's pharmacokinetic defects.

Conclusion: Resveratrol alleviates SAE through multi-modal gut-brain axis regulation. Novel microbiota- targeted delivery carriers and standardized clinical trials focusing on delayed intervention are urgently needed to overcome translational limitations and facilitate the clinical application of resveratrol as an adjuvant therapy for SAE.