The role of microglia in sepsis-associated encephalopathy: a narrative review.

Abstract

<h4>Background and objective</h4>Sepsis-associated encephalopathy (SAE) is a severe multifactorial brain dysfunction triggered by severe infections, characterized by neuroinflammation, blood-brain barrier (BBB) breakdown, and persistent neurocognitive deficits. Accumulating evidence indicates that phenotypic polarization of microglia-resident immune cells in the central nervous system (CNS)-plays a central role in SAE pathogenesis. In SAE, microglia exhibit an imbalance in polarization, with sustained pro-inflammatory states and impaired reparative functions, accompanied by activation of the NLRP3 inflammasome, forming a deleterious cycle of neuroinflammation and neuronal damage. This review focuses on three underexplored domains in SAE: neuronal/glial dysfunction, circadian disruption, and gut-brain axis dysregulation.<h4>Methods</h4>A systematic literature search was performed in PubMed (1985-2025) using fuzzy-matching mode, with search terms including "microglia", "sepsis-associated encephalopathy", "blood-brain barrier (BBB)", "microglia polarization", "M1/M2 polarization", "NLRP3 inflammasome", "inflammation" "quercetin", and related Medical Subject Headings (MeSH) terms.<h4>Key content and findings</h4>This review elaborates on the mechanisms underlying neuronal/glial dysfunction, circadian rhythm disruption, and gut-brain axis imbalance in SAE, emphasizing their interactions with microglial polarization and neuroinflammation. Experimental interventions targeting microglial activity (e.g., CSF1R inhibitors) show promise, but complete suppression of microglia is inadvisable due to their essential role in maintaining neural network homeostasis.<h4>Conclusions</h4>Future therapeutic strategies for SAE should aim to balance the inhibition of harmful inflammatory responses with the preservation of microglia-mediated reparative processes, while targeting the underexplored domains identified herein to improve neuroprotective efficacy and ultimately translate into tangible clinical benefits for patients.