Akkermansia muciniphila improves synaptic remodeling and alleviates sepsis-associated cognitive dysfunction via regulating the gut-brain axis

Abstract

Sepsis-associated cognitive impairment (SACI) is a frequent long-term complication of sepsis characterized by hippocampal neuroinflammation, synaptic loss and gut microbial dysbiosis. Akkermansia muciniphila (AKK) possesses anti-inflammatory and intestinal barrier-protective functions, yet its role and mechanism in SACI remain poorly understood. In this study, a CLP-induced septic mouse model was used to explore the protective effect of AKK. Behavioral tests were performed to evaluate anxiety and cognitive function. Hippocampal neuronal injury, microglial activation and synaptic plasticity were assessed by HE staining, immunofluorescence, Western blotting and TEM. Intestinal barrier function, gut microbiota composition and metabolic profiles were analyzed via 16S rRNA sequencing and untargeted metabolomics, with FMT applied for mechanistic verification. AKK intervention remarkably alleviated anxiety-like behaviors and rescued cognitive deficits in septic mice. AKK inhibited microglial overactivation, activated the BDNF/P-TrkB pathway, and restored the expression of synaptic SYP and PSD95. Meanwhile, AKK preserved intestinal tight junction integrity, reshaped gut microbiota structure, and reversed sepsis-related metabolic disturbances. FMT further provided evidence that AKK-modulated gut microbiota improved survival and cognitive performance. In conclusion, AKK ameliorates SACI by suppressing hippocampal neuroinflammation, restoring synaptic plasticity and remodeling the microbiota-gut-brain axis, indicating its potential as a promising candidate for SACI intervention.