Gut microbiota mediates repeated sevoflurane-induced cognitive impairment via the gut-brain axis

Jun 11, 2026Behavioural brain research

Gut Bacteria May Link Repeated Sevoflurane Use to Memory Problems Through the Gut-Brain Connection

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Abstract

Rats exposed to sevoflurane exhibited significant impairments in spatial learning and memory.

Sevoflurane exposure was linked to increased levels of inflammatory markers such as lipopolysaccharide (LPS) and pro-inflammatory cytokines in serum and the hippocampus.
There was a reduction in the expression of the tight junction protein ZO-1 in colonic and hippocampal tissues after sevoflurane exposure.
Elevated protein levels of TLR4, phosphorylated NF-κB p65, and NLRP3 were observed in the hippocampus following sevoflurane exposure.
Antibiotic pretreatment appeared to reduce the inflammatory changes induced by sevoflurane.
Sevoflurane exposure was associated with significant shifts in gut microbiota composition, including increased levels of certain bacterial genera.

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OBJECTIVE: This study investigated whether repeated Sev exposure induces cognitive impairment in developing rats and examined the involvement of gut-derived inflammatory mediators.

METHODS: Thirty postnatal Sprague-Dawley rats were randomly assigned to five groups: control, sevoflurane (Sev), sevoflurane control (Sev-Con), antibiotic-treated (ANT), and sevoflurane plus antibiotic-treated (Sev+ANT). Cognitive performance was assessed using the Morris water maze, while inflammatory markers, barrier-related proteins, microbial metabolites, and gut microbiota composition were analyzed using western blotting, immunohistochemistry, gas chromatography, and 16S rRNA gene sequencing.

RESULTS: Rats in the Sev group exhibited significant impairments in spatial learning and memory compared with controls. Sev exposure increased serum and hippocampal levels of lipopolysaccharide (LPS), trimethylamine N-oxide (TMAO), and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), while reducing the expression of the tight junction protein ZO-1 in colonic and hippocampal tissues. In addition, protein levels of TLR4, phosphorylated NF-κB p65, and NLRP3 were elevated in the hippocampus. Antibiotic pretreatment attenuated these alterations. No significant differences in short-chain fatty acid (SCFA) levels were observed following sevoflurane exposure. 16S rRNA gene sequencing revealed sevoflurane-associated shifts in gut microbiota composition at the genus level, characterized by increased relative abundances of Ligilactobacillus, Faecousia, and Alloprevotella and a decreased abundance of Lactobacillus.

CONCLUSION: Repeated sevoflurane exposure during development was associated with cognitive impairment and alterations in gut microbiota-related inflammatory signaling along the gut-brain axis. Broad-spectrum antibiotic pretreatment attenuated these changes, suggesting that gut microbiota-related processes may contribute to sevoflurane-associated neurocognitive dysfunction, although causal inference remains limited because antibiotics may exert microbiota-independent effects.