Exploratory microbiota-metabolite alterations associated with cognitive impairment after repeated low-dose sevoflurane exposure in mice.

Background: Repeated low-dose sevoflurane exposure may affect cognition, but the relationship between such exposure, gut microbial composition, and circulating metabolites remains unclear. This study examined an experimental proof-of-concept exposure model and treated microbiota-metabolite findings as exploratory associations. Methods: Mice were exposed to 100 ppm sevoflurane for 2 h/day over 7 consecutive days, followed by Morris water maze testing without a long-term recovery follow-up. Gut microbiota and serum metabolites were profiled by shotgun metagenomic sequencing and LC-MS metabolomics, respectively, and machine-learning analyses were used only for exploratory feature ranking. Results: Sevoflurane-exposed mice exhibited poorer Morris water maze performance (Day 6 escape latency: 28.6 ± 3.4 s vs. 12.5 ± 1.8 s in controls, p < 0.01), although interpretation is limited by unequal behavioral sample sizes. Serum metabolomics suggested nominal and exploratory alterations in bile acid- and sphingolipid-related pathways. Shotgun metagenomics (n = 3/group) identified preliminary relative-abundance shifts, including a lower Conclusions: In this proof-of-concept model, repeated low-dose sevoflurane exposure was associated with impaired spatial learning and memory and with exploratory serum metabolic and gut microbial alterations. The findings do not establish persistent long-term deficits, routine occupational risk, or causal microbiota-metabolite mediation. Larger cage-aware studies, an ambient-air comparison group, targeted validation, and interventional experiments are required.