The role of intestinal homeostasis in sevoflurane-induced myelin development and cognitive impairment in neonatal mice.

Abstract

Background: Inhalational anesthetic sevoflurane is commonly used in pediatric anesthesia. Multiple exposures to sevoflurane in early postnatal life have been associated with long-term abnormalities in myelin development and cognitive and memory impairments, although the underlying mechanisms remain incompletely elucidated. Disruption of gut microbiota is recognized as an important contributor to neurological diseases. Here, we explore the potential mechanisms underlying the abnormal myelin development induced by multiple sevoflurane exposures in neonatal rats by analyzing gut homeostasis.

Methods: Six-day-old (P6) C57BL/6 mice were exposed to 3% sevoflurane for 2 hours per day for three consecutive days. Mice exposed to a mixture of 60% nitrogen and oxygen under the same conditions and duration served as controls. Behavioral tests were conducted between P32 and P42. At P9 (24 hours after the last sevoflurane exposure) and P42 (after the completion of behavioral tests), intestinal and brain examinations were performed to investigate the effects of sevoflurane exposure during the lactation and adolescent periods on gut homeostasis and myelin development in mice. Subsequently, the ameliorative effects of butyrate supplementation on sevoflurane-induced abnormalities in myelin development and cognitive and memory impairments were observed.

Results: After repeated exposure to sevoflurane, neonatal mice developed persistent gut microbiota imbalance accompanied by a decrease in short-chain fatty acids. Short-term intestinal inflammation emerged, with damage to the mucus layer and barrier function. In the hippocampus and prefrontal cortex, the expression of genes and transcription factors related to oligodendrocyte differentiation and myelin development was significantly affected, and these changes persisted even after the exposure ended. There was a reduction in proteins associated with oligodendrocytes and myelin formation, which had a certain impact on memory and cognitive behavior. This study also explored the potential connections between microbiota, metabolism, the gut, the brain, and behavior. Timely supplementation with butyrate could effectively reverse these changes, indicating that gut homeostasis is crucial for brain neurodevelopment.

Conclusion: Multiple exposures to sevoflurane in neonatal mice disrupt gut homeostasis and affect oligodendrocyte differentiation and myelin development in the hippocampus and prefrontal cortex, inducing cognitive and memory impairments. Supplementation with butyrate can alleviate these changes.