Gut Microbiota–Metabolite–Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice

Abstract

Background: The mechanisms underlying social dysfunction caused by repeated sevoflurane in early life remain unclear. Whether the gut microbiota–metabolite–brain axis is involved in the mechanism of sevoflurane developmental neurotoxicity still lacks report. Methods: Mice received 3% sevoflurane at postnatal day (PND) 6, 7, and 8 for 2 h per day. Metagenomic sequencing and untargeted metabolomic analysis were applied to investigate the effects of sevoflurane on gut microbiota and metabolism. The animal social behavior and the synaptic development were analyzed during PND 35. Subsequently, fecal microbiota transplantation (FMT) from the control group and bile acid administration were performed to see the expected rescuing effect on socially related behaviors that were impaired by repeated sevoflurane exposure in the mice. Results: In the 3-chamber test, sevoflurane-exposed mice spent less time with stranger mice compared with the control group. The density of both the apical and basal spine decreased in mice exposed to sevoflurane. In addition, repeated sevoflurane exposure led to a notable alteration in the gut microbiota and metabolite synthesis, particularly bile acid. FMT reduced the production of intestinal bile acid and attenuated the effect of sevoflurane exposure on social function and synaptic development. Cholestyramine treatment mimics the protective effects of FMT. Conclusions: The gut microbiota–metabolite–brain axis underlies social dysfunction caused by sevoflurane exposure in early age, and bile acid regulation may be a promising intervention to this impairment.