Gut Microbiota–Metabolite–Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice
Youyi Zhao,
Sanxing Ma,
Lirong Liang,
Shuhui Cao,
Ze Fan,
Danyi He,
Xiaotong Shi,
Yao Zhang,
Bing Liu,
Meiting Zhai,
Shengxi Wu,
Fang Kuang,
Hui Zhang
Affiliations
Youyi Zhao
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Sanxing Ma
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Lirong Liang
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Shuhui Cao
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Ze Fan
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Danyi He
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Xiaotong Shi
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Yao Zhang
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Bing Liu
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Meiting Zhai
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Shengxi Wu
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Fang Kuang
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
Hui Zhang
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology,
School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China.
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.
