Abstract
Fetal exposure to inhaled anesthetics, such as isoflurane, may lead to neurodevelopmental impairment in offspring. Yet, the mechanisms of prenatal isoflurane–induced developmental neurotoxicity have not been fully elucidated. Gut microbiota is a pivotal modulator of brain development and functions. While the antibiotic effect of isoflurane has been previously investigated, the relationship between prenatal isoflurane exposure and postnatal gut microbiota, brain biology, and behavior remains unknown. In the present study, we treated pregnant rats with 2% isoflurane for 4 h on gestational day 14. Their offspring were tested with novel object recognition task on postnatal day 28 (P28) to assess cognition. Fecal microbiome was assessed using 16S RNA sequencing. We also analyzed hippocampal expression of brain-derived neurotrophic factor (BDNF) in P28 rat brains. To further explore the role of gut microbiota on prenatal isoflurane–induced developmental neurotoxicity, we treated rats with mixed probiotics on P14 for 14 days and evaluated novel object recognition and hippocampal expression of BDNF on P28. Results indicate that prenatal exposure to isoflurane significantly decreased novel object recognition (novel object preference ratio: mean difference (MD) − 0.157; 95% confidence interval (CI) − 0.234 to − 0.080, P < 0.001) paralleled by diminished expression of hippocampal BDNF in juvenile rats. Prenatal exposure to isoflurane also significantly altered the diversity and composition of gut microbiota. Treatment with probiotics mitigated these changes in cognition (novel object preference ratio: isoflurane group vs. control group: MD − 0.177; 95% CI − 0.307 to − 0.047, P = 0.006; probiotic group vs. isoflurane group: MD 0.140; 95% CI 0.004 to 0.275, P = 0.042) and BDNF expression. Taken together, our findings suggest that gut dysbiosis may be involved in the pathogenesis of maternal isoflurane exposure–induced postnatal cognitive impairment. To determine the causal relationship between gut microbiota and cognition in prenatal anesthetic–induced developmental neurotoxicity, further studies are needed.
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Abbreviations
- ANOVA:
-
Analysis of variance
- BCA:
-
Bicinchoninic acid
- BDNF:
-
Brain-derived neurotrophic factor
- CI:
-
Confidence interval
- CNS:
-
Central nervous system
- FDA:
-
Food and Drug Administration
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- LDA:
-
Linear discriminant analysis
- LEfSe:
-
Linear discriminant analysis effect size
- MAC:
-
Minimum alveolar concentration
- MD:
-
Mean difference
- NOR:
-
Novel object recognition
- OTUs:
-
Operational taxonomic units
- PCoA:
-
Principal coordinate analysis
- PERMANOVA:
-
Permutational multivariate analysis of variance
- qPCR:
-
Quantitative polymerase chain reaction
- SCFA:
-
Short-chain fatty acid
- SD:
-
Standard deviation
- SPF:
-
Specific-pathogen-free.
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Acknowledgements
The authors thank Dr. Miao Liu and Dr. Jing-Sheng Li for their kind support. The authors also thank Nissi S. Wang, MSc, for the developmental editing of the manuscript.
Funding
The present study was supported by the Research Foundation of Peking University School and Hospital of Stomatology (No. PKUSS20180109 to Hai-Yin Wu and No. PKUSS20190113 to Li-Kuan Wang).
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Li-Kuan Wang helped conceive and design the study, acquired the data, analyzed and interpreted the data, and drafted and critically revised the manuscript. Xu-Dong Yang helped conceive and design the study, analyzed and interpreted the data, and drafted the manuscript. Dan Zhou helped in the animal allocation and data analysis. Tong Cheng helped conceive and design the study and analyzed the data. Xiang Zhang helped design the study. Hai-Yin Wu helped conceive and design the study, analyzed and interpreted the data, wrote and critically revised the manuscript, and approved the final version to be submitted.
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Wang, LK., Yang, XD., Zhou, D. et al. Prenatal Isoflurane Exposure Induces Developmental Neurotoxicity in Rats: the Role of Gut Microbiota. Neurotox Res 40, 485–497 (2022). https://doi.org/10.1007/s12640-022-00487-6
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DOI: https://doi.org/10.1007/s12640-022-00487-6