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Whole brain radiotherapy induces cognitive dysfunction in mice: key role of gut microbiota

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Abstract

Rationale

Approximately 20–40% of patients with cancer will experience brain metastasis (BM), which has a great impact on the quality of life and survival rates of patients. Whole brain radiotherapy (WBRT) is an effective method for the treatment of BM. However, it cannot be ignored that WBRT might induce a series of neuropsychiatric side effects, including cognitive dysfunction (CD). Accumulating evidence shows that the gut microbiota and the gut-microbiota–brain axis may play a vital role in the pathogenesis of CD.

Objective and methods

We adopted WBRT to mimic CD after a hierarchical cluster analysis of the Morris water maze test (MWMT) results. In addition, we observed the effects of antibiotics and prebiotics on WBRT-induced CD. Variations were revealed via the 16S rRNA sequencing analysis at different levels.

Results

The 16S rRNA sequencing analysis revealed an altered composition of gut microbiota between CD and non-CD phenotypes. Furthermore, we observed a decrease in the levels of Phylum-Bacteroidete, Class-Bacteroidia, and Order-Bacteroidales in the CD group and an increase in the Genus-Allobaculum level after WBRT. Pretreatment with antibiotics caused a significant decrease in the level of Phylum-TM7 01, whereas an increase in the levels of Class-Gammaproteobacteria, Order-Enterobacteriales, and Species-Escherichia coli. After pretreatment with probiotics, the levels of Phylum-Cyanobacteria, Class-4C0d-2, and Order-YS2 were decreased, while the levels of Family-Bacteroidaceae, Genus-Bacteroides, and Species-Parabacteroides distasonis were increased.

Conclusions

WBRT-induced CD might be highly related to abnormal composition of gut microbiota. Strategies improving the composition of the gut microbiota may provide beneficial effects on CD in individuals exposed to WBRT.

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Abbreviations

CD:

Cognitive dysfunction

MWMT:

Morris water maze test

WBRT:

Whole brain radiotherapy

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Funding

This study was supported by grants from the National Natural Science Foundation of China [81071832 (to X.Y.), 81703482 and 81974171 (to C.Y.), 81571047 and 81771159 (to A.L.)].

Author information

Authors and Affiliations

  1. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 30030, China

    Xiao-Xiao Luo & Xiang-Lin Yuan

  2. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Chun Yang

  3. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Gao-Feng Zhan, Shan Li, Dong-Yu Hua & Ai-Lin Luo

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  1. Xiao-Xiao Luo
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  4. Shan Li
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  6. Ai-Lin Luo
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Contributions

X.L., C.Y., A.L., and X.Y. designed this study and wrote the protocol and the manuscript. X.L., G.Z., S.L., and D.H. performed the experiments. X.L. and G.Z. conducted the statistical analysis. X.L. and C.Y. revised the manuscript. All of the authors contributed to this study and approved the final manuscript and this submission.

Corresponding author

Correspondence to Xiang-Lin Yuan.

Ethics declarations

All experiments were approved by the Ethical Committee on Animal Experimentation of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China) and were performed in strict accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 80-23, revised in 1996).

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The authors declare that they have no conflict of interest.

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Luo, XX., Yang, C., Zhan, GF. et al. Whole brain radiotherapy induces cognitive dysfunction in mice: key role of gut microbiota. Psychopharmacology 237, 2089–2101 (2020). https://doi.org/10.1007/s00213-020-05520-0

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