The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats

Yu-Chieh Chen; Chih-Yao Hou; Mei-Hsin Hsu; Li-Tung Huang; Chih-Cheng Hsiao; Jiunn-Ming Sheen

doi:10.3390/biomedicines12040908

The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats

Biomedicines. 2024 Apr 19;12(4):908. doi: 10.3390/biomedicines12040908.

Authors

Yu-Chieh Chen^{1

2

3}, Chih-Yao Hou⁴, Mei-Hsin Hsu¹, Li-Tung Huang¹, Chih-Cheng Hsiao^{1

2

3}, Jiunn-Ming Sheen^{1

2}

Affiliations

¹ Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
² Department of Traditional Medicine, Chang Gung University, Taoyuan 333, Taiwan.
³ School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung 804, Taiwan.
⁴ Department of Seafood Science, College of Hydrosphere, National Kaohsiung University of Science and Technology, Kaohsiung 807, Taiwan.

Abstract

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut-brain axis communication.

Keywords: chemotherapy; cognitive impairment; gut microbiota; methotrexate; neurotoxicity.

Grants and funding

This work was supported by grants CMRPG8K0991 and CMRPG8K0992 from the Kaohsiung Chang Gung Memorial Hospital, Taiwan, and MOST 111-2314-B-182A-096 from the National Science and Technology Council, Taiwan.