Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior

Christa Corley; Taylor McElroy; Bhavana Sridharan; Madison Trujillo; Pilar Simmons; Sangam Kandel; Delawrence J Sykes; Michael S Robeson 2nd; Antiño R Allen

doi:10.3389/fnins.2023.1212791

Physiological and cognitive changes after treatments of cyclophosphamide, methotrexate, and fluorouracil: implications of the gut microbiome and depressive-like behavior

Front Neurosci. 2023 Oct 6:17:1212791. doi: 10.3389/fnins.2023.1212791. eCollection 2023.

Authors

Christa Corley^{1

2}, Taylor McElroy^{1

2

3}, Bhavana Sridharan^{1

2}, Madison Trujillo^{1

2}, Pilar Simmons^{1

2

3}, Sangam Kandel⁴, Delawrence J Sykes⁵, Michael S Robeson 2nd⁴, Antiño R Allen^{1

2

3}

Affiliations

¹ Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
² Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
³ Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁴ Department of Bioinformatics, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
⁵ Department of Biology, Berry College, Mount Berry, GA, United States.

Abstract

Introduction: Chemotherapy-induced cognitive impairment colloquially referred to as chemobrain is a poorly understood phenomenon affecting a highly variable proportion of patients with breast cancer. Here we investigate the association between anxiety and despair-like behaviors in mice treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) along with host histological, proteomic, gene expression, and gut microbial responses.

Methods: Forced swim and sociability tests were used to evaluate depression and despair-like behaviors. The tandem mass tag (TMT) proteomics approach was used to assess changes in the neural protein network of the amygdala and hippocampus. The composition of gut microbiota was assessed through 16S rRNA gene sequencing. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate changes in intestinal gap junction markers.

Results and discussion: We observed that CMF induced social and despair-like behavior in mice 96 hours following treatment. Proteomic analysis identified changes in various proteins related to progressive neurological disease, working memory deficit, primary anxiety disorder, and gene expression revealing increases in NMDA and AMPA receptors in both the hippocampus and the amygdala because of CMF treatment. These changes finally, we observed immediate changes in the microbial population after chemotherapy treatment, with a notable abundance of Muribaculaceae and Romboutsia which may contribute to changes seen in the gut.

Keywords: 5-fluorouracil; amygdala; cyclophosphamide; hippocampus; methotrexate; microbiome.

Abstract

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