Patel Chadni, Willekens Jeremy, Diglio Frank, Cole Peter D
Rutgers Graduate Program in Cellular and Molecular Pharmacology, The State University of New Jersey, Rutgers, New Brunswick, NJ, USA.
Division of Pediatric Hematology & Oncology, Rutgers Cancer Institute, 195 Little Albany Street, New Brunswick, NJ, 08901, USA.
Sci Rep. 2025 Jul 28;15(1):27448. doi: 10.1038/s41598-025-12352-5.
Many survivors of childhood cancer experience significant side effects leading to inferior quality of life like chemotherapy-induced cognitive impairment (CICI). A growing body of literature implies that the gut-brain axis modulates neurological and inflammatory physiology. Cancer therapy may alter the gut microbiome in ways that modify the risk of CICI. We utilized a commonly used pediatric cancer chemotherapy drug, doxorubicin (DOXO), in our juvenile rat model, including both male and female rats. At 5 weeks of age, Long Evans rats were treated with weekly intraperitoneal DOXO (2 mg/kg/dose for 4 weeks). Compared to PBS-treated rats, DOXO treatment caused impairment of visual memory among female rats and spatial memory among male rats, when tested 3-4 weeks after DOXO exposure. In both sexes, DOXO-induced cognitive deficits do not persist among the surviving animals. Microbiome analyses were conducted in fecal samples collected 48 hours following the final DOXO injection. Compared to PBS-treated rats, female DOXO-treated rats had significant differences in beta diversity. Significant changes in the abundances of specific species, genera, and phyla were observed. These experimental results set the stage for further investigations of how chemotherapy-induced changes in gut microbiome might contribute to CICI, and point toward therapeutic interventions.
许多儿童癌症幸存者会经历严重的副作用，导致生活质量下降，如化疗引起的认知障碍（CICI）。越来越多的文献表明，肠道-脑轴调节神经和炎症生理。癌症治疗可能会以改变CICI风险的方式改变肠道微生物群。我们在幼年大鼠模型中使用了一种常用的儿科癌症化疗药物阿霉素（DOXO），包括雄性和雌性大鼠。5周龄时，Long Evans大鼠每周接受腹腔注射DOXO（2mg/kg/剂量，共4周）。与接受PBS治疗的大鼠相比，在DOXO暴露3-4周后进行测试时，DOXO治疗导致雌性大鼠视觉记忆受损，雄性大鼠空间记忆受损。在两性中，DOXO诱导的认知缺陷在存活动物中不会持续存在。在最后一次DOXO注射48小时后收集的粪便样本中进行微生物群分析。与接受PBS治疗的大鼠相比，接受DOXO治疗的雌性大鼠在β多样性方面存在显著差异。观察到特定物种、属和门的丰度有显著变化。这些实验结果为进一步研究化疗引起的肠道微生物群变化如何导致CICI奠定了基础，并指向治疗干预措施。
