Disturbances of the gut microbiome have been widely suggested to be associated with 5-fluorouracil (5-Fu) induced digestive pathologies. Furthermore, it has been elucidated that the gut microbiome may play a key role in the pathogenesis of depressive disorders via the microbiota-gut-brain axis. Despite the speculation, there exists no direct evidence proving the causality between disturbances in the gut microbiome induced by 5-Fu and depressive mood dysregulation. Herein, behavioral testing was used to evaluate depressive-like behaviors in 5-Fu treated rats. Subsequently, the gut microbiota and prefrontal cortex (PFC) metabolic were analyzed by 16S rRNA sequencing and ¹H nuclear magnetic resonance (¹H NMR). To clarify the association between the gut microbiota and their role on depressive-like behaviors caused by 5-Fu, a fecal microbiota transplantation (FMT) experiment was carried out. The results suggested that 5-Fu could significantly alter the diversity and abundance of the gut microbiome, and induce PFC metabolic disorders, as well as depressive behaviors in rats. Transplantation of fecal microbiota from healthy control into 5-Fu treated rats significantly alleviated the PFC metabolic disorder and depressive-like behaviors. In conclusion, this study demonstrated that the gut microbiome was actively involved in the occurrence of 5-Fu induced depressive-like behaviors, and manipulation of specific gut microbiome parameters may serve as a promising novel target for side effects of 5-Fu treatment.

肠道微生物组的紊乱已被广泛认为与5-氟尿嘧啶（5-Fu）诱导的消化道疾病有关。此外，已经阐明肠道微生物组可能通过微生物群-肠-脑轴在抑郁症的发病机理中起关键作用。尽管有推测，但尚无直接证据证明由5-Fu引起的肠道微生物组紊乱与抑郁性情绪失调之间存在因果关系。在此，使用行为测试来评估5-Fu处理的大鼠中的抑郁样行为。随后，通过16S rRNA测序和¹ H核磁共振分析了肠道菌群和前额叶皮层（PFC）代谢（¹1 H NMR）。为了阐明肠道菌群及其在5-Fu引起的抑郁样行为中的作用之间的关联，进行了粪便菌群移植（FMT）实验。结果表明5-Fu可以显着改变肠道微生物组的多样性和丰度，并诱导PFC代谢紊乱以及大鼠的抑郁行为。将粪便微生物群从健康对照移植到5-Fu处理的大鼠中，可显着减轻PFC代谢紊乱和抑郁样行为。总之，这项研究表明肠道微生物组积极参与了5-Fu诱导的抑郁样行为的发生，并且对特定肠道微生物组参数的操作可能成为5-Fu治疗副作用的有希望的新靶标。