Grant C V, Loman B R, Bailey M T, Pyter L M
Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA.
Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Brain Behav Immun. 2021 Jul;95:401-412. doi: 10.1016/j.bbi.2021.04.014. Epub 2021 Apr 22.
Chemotherapy treatment is associated with acute behavioral side effects (fatigue, anorexia) that significantly reduce patient quality of life and are dose-limiting, thereby increasing mortality (Kidwell et al., 2014). Disruptions to gut homeostasis (diarrhea, constipation, microbial dysbiosis) are also observed in patients receiving chemotherapy. In non-oncological patients, facets of mental health (fatigue, anxiety, depression) correlate with alterations in the gut microbiome, suggestive of a contribution of the gut in CNS disease etiology. The potential gut-to-brain pathway is poorly understood in patients receiving chemotherapy. Our prior studies have demonstrated a correlation between chemotherapy treatment, gut changes, peripheral and central inflammation, and behavioral symptoms in mice. Here we aimed to determine the extent to which chemotherapy-associated gut manipulations modulate the behavioral and biological consequences of chemotherapy. We measured sickness behaviors, peripheral and central inflammatory mediators, and anxiety in conventional or germ-free female mice: 1) cohabitating with mice of the opposite treatment group, 2) pre-treated with broad-spectrum antibiotics, or 3) given an intra-gastric gavage of gut content from chemotherapy-treated mice. In cohabitation studies, presumed coprophagia promoted body mass recovery, however strong associations with inflammation and behavior were not observed. Reduction of gut microbial alpha diversity via antibiotics did not prevent chemotherapy-associated side effects, however the relative abundances of the genera Tyzzerella, Romboutsia, and Turicibacter correlated with circulating inflammatory (IL-1β) and behavioral outcomes (lethargy, anxiety-like behavior). A gut microbiota transplant from chemotherapy-treated mice decreased central locomotion in open field testing, increased circulating CXCL1, and increased hippocampal Il6 and Tnfa in germ-free mice compared to germ-free mice that received a transplant from vehicle-treated mice. Taken together, these data provide further evidence that the gut microbiota likely contributes to the development of chemotherapy-associated side effects. This work has significant implications in the future treatment of anxiety in patients, and warrants future studies using microbe-based treatment options.
化疗治疗会引发急性行为副作用（疲劳、厌食），这些副作用会显著降低患者的生活质量，并且具有剂量限制性，从而增加死亡率（基德韦尔等人，2014年）。接受化疗的患者还会出现肠道内环境稳态紊乱（腹泻、便秘、微生物群落失调）。在非肿瘤患者中，心理健康方面（疲劳、焦虑、抑郁）与肠道微生物群的改变相关，这表明肠道在中枢神经系统疾病病因学中发挥了作用。在接受化疗的患者中，潜在的肠-脑通路尚不清楚。我们之前的研究表明，化疗、肠道变化、外周和中枢炎症以及小鼠行为症状之间存在关联。在这里，我们旨在确定化疗相关的肠道操作在多大程度上调节化疗的行为和生物学后果。我们测量了常规或无菌雌性小鼠的疾病行为、外周和中枢炎症介质以及焦虑水平：1）与相反治疗组的小鼠同居，2）用广谱抗生素预处理，或3）给予化疗处理小鼠的肠道内容物灌胃。在同居研究中，推测的粪食行为促进了体重恢复，但未观察到与炎症和行为的强烈关联。通过抗生素降低肠道微生物α多样性并不能预防化疗相关的副作用，然而，泰泽菌属、罗姆布茨菌属和Turicibacter属的相对丰度与循环炎症（IL-1β）和行为结果（嗜睡、焦虑样行为）相关。与接受载体处理小鼠移植的无菌小鼠相比，来自化疗处理小鼠的肠道微生物群移植在旷场试验中降低了无菌小鼠的中枢运动能力，增加了循环CXCL1，并增加了海马体中的Il6和Tnfa。综上所述，这些数据进一步证明肠道微生物群可能促成了化疗相关副作用的发生。这项工作对未来患者焦虑症的治疗具有重要意义，并且值得未来开展基于微生物的治疗方案研究。
