Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Department of Surgery, GROW School for Oncology and Developmental Biology, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands.
Int J Cancer. 2023 Jan 15;152(2):214-226. doi: 10.1002/ijc.34252. Epub 2022 Sep 2.
The underlying biological mechanisms causing persistent fatigue complaints after colorectal cancer treatment need further investigation. We investigated longitudinal associations of circulating concentrations of 138 metabolites with total fatigue and subdomains of fatigue between 6 weeks and 2 years after colorectal cancer treatment. Among stage I-III colorectal cancer survivors (n = 252), blood samples were obtained at 6 weeks, and 6, 12 and 24 months posttreatment. Total fatigue and fatigue subdomains were measured using a validated questionnaire. Tandem mass spectrometry was applied to measure metabolite concentrations (BIOCRATES AbsoluteIDQp180 kit). Confounder-adjusted longitudinal associations were analyzed using linear mixed models, with false discovery rate (FDR) correction. We assessed interindividual (between-participant differences) and intraindividual longitudinal associations (within-participant changes over time). In the overall longitudinal analysis, statistically significant associations were observed for 12, 32, 17 and three metabolites with total fatigue and the subscales "fatigue severity," "reduced motivation" and "reduced activity," respectively. Specifically, higher concentrations of several amino acids, lysophosphatidylcholines, diacylphosphatidylcholines, acyl-alkylphosphatidylcholines and sphingomyelins were associated with less fatigue, while higher concentrations of acylcarnitines were associated with more fatigue. For "fatigue severity," associations appeared mainly driven by intraindividual associations, while for "reduced motivation" stronger interindividual associations were found. We observed longitudinal associations of several metabolites with total fatigue and fatigue subscales, and that intraindividual changes in metabolites over time were associated with fatigue severity. These findings point toward inflammation and an impaired energy metabolism due to mitochondrial dysfunction as underlying mechanisms. Mechanistic studies are necessary to determine whether these metabolites could be targets for intervention.
结直肠癌治疗后持续疲劳抱怨的潜在生物学机制需要进一步研究。我们调查了在结直肠癌治疗后 6 周至 2 年内循环浓度为 138 种代谢物与总疲劳和疲劳子领域之间的纵向关联。在 I-III 期结直肠癌幸存者（n=252）中，在治疗后 6 周、6、12 和 24 个月时采集血样。使用经过验证的问卷测量总疲劳和疲劳子领域。串联质谱法（BIOCRATES AbsoluteIDQp180 试剂盒）用于测量代谢物浓度。采用线性混合模型分析混杂因素调整后的纵向关联，并进行错误发现率（FDR）校正。我们评估了个体间（参与者之间的差异）和个体内纵向关联（随时间的个体内变化）。在整体纵向分析中，观察到 12、32、17 和三种代谢物与总疲劳和“疲劳严重程度”、“降低动力”和“降低活动”子量表分别具有统计学意义的关联。具体而言，几种氨基酸、溶血磷脂酰胆碱、二酰基磷脂酰胆碱、酰基-烷基磷脂酰胆碱和神经鞘磷脂的浓度升高与疲劳程度降低有关，而酰基肉碱的浓度升高与疲劳程度增加有关。对于“疲劳严重程度”，关联主要由个体内关联驱动，而对于“降低动力”，则发现更强的个体间关联。我们观察到几种代谢物与总疲劳和疲劳子量表的纵向关联，并且代谢物随时间的个体内变化与疲劳严重程度相关。这些发现表明，炎症和由于线粒体功能障碍导致的能量代谢受损是潜在的机制。需要进行机制研究以确定这些代谢物是否可以成为干预的靶点。
