Longitudinal associations of plasma metabolites with persistent fatigue among colorectal cancer survivors up to 2 years after treatment

Abstract

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.

Keywords: amino acids; cancer-related fatigue; colorectal cancer; phospholipids; targeted metabolomics.

FIGURE 1

Self‐reported (A) mean and SD of sex‐stratified total fatigue scores, (B) mean fatigue subscale scores in women and (C) mean fatigue subscale scores in men, at posttreatment time points among colorectal cancer survivors included in the current analysis (n = 252). The total ranges in scores of fatigue variables are depicted in the y‐axis of the title (A) and figure legends (B and C), the total ranges reported by the study population were 20‐134 for total fatigue, 8‐56 for “fatigue severity”, 5‐34 for “concentration problems,” 4‐28 for “reduced motivation” and 3–21 for “reduced activity”

FIGURE 2

Forest plots showing effect estimates and 95% confidence intervals of metabolites that were statistically significantly (FDR q‐value <0.05) related, in the overall, interindividual and/or intraindividual longitudinal analysis, to (A) total fatigue and the subscales (B) “fatigue severity,” (C) “reduced motivation” and (D) “reduced activity” among colorectal cancer survivors, between 6 weeks and 2 years posttreatment. Asterisk (*) denotes statistical significance after FDR‐adjustment. Since the subscale “concentration problems” was not statistically significantly associated with any of the metabolites, these results are not shown. Full results for all fatigue variables and metabolites are included in Table S2 Analyzed with multivariable linear mixed regression models analyzing associations of the batch‐adjusted ln‐transformed metabolite residuals (see Section 2, 2.5) as the main independent variables and as dependent variables the fatigue variables, with a separate model for each metabolite and each fatigue variable. Models were adjusted for: sex; age at 6 weeks posttreatment (y; continuous), time since treatment (per 6 months; continuous), center (Maastricht UMC+; VieCuri Medical Center; Zuyderland Medical Centre), body mass index (kg/m²; continuous), smoking status (current; former; never), self‐reported alcohol consumption (grams/day), self‐reported hours/week of moderate‐to‐vigorous physical activity, number of comorbidities (no comorbidity; 1 comorbidity; ≥2 comorbidities), neo‐adjuvant treatment (yes/no) and adjuvant treatment (yes/no). ACs, acylcarnitines; PCs, phosphatidylcholines; SMs, sphingomyelins