A Pilot Study of Metabolomic Pathways Associated With Fatigue in Survivors of Colorectal Cancer

Abstract

Background: Over 30% of cancer survivors experience chronic fatigue. An alteration in energy metabolism is one of the hypothesized mechanisms for cancer-related fatigue (CRF). No studies have evaluated for changes in metabolic profiles in cancer survivors with CRF. The purpose of this pilot study was to evaluate for differences in metabolic profiles between fatigued and non-fatigued survivors of colorectal cancer (CRC). Methods: Survivors were recruited from the surgical outpatient department and the oncology clinic of a medical center in northern Taiwan. Fatigue was assessed using the Fatigue Symptom Inventory. Fasting blood samples were collected on the day the fatigue questionnaire was completed. Metabolomic profile analysis was performed using non-targeted, liquid chromatography/time-of-flight mass spectrometry. Fold change analyses, t-tests, and pathway analyses were performed to identify differences in metabolomic profiles between the fatigued and non-fatigued survivors. Results: Of the 56 CRC survivors in this study, 28.6% (n = 16) were in the fatigue group. Statistically significant differences in carnitine, L-norleucine, pyroglutamic acid, pyrrolidonecarboxylic acid, spermine, hydroxyoctanoic acid, and paraxanthine were found between the two fatigue groups. In addition, two pathways were enriched for these metabolites (i.e., glutathione metabolism, D-glutamine and D-glutamate metabolism). Conclusions: Findings from this pilot study provide preliminary evidence that two pathways that are involved with the regulation of ATP production and cellular energy (i.e., glutathione metabolism, D-glutamine and D-glutamate metabolism) are associated with fatigue in CRC survivors. If these findings are confirmed, they may provide new therapeutic targets to decrease fatigue in cancer survivors.

Discovery and Validation of Potential Serum Biomarkers with Pro-Inflammatory and DNA Damage Activities in Ulcerative Colitis: A Comprehensive Untargeted Metabolomic Study

“…More importantly, it is also a biomarker for a variety of cancers. The levels of pyroglutamic acid in the serum of patients with cervical cancer, gastric cancer, and breast cancer are significantly increased [ 41 , 42 , 43 , 44 , 45 ]. In our study, the statistics on the relative abundance of pyroglutamate showed that 74.2% (23/31) of UC patients had values higher than the 95% confidence interval of healthy controls, and 32.3% (10/31) had values more than 1.5-times higher than the 95% confidence interval.…”

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

“…48 In line with this hypothesis, a pilot study among colorectal cancer survivors found significant differences in other metabolites involved in metabolic pathways regulating ATP production and cellular energy between fatigued and nonfatigued survivors. 19 We also observed longitudinal associations with several lipid metabolites including lysoPCs, diacylPCs, acyl-alkylPCs and SMs. In line with our findings, based on nontargeted metabolomics data and a pathways analysis, significant overrepresentation by metabolites involved in sphingolipid metabolism have previously been observed when comparing fatigued (mostly prostate) cancer patients before treatment with healthy controls, although the (direction of) associations with individual metabolites were not reported.…”

A Molecular Approach to Understanding the Role of Diet in Cancer-Related Fatigue: Challenges and Future Opportunities

“…Numerous metabolic pathways have been associated with CRF in different cancer populations. Mechanisms that may lead to dysregulation include the regulation of ATP production and cellular energy, metabolism, and the steroid hormone biosynthesis pathway [ 65 , 66 , 67 ].…”

“…In a recent longitudinal study of cancer survivors with mixed cancer types, metabolites involved in sphingolipid, histidine, cysteine, and methionine metabolism were associated with increased CRF in cancer survivors as compared to cancer-free individuals [ 66 ]. A pilot study of post-treatment colorectal cancer survivors found that fatigue was associated with two metabolomic pathways involved in the regulation of ATP production and cellular energy (i.e., glutathione metabolism, and D-glutamine and D-glutamate metabolism) [ 67 ]. Fatigue worsens over time following androgen deprivation therapy (ADT) initiation, in a study of prostate cancer survivors receiving ADT, androstenedione, androgen, estrogen, amino acid, and glutathione metabolic pathways discriminated patients receiving ADT from those not receiving the treatment [ 65 ].…”