- Grant awarded: November 2020
This project investigates whether and how potential diet-dependent neuro-inflammatory metabolites of the kynurenine pathway are longitudinally associated with worse health related quality of life, including higher rates of depression, anxiety, cognitive impairment and fatigue among colorectal cancer survivors up to 5 years post-treatment.
– Simone Eussen
Background
The number of people surviving large bowel cancer (colorectal cancer; CRC) is increasing due to an ageing population, earlier diagnosis, and better treatments. As a result, more CRC survivors are facing long-term health problems caused by both the cancer and its treatment. Around two-thirds of CRC survivors deal with ongoing fatigue, and many also experience anxiety and depressive symptoms. Therefore, identifying lifestyle factors that can help reduce symptoms and improve quality of life after a CRC diagnosis is essential.
Research suggests that diet might affect quality of life after cancer, but the specific dietary factors and evidence for CRC survivors are limited. Additionally, biological mechanisms that explain how diet impacts quality of life after cancer is still unclear. One possible mechanism is the tryptophan-kynurenine pathway, which breaks down the essential amino acid tryptophan. This pathway is linked to inflammation and involves neuroactive metabolites (=kynurenines).
Aims and objectives
The aim of this project was to explore how these kynurenines, along with dietary intake, are related over time to quality of life in CRC survivors in the first year after CRC-treatment. Specifically, we studied three objectives:
- how diet is related to kynurenines
- how kynurenines are related to domains of quality of life
- how diet is related to quality of life, with kynurenines as the underlying mechanism.
Methods
The project used data from the Energy for life after ColoRectal cancer (EnCoRe) study, which followed CRC survivors over time.
Between 2012 and 2016, individuals diagnosed with stage I-III CRC were recruited in three Dutch hospitals (n=249) and followed up until 12-months after the end of CRC-treatment. Repeated measurements were performed at 6-weeks, 6-months, and 12-months post-treatment.
Dietary intake was assessed using seven-day food diaries, nine kynurenine pathway metabolites were analyzed in overnight fast blood samples using high-quality analytical techniques, and domains of quality of life, including fatigue, depression, and anxiety, were assessed with validated questionnaires.
Several statistical analyses were performed.
Key findings
The study found that certain dietary factors are related to kynurenines and that kynurenines are related to fatigue and quality of life, but not to anxiety and depression. Additionally, the study found that certain dietary factors are related to fatigue and quality life, but that all kynurenines taken together did not explain these associations, while established ratios between kynurenines did. Specifically, higher intakes of protein, fat, fiber, and alcohol, and lower intakes of carbohydrates (especially simple sugars) were linked to a more favourable kynurenine profile. Higher fat intake was linked to higher tryptophan levels. A more favourable kynurenine profile was in turn related to less fatigue, better functioning, and better quality of life.
Additionally, higher intakes of (plant-based) protein and fat, along with lower carbohydrate intake (mainly simple sugars), were generally related to less fatigue, better functioning, and improved quality of life.
Conclusions
Although the study cannot prove cause and effect, the findings are promising and suggest that dietary recommendations for CRC survivors could improve their quality of life. However, further research is needed.
Impact
This project has been the first to investigate associations between plasma kynurenines and dietary intake, and between plasma kynurenines and quality of life in colorectal cancer survivors. The findings could ultimately lead to tailored dietary recommendations for cancer survivors to improve quality of life.
Grant publications
- Holthuijsen, Daniëlle D. B., Eline H. van Roekel, Martijn J. L. Bours, Per M. Ueland, Stéphanie O. Breukink, Maryska L. G. Janssen‑Heijnen, Eric T. P. Keulen, Biljana Gigic, Andrea Gsur, Klaus Meyer, Jennifer Ose, Arve Ulvik, Matty P. Weijenberg, and Simone J. P. M. Eussen. “Longitudinal Associations of Plasma Kynurenines and Ratios with Anxiety and Depression Scores in Colorectal Cancer Survivors up to 12 Months Post‑Treatment.” Psychoneuroendocrinology, vol. 163, 2024, article 106981. doi:10.1016/j.psyneuen.2024.106981.
- Holthuijsen, Daniëlle D. B., Eline H. van Roekel, Martijn J. L. Bours, Per M. Ueland, Stéphanie O. Breukink, Maryska L. G. Janssen‑Heijnen, Eric T. P. Keulen, Andrea Gsur, Dieuwertje E. Kok, Arve Ulvik, Matty P. Weijenberg, and Simone J. P. M. Eussen. “Longitudinal Associations of Macronutrient and Micronutrient Intake with Plasma Kynurenines in Colorectal Cancer Survivors up to 12 Months Posttreatment.” The American Journal of Clinical Nutrition, vol. 118, no. 5, 2023, pp. 865–880. doi:10.1016/j.ajcnut.2023.08.003.
- Holthuijsen, D. D. B., Martijn J. L. Bours, Eline H. van Roekel, Stéphanie O. Breukink, Maryska L. G. Janssen‑Heijnen, Eric T. P. Keulen, Per M. Ueland, Øivind Midttun, Stefan Brezina, Biljana Gigic, Andrea Gsur, Dieuwertje E. Kok, Jennifer Ose, Cornelia M. Ulrich, Matty P. Weijenberg, and Simone J. P. M. Eussen. “Longitudinal Associations of Adherence to the Dietary World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and Dutch Healthy Diet (DHD) Recommendations with Plasma Kynurenines in Colorectal Cancer Survivors after Treatment.” Nutrients, vol. 14, no. 23, Dec. 3, 2022, article 5151. doi:10.3390/nu14235151.
- Holthuijsen, Daniëlle D. B., et al. “Modeling How Iso‑Caloric Macronutrient Substitutions Are Longitudinally Associated with Plasma Kynurenines in Colorectal Cancer Survivors up to 12 Months Post‑Treatment.” The Journal of Nutritional Biochemistry, vol. 141, July 2025, article 109910, doi:10.1016/j.jnutbio.2025.109910.
- Holthuijsen, Daniëlle D. B., Judith J. M. Rijnhart, Martijn J. L. Bours, et al. “Longitudinal Associations of Dietary Intake with Fatigue in Colorectal Cancer Survivors up to 1 Year Post‑Treatment, and the Potential Mediating Role of the Kynurenine Pathway.” Brain, Behavior, and Immunity, 2025, doi:10.1016/j.bbi.2025.03.012.
- Holthuijsen, Daniëlle D. B., et al. “Longitudinal Associations of Plasma Kynurenines and Ratios with Fatigue and Quality of Life in Colorectal Cancer Survivors up to 12 Months Post‑Treatment.” International Journal of Cancer, vol. 155, no. 7, May 2024, pp. 1172–1190, doi:10.1002/ijc.34992.
