One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients:results from the ColoCare Study

B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinearlinear=0.003), IL-6 (r=-0.39, plinear linear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinearlinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.</p

Vitamin D, magnesium, calcium, and their interaction in relation to colorectal cancer recurrence and all-cause mortality

Background: Higher concentrations of 25-hydroxyvitamin D3 [25(OH)D3] at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in vitamin D metabolism. Objectives: We aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality. Methods: The study population included 1169 newly diagnosed stage I-III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another. Results: Serum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed. Conclusions: Our findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099. </p

The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis

Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D3 (25(OH)D3) levels and inflammatory markers (IL10, IL8, IL6, TNFα and hsCRP) in the 2 years following CRC diagnosis. Methods: Circulating 25(OH)D3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. Results: Higher 25(OH)D3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (β −0.06, 95% CI −0.08 to −0.04). In addition, 25(OH)D3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (β −0.17, 95% CI −0.25 to −0.08). In addition, a significant inverse association between 25(OH)D3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D3 and IL10, IL6 and TNFα. No statistically significant associations between 25(OH)D3 and IL8 and hsCRP levels were observed. Conclusions: Serum 25(OH)D3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence

The association between circulating levels of vitamin D and inflammatory markers in the first 2 years after colorectal cancer diagnosis

Background: Calcitriol, the active form of vitamin D, may inhibit colorectal cancer (CRC) progression, which has been mechanistically linked to an attenuation of a pro-inflammatory state. The present study investigated the associations between circulating 25 hydroxy vitamin D-3 (25(OH)D-3) levels and inflammatory markers (IL10, IL8, IL6, TNF alpha and hsCRP) in the 2 years following CRC diagnosis. Methods: Circulating 25(OH)D-3 levels and inflammatory markers were assessed at diagnosis, after 6, 12 and 24 months from 798 patients with sporadic CRC participating in two prospective cohort studies. Associations between 25(OH)D-3 levels and individual inflammatory markers as well as a summary inflammatory z-score were assessed at each time point by multiple linear regression analyses. To assess the association between 25(OH)D-3 and inflammatory markers over the course of 2 years, linear mixed model regression analyses were conducted. Results: Higher 25(OH)D-3 levels were associated with lower IL6 levels at diagnosis, at 6 months after diagnosis and over the course of 2 years (beta -0.06, 95% CI -0.08 to -0.04). In addition, 25(OH)D-3 levels were inversely associated with the summary inflammatory z-score at diagnosis and over the course of 2 years (beta -0.17, 95% CI -0.25 to -0.08). In addition, a significant inverse association between 25(OH)D-3 levels and IL10 was found over the course of 2 years. Intra-individual analyses showed an inverse association between 25(OH)D-3 and IL10, IL6 and TNF alpha. No statistically significant associations between 25(OH)D-3 and IL8 and hsCRP levels were observed. Conclusions: Serum 25(OH)D-3 levels were inversely associated with the summary inflammatory z-score and in particular with IL6 in the years following CRC diagnosis. This is of potential clinical relevance as IL6 has an important role in chronic inflammation and is also suggested to stimulate cancer progression. Further observational studies should investigate whether a possible 25(OH)D-3-associated reduction of inflammatory mediators influences treatment efficacy and CRC recurrence

Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer

Background: Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. Objectives: We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. Methods: A total of 2031 patients with stage I–III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. Results: After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16–32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Conclusion: Higher preoperative vitamin B6 status is associated with improved OS among stage I–III CRC patients. Am J Clin Nutr 2022;116:303–313

Circulating Folate and Folic Acid Concentrations:Associations With Colorectal Cancer Recurrence and Survival

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n=296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence. </p