Vitamin B6 Reduces Risk of Colorectal Cancer

Colorectal cancer is one of the most frequently diagnosed types of cancer in the UK, particularly within those aged over 65 years, and is the second biggest contributor to cancer deaths [1].  Associations between nutrition and risk of colorectal cancer frequently focus on reducing consumption of red or processed meat or increasing dietary fibre, however a study by Gylling et al. has suggested that vitamin B6 status is also of importance [2]. From discussing their findings in the context of wider research, it has been concluded that regularly meeting recommended daily intake of vitamin B6, of 1.4mg/day for men and 1.2mg/day for women, ideally from dietary sources, may reduce risk of colorectal cancer.  

Colorectal cancer (CRC) accounts for 11% of all cancer cases in the UK, with 41,000 people diagnosed each year [3]. The most common form of CRC is adenocarcinoma, which originates from polyp growth in the gland cells of the bowel lining. If left untreated, these benign polyps can become cancerous [4] due to mutations in oncogenes or tumour suppressor genes in epithelial cells, stimulating uncontrolled proliferation and self-renewal [5]. These abnormal cells have the potential to travel to the liver via the bloodstream, or in the lymphatic system to lymph nodes, such as those of the abdomen, forming secondary tumours [3]. Half of those with CRC survive for at least 5 years post-diagnosis [1] but tumour spread in the later stages of cancer development leads to poor prognosis.

Major risk factors for CRC include age, genetic predisposition or inherited conditions, family history, inflammatory bowel diseases and presence of polyps [6]. However, it has been estimated that diet and nutrition can explain as much as 30-50% of worldwide cases of CRC [7]. Diets with frequent consumption of red or processed meat [8] and low fibre intake [9] have been shown to elevate risk, which is also said to be one third higher for those with a BMI in the obese compared to the healthy range [6]. In addition, the role of B vitamins as coenzymes in one-carbon metabolism, a process required for DNA replication, repair and regulation of gene expression [10], results in their intake often being discussed with reference to CRC risk, notably that of vitamin B6. 

Vitamin B6 describes a group of chemically similar interconvertible compounds. The active form pyridoxal 5’-phosphate (PLP) is a coenzyme in a number of essential metabolic reactions including transamination, haemoglobin synthesis, tryptophan metabolism, glycogen phosphorylation, steroid hormone regulation and nucleic acid synthesis [11]. Although vitamin B6 deficiency is considered rare due to the wide variety of dietary sources and its high bioavailability [12], it has been hypothesised that low plasma vitamin B6 concentration may increase risk of CRC, suggesting that ensuring sufficiency and potentially optimising intake may be of benefit. The recent case-control study by Gylling et al. investigated this association using more accurate markers of vitamin B6 status than in much of the previous research to discriminate between increased risk of CRC as a consequence of inflammation, which also tends to correlate with lower PLP status, and that due to vitamin B6 intake [2]. This review will compare the conclusions made by Gylling et al. to wider literature to discuss whether individuals meeting vitamin B6 recommendations, through diet and/or supplements, may have a decreased risk of CRC.

Method

Study participants

Participants were from two population based cohorts, the Västerbotten Intervention Programme (VIP) (78.2%) and Mammography Screening Project (MSP) (21.8%). Cases of colorectal cancer were identified using the Cancer Registry of Northern Sweden, with tumour site verified by patient records. Two matched controls matched were selected for each case.

Blood sampling and analysis

Blood samples were obtained in the VIP and MSP from which riboflavin, creatinine, vitamin B6 markers, folate and vitamin B12 concentrations were measured. Vitamin B6 was assessed by pyridoxal 5’-phosphate (PLP), 3-hydroxykynurenine (HK) to xanthurenic acid (XA) ratio (HK:XA) and pyridoxic acid (PA) to PLP and pyridoxal (PLP+PL) ratio (PAr).

Statistical analysis

The group was divided into quartiles and risk of CRC relative to the vitamin B6 biomarkers was calculated as odds ratios (OR). Continuous log-transformed vitamin B6 markers were modelled relative to CRC risk to assess dose-response and linearity.

Subgroup specific ORs for CRC were also estimated. Heterogeneity was tested using continuous vitamin B6 markers to identify any difference based on the two study designs.

Results

Subject characteristics

613 CRC cases and 1190 matched controls were studied. The median age for CRC diagnosis was 65.2 years. Cases had lower PLP concentrations and higher HK:XA and PAr than controls. Lower PLP was seen for ex-smokers, those with BMI ≥30, lower alcohol intake and lower dietary fibre intake.

Results of statistical analysis

The strongest inverse association between PLP and CRC risk was observed between the third and first quartile, and PLP sufficiency was associated with lower risk of CRC than deficiency.

A positive association was observed between CRC risk and both HK:XA and PAr for the fourth compared to the first quartile. A U-shaped association was observed for the relationship between PLP and CRC risk with a high risk for low concentrations.

Discussion

The study by Gylling et al. observed a strong inverse association between PLP and CRC risk [2]. Similar findings gave been reported by Larsson et al., who found a 49% decrease in risk of CRC for every 100pmol/ml increase in plasma PLP [13], and Lee et al., where men in the highest quartile of PLP had a 51% lower risk of CRC than those in the lowest [14]. As both dietary and total vitamin B6 intake have been shown to correlate with serum and plasma PLP [13], it could be concluded that high vitamin B6 intake reduces risk of CRC, with a potentially dose-dependent relationship [15].

The effect has been proven in animal models where vitamin B6 reduced the number of tumours in the colon [16], and can be explained by the role of PLP as a cofactor for serine hydroxymethyltransferase. This enzyme catalyses the formation of 5,10-methyltetrahydrofolate [17] which is required for DNA synthesis, repair and methylation, particularly due to its role in aiding the conversion of uracil to thymidylate in nucleotide synthesis. Misincorporation of uracil instead of thymidylate in DNA results in chromosomal instability [18], contributing to tumour progression. Moreover, mechanisms independent of one carbon metabolism have been proposed such as the reduction of oxidative and nitrosative stress [15], which can otherwise cause DNA mutations.

It has been questioned whether inverse associations between PLP and CRC risk do not reflect the role of PLP in suppressing tumour development, but instead indicate inflammation, which both increases risk of CRC and reduces PLP concentration. However, Gylling et al. used additional markers of vitamin B6 status, HK:XA and PAr, to discriminate high inflammatory status, finding a positive association with CRC risk [2] and so detrimental effects of low vitamin B6 status. Zuo et al. used the same markers to investigate the association with all cancer risk and also observed positive associations [19].

Despite results within the literature tending to draw fairly consistent conclusions regarding the beneficial role of vitamin B6 in reducing CRC risk, a U-shaped relationship is often described [10], suggesting vitamin B6 intake to be positively associated with CRC risk at high levels. However, it may be possible to explain this by a potentially higher meat intake, with red and processed meat independently increasing risk of CRC [20]. Moreover, control of confounders may cause bias as it has been observed that vitamin B6 status is often related to other CRC protective factors such as increased physical activity, less smoking and lower levels of alcohol consumption [13]. Incorrect adjustment may therefore elevate or attenuate risk of CRC observed.

The study by Gylling et al. only investigated the relationship between vitamin B6 and CRC risk, but the role of other B vitamins in one carbon metabolism, particularly folic acid, suggests a similar risk reduction may occur. Sanjoaquin et al. reported that risk of CRC may be 25% lower for those with highest dietary folate intake compared to those with the lowest [21], which may be due to folate deficiency causing hypermethylation of gene promoters and consequently silencing tumour suppressor genes [22]. Nonetheless, there are inconsistencies within research regarding the association between folate and CRC risk, with de Vogel et al. observing no effect [23] and Theodoratou et al. suggesting that vitamin B6 association is much stronger than that of folate [15]. Furthermore, June et al. found a protective effect only for those within quintile 2 compared to quintile 1 of folate intake [24]. High folate is, in fact, thought likely to increase CRC risk if premalignant or malignant epithelial cells are already present [24], indicating that folate sufficiency but not excess intake may be enough to have a positive effect on CRC risk. 

Impacts

The conclusion by Gylling et al., that vitamin B6 deficiency is associated with increased risk of CRC [2], seems to be consistent with wider research. This suggests that meeting or exceeding daily recommended intake of vitamin B6 of 1.4mg/day for men and 1.2mg/day for women [25] may reduce risk of CRC, although there is some evidence to suggest that intake greatly in excess of this would not be advisable [10]. On a population-wide scale it should be achievable for vitamin B6 recommendations to be met due to the variety of dietary sources, such as meat, poultry, fish, potatoes and other starchy vegetables, and fortified cereals [18]. However, if an individual has suboptimal levels or cannot obtain sufficient vitamin B6 from food, a multivitamin supplement may be beneficial to increase plasma PLP [14], although there remains some uncertainty surrounding their influence on CRC risk [16]. Future research should be conducted, with length of use being considered as a factor that may modify the observed effect [26]. It has also been discussed that ensuring folate sufficiency may further contribute to reducing risk of CRC. However, the potential for high folate to have adverse effects by promoting tumour progression suggests that taking multivitamin supplements may be harmful for those with already adequate status. The overall recommendation to reduce risk of CRC would therefore be to consume a balanced diet containing a variety of foods rich in B vitamins to ensure satisfactory intake of all and to prevent detrimental elevation of levels of any individual compound, as may occur with supplementation.

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