Antioxidants, Minerals and Vitamins in Relation to Crohn's Disease and Ulcerative Colitis

A Mendelian Randomization Study

Jie Chen; Xixian Ruan; Shuai Yuan; Minzi Deng; Han Zhang; Jing Sun; Lili Yu; Jack Satsangi; Susanna C. Larsson; Evropi Therdoratou; Xiaoyan Wang; Xue Li


Aliment Pharmacol Ther. 2023;57(4):399-408. 

In This Article

Abstract and Introduction


Background: Evidence for antioxidants, minerals and vitamins in relation to the risk of Crohn's disease (CD) and ulcerative colitis (UC) is limited and inconsistent. This mendelian randomization (MR) study aimed to examine the causal associations of circulating levels of antioxidants, minerals and vitamins with CD and UC.

Methods: Single-nucleotide polymorphisms associated with antioxidants (beta-carotene, lycopene and uric acid), minerals (copper, calcium, iron, magnesium, phosphorus, zinc and selenium), and vitamins (folate, vitamins A, B6, B12, C, D, E and K1) were employed as instrumental variables. Genetic associations with CD and UC were extracted from the UK Biobank, the FinnGen study and the International Inflammatory Bowel Disease Genetics Consortium. The inverse variance weighted method and sensitivity analyses were performed.

Results: Genetically predicted higher lycopene (OR = 0.94, 95% CI: 0.91–0.97), vitamins D (OR = 0.65, 95% CI: 0.54–0.79) and K1 (OR = 0.93, 95% CI: 0.90–0.97) levels were inversely associated with CD risk, whereas genetically predicted higher magnesium (OR = 1.53, 95% CI: 1.23–1.90) levels were positively associated with CD risk. Higher levels of genetically predicted lycopene (OR = 0.91, 95% CI: 0.88–0.95), phosphorus (OR = 0.69, 95% CI: 0.58–0.82), selenium (OR = 0.91, 95% CI: 0.85–0.97), zinc (OR = 0.91, 95% CI: 0.89–0.94), folate (OR = 0.71, 95% CI: 0.56–0.92) and vitamin E (OR = 0.78, 95% CI: 0.69–0.88) were associated with reduced UC risk, whereas genetically predicted high levels of calcium (OR = 1.46, 95% CI: 1.22–1.76) and magnesium (OR = 1.24, 95% CI: 1.03–1.49) were associated with increased risk of UC.

Conclusions: Our study provided evidence that circulating levels of antioxidants, minerals and vitamins might be causally linked to the development of IBD.


Inflammatory bowel disease (IBD), including Crohn's Disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract with a rising incidence in populations.[1] Although the precise aetiology of IBD remains unclear, accumulating evidence from observational studies suggests that dietary nutrients especially antioxidants, minerals and vitamins contribute to the pathogenesis of IBD.[2,3] Unfortunately, published research on the associations between dietary nutrients, especially antioxidants, minerals and vitamins and IBD is scarce and inconclusive. An umbrella review of meta-analyses found that high vitamin D levels decreased the risk of CD and UC;[4] however, a randomised controlled trial (RCT) examining the effect of supplemental vitamin D did not show a significant clinical benefit.[5] Large prospective cohort studies have reported that dietary zinc intake was inversely associated with incident CD,[6,7] whereas in a small RCT, zinc supplementation seemed to play little part in restraining inflammation in patients with IBD.[8] Potential explanations for these inconsistent results may relate to the substantial biases (residual confounding and reverse causation) in observational studies as well as low adherence to treatment, low treatment doses, short trial duration and low statistical power in RCTs. The causal role of antioxidants, minerals and vitamins in the development of CD or UC remains unclear.

Mendelian randomization (MR) utilises genetic variants as instruments to make inferences in causal relationships between risk factors and disease outcomes.[9] As germline genetic variants are randomly allocated at meiosis, MR design minimises confounding and is not influenced by environmental or self-adopted factors and therefore strengthens causal inference. Construction of a validated MR association relies on three key assumptions: (1) genetic variant is associated with the exposure; (2) the genetic variant is not related to confounding; (3) the genetic variant has no effect on outcome directly.[10] A previous MR study including 25,042 IBD cases indicated no association of genetically predicted vitamin D levels with CD or UC risk.[11] Still, the MR associations of antioxidants, minerals and vitamins with CD or UC risk have not been systematically evaluated. Here, we conducted an MR investigation to comprehensively explore the causal associations of antioxidants, minerals and vitamins with CD and UC.