Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 3392 2022-11-02 13:54:07 |
2 layout Meta information modification 3392 2022-11-04 04:12:21 | |
3 layout Meta information modification 3392 2022-11-04 04:14:59 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Dragasevic, S.;  Stankovic, B.;  Kotur, N.;  Milutinovic, A.S.;  Milovanovic, T.;  Lalosevic, M.S.;  Stojanovic, M.;  Pavlovic, S.;  Popovic, D. Vitamins in Inflammatory Bowel Disease. Encyclopedia. Available online: (accessed on 20 April 2024).
Dragasevic S,  Stankovic B,  Kotur N,  Milutinovic AS,  Milovanovic T,  Lalosevic MS, et al. Vitamins in Inflammatory Bowel Disease. Encyclopedia. Available at: Accessed April 20, 2024.
Dragasevic, Sanja, Biljana Stankovic, Nikola Kotur, Aleksandra Sokic Milutinovic, Tamara Milovanovic, Milica Stojkovic Lalosevic, Maja Stojanovic, Sonja Pavlovic, Dragan Popovic. "Vitamins in Inflammatory Bowel Disease" Encyclopedia, (accessed April 20, 2024).
Dragasevic, S.,  Stankovic, B.,  Kotur, N.,  Milutinovic, A.S.,  Milovanovic, T.,  Lalosevic, M.S.,  Stojanovic, M.,  Pavlovic, S., & Popovic, D. (2022, November 02). Vitamins in Inflammatory Bowel Disease. In Encyclopedia.
Dragasevic, Sanja, et al. "Vitamins in Inflammatory Bowel Disease." Encyclopedia. Web. 02 November, 2022.
Vitamins in Inflammatory Bowel Disease

The pathogenesis of inflammatory bowel disease (IBD) highlights the role of mucosal immunology and changes in the gut microbiome triggered by genetic and environmental factors including diet regiments, as suggested by many nutritional studies. Along with medications usually used for IBD treatment, therapeutic strategies also include the supplementation of micronutrients such as vitamin D, folic acid, iron, and zinc.

IBD genetics vitamin D B9

1. Introduction

The pathogenesis of inflammatory bowel disease (IBD) highlights the role of mucosal immunology and changes in the gut microbiome triggered by genetic and environmental factors including diet regiments, as suggested by many nutritional studies [1][2][3][4]. Oxidative damage that occurs in CD and UC is a result of an altered balance between free radical production with antioxidant depletion and micronutrients, leading to antioxidant repletion [1][2][3][4]. The presence or absence of anti-inflammatory agents such as antioxidants obtained through dietary intake or supplementation can impact the course of IBD. The intestinal tissue damage and altered gut microbiota caused by oxidative stress are significantly impacted by the presence of tissue repair mediators. Modulating the intestinal microbiota remains an attractive therapeutic potential for IBD [1][2][3][4]. Changes in dietary habits were also found to be strongly associated with a determined increased risk of autoimmune disease in a pediatric population [5][6]. So far, dietary constituents have been considered precipitants or promoters of complex interactions in IBD pathology, while nutritional deficiency with imbalances of specific micronutrients has been associated with the course of the disease [1][2]. Nevertheless, the role of modifiable environmental and behavioral factors such as diet remains poorly understood.
The majority of IBD patients show an interest in the active management of their disease, especially through dietary modifications [7]. Specifically, long-term dieting has shown the most significant effect in shaping the intestinal microbiome [8]. Therapeutic strategies in IBD, along with medications, encompass nutritional interventions including not only the elimination of potential food triggers but also the improvement of the nutritional status of patients [1][2][9]. The supplementation of micronutrients and macronutrients is important in everyday clinical practice in reducing the primary or secondary symptoms of disease [2]. Nevertheless, overuse or treatment with doses far exceeding the recommended daily allowances can be harmful and lead to adverse effects on the course of IBD. Especially during the coronavirus (COVID-19) pandemic, the frequent use of over-the-counter supplements among IBD patients has contributed to inadequate and uncontrolled strategies in therapy management.

2. Role of Vitamins in Inflammatory Bowel Disease

2.1. Vitamin D

According to numerous investigations, the deficiency of vitamin D has been highlighted as a key factor in the pathogenesis of IBD (Table 1) [10][11]. Vitamin D is a liposoluble vitamin, and its hormonal form of 1,25-dihydroxy vitamin D3 [1,25(OH)2D3], also called calcitriol, is important for various pathways of the immune system mediated via nuclear vitamin D receptor (VDR) in immune cells such as T and B lymphocytes, monocytes and macrophages. Vitamin D has a role in immune cell differentiation, the modulation of the gut microbiota, gene transcription, and barrier integrity [11]. A reduction in the serum levels of vitamin D is associated with an increased risk for infection (Table 1) [10][11]. The role of vitamin D includes the support of intestinal epithelial junctions and the upregulation of junction proteins including claudins, ZO-1, and occludins. The disruption of the mucosal barrier was noted in an IBD investigation in polarized epithelial Caco-2bbe cells grown in a medium with or without vitamin D and challenged with adherent invasive E. coli strain (AIEC). The investigation showed that Caco-2bbe cells incubated with 1,25(OH)2D3 were protected against AIEC-induced disruption. Additionally, vitamin D-deficient mice with DSS-induced colitis showed significant increases in the quantities of Bacteroidetes and were more susceptible to AIEC colonization. According to previous studies, vitamin D contributes to the homeostasis of the intestinal barrier function and protection against adherent invasive E. coli [12]. Additionally, it has been suggested that patients with IBD are at an increased risk of Clostridium difficile infection. Vitamin D has a prophylactic role against infection, influencing the production of antimicrobial compounds such as cathelicidins and modulating the microbiome [13]. VDR regulates the biological action of 1,25(OH)2D3 and has a role in the genetic, immune, environmental and microbial aspects of IBD. Dionne at al. study indicated that 1,25(OH)2D3 in CD patients significantly decreases the proinflammatory activity of M1-type macrophage but does not provide a reduction in the anti-inflammatory actions of M2-type macrophages. The level of anti-inflammatory cytokine IL-10 was not affected in the investigation [14]. The deficiency of vitamin D is also correlated with disease activity in IBD patients, so administration targeting a concentration of 30 ng/mL could potentially reduce disease activity [11]. Even though reports have shown lower vitamin D levels in IBD patients compared with the healthy population, it is not clear yet if the vitamin D deficiency is a consequence of the disease itself or if it has a role in disease pathogenesis. A study that followed subjects in two time points before (up to 8 years) and one time point after IBD diagnosis showed that the vitamin D level was not altered in IBD patients prior to disease onset compared with matched controls, but it was reduced after the disease was established [15].
Table 1. Frequent deficiencies of micronutrients in IBD.
According to conducted studies, VDR regulates the function of T cells and Paneth cells while modulating the release of antimicrobial peptides in the gut interaction pathways. Furthermore, beneficial microbial metabolites, including butyrate, stimulate VDR signaling [11]. Ananthakrishnan et al. showed that one third of IBD patients included in their study had a vitamin D deficiency and that its decreased levels correlated with colon cancer incidence in patients with IBD [26]. For the most common confounders of vitamin D deficiency have been indicated low intensity of sunlight and dis-ease duration and activity [26]. Further studies determined that 30 ng/mL of serum circulated vitamin D form, 25(OH)D3, can inhibit the secretion of proin-flammatory cytokines (IL-6 and TNF-α) induced by lipopolysaccharide (LPS) of the bacterial wall [27][28].

2.2. Vitamin D-Related Genetics

It has been demonstrated in numerous candidate gene approach and genome-wide association studies (GWAS) that vitamin D status is partly determined by genetic factors. Several genes and genetic variants located in or near those genes, such as DHCR7, GC, CYP2R1, CYP24A1 and VDR, have been recognized as significant modulators of vitamin D level and bioavailability [29]. Indicated genes encode proteins/enzymes involved in vitamin D transport and metabolism, namely, DHCR7 encodes enzymes expressed in the skin that are involved in cholecalciferol synthesis, GC encodes a vitamin D-binding protein that has a role in vitamin D precursor transport, CYP2R1 is a 25-hydroxylase involved in vitamin D precursor activation, and a CYP24A1 encodes 24-hydroxylase that participates in the inactivation of vitamin D metabolites. Variants of DHCR7 (rs12785878), GC (rs4588; rs7041), CYP2R1 (rs10741657, rs1993116, and rs10766197) and CYP24A1 (rs6013897) genes have been found to be associated with the serum level of 25-OHD [30][31], a form in which vitamin D is abundantly present in the circulation. The VDR gene encodes the vitamin D receptor, a transcription factor that regulates the expression of numerous genes after binding to the active form of vitamin D. Variants in this gene have been linked with the disease phenotype rather than with the level of the vitamin D.
It was demonstrated by Chip-seq that VDR-binding sites were significantly enriched near autoimmune-associated genes identified in GWAS, including the PTPN2 gene linked to Crohn’s disease [32]. Research on different experimental models of the inflamed gut showed that intestinal epithelial VDR regulates the IBD-associated autophagy gene ATG16L1 and lysozyme expression, as well as gut microbial assemblage—all important for maintaining the intestinal homeostasis [33]. Numerous studies have evaluated the association between IBD occurrence and genetic variants in the VDR gene since this gene maps to the region on chromosome 12 shown to be linked to IBD. The results regarding the association between VDR and IBD have been inconsistent, probably due to underpowered studies, different prevalences of vitamin D deficiency, and genetic diversity between different ethnic groups [15][34][35][36][37][38][39][40].
The FokI variant (rs2228570), which introduces an alternative translation start site, and three silent genetic variants of BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) in the VDR gene appear to be sporadically associated with IBD in diverse populations (Table 2). The association between the TaqI “t” (nucleotide C) allele and CD occurrence has been demonstrated in Caucasian populations [15][34][35][36]. Although the TaqI variant is a synonymous, “silent” variant located in the exon 9 of the VDR gene, it was shown that homozygous “tt” (genotype CC) carriers had significantly lower levels of the VDR protein in the PBMC of CD patients. The study also demonstrated that lower VDR levels were not associated with the changes in the mRNA expression nor with the production of the truncated protein [41]. In addition, CD carriers of the “tt” genotype exhibited a significantly higher risk (OR = 3.6) of having a B3-penetrating phenotype [41]. Regarding other variants, the results are not uniform; the FokI “f” (nucleotide T) variant was associated with CD in Iranian population [39] and with UC in Asian populations [36][40]; the presence of the BsmI “B” allele (nucleotide T) has been linked with an increased susceptibility to UC in Israeli Ashkenazi [37] and Han Chinese patients [38]; a meta-study indicated that carriers of the Apal “AA” genotype (TT genotype) had an increased risk for CD regardless of population stratification [36]. Overall, these results highlight the importance of examining population genetics in assessing disease burden or defining strategies for precision medicine/nutrition.
Table 2. Genetic variants that are associated with micronutrient levels and are potentially relevant to IBD pathogenesis, comorbidities or treatment.
Compared with the VDR gene, only a few studies have assessed the association between IBD and other vitamin D-related genes, such as DHCR7, CYP2R1 and GC [54][55]. They have previously been mostly examined in relation to vitamin D level and deficiency [30][31]. The role of those genes in IBD pathogenesis and treatment response should be more thoroughly analyzed in the future studies considering other factors that influence vitamin D level, such as vitamin D intake, nutrient supplement use, body mass index, physical activity, and lifestyle factors. The potential contribution of the VDR variants in response to the vitamin D treatment of IBD patients is promising. A recent meta-study conducted on a general population showed that VDR could play a role in the modulation of the response to vitamin D supplementation, showing that the FF genotype of the FokI variant and Tt + tt genotypes of the TaqI variant were associated with a better response to vitamin D supplementation [56].

2.3. Folate and Vitamin B12

Folate (vitamin B9) is a one-carbon moiety donor cofactor involved in nucleotide synthesis and methylation metabolic pathways. Due to an impaired methylation cycle, folate deficiency causes the accumulation of homocysteine, a metabolite associated with oxidative stress and inflammation (Table 1). Folate deficiency and elevated homocysteine levels are related to various pathological conditions such as anemia, low bone mineral density, thromboembolic events and birth defects [16].
In IBD, folate deficiency and elevated homocysteine levels are related to markers of intestinal inflammation [17][57][58], the reduced survival of regulatory T cells in the small bowel [59], and the active stage of the disease [17][18]. Folate deficiency may cause DNA hypomethylation, which is related to higher inflammation and colorectal cancer risk in IBD patients [60][61]. Results from a meta-analysis suggested that high folate levels can reduce the risk of IBD [62]. Due to these findings, it has been proposed that folate supplementation may be utilized to reduce complications of IBD [59][62].
Among IBD patients, around 20% have reduced folate levels and around 30% have increased homocysteine levels, which is much more common than in healthy people [17][63][64][65]. Bermejo et al. reported a higher prevalence of folate deficiency among CD patients (22%) compared with UC patients (4.3%), as well as an association with disease severity but not ileal resection (Table 1) [42]. Folate deficiency may be due to a reduced folate intake caused by the avoidance of folate-rich food, active inflammation that causes higher folate utilization, and the reduced absorption of folate due to intestinal damage, small bowel resection, or certain medications often prescribed to IBD patients (such as methotrexate and sulfasalazine) [66]. A recent meta-analysis showed that IBD patients consume an inadequate amount of cereals, legumes, fruit, vegetables, and dairy, which causes a lower intake of energy, calcium, fiber, and folate [67]. Vitamin B9 metabolites are absorbed in the proximal parts of the small bowel, so small bowel resection and severe intestinal inflammation related to IBD (which causes structural alterations of the bowel) reduce folate absorption [16]. To avoid folate deficiency, regular folate level monitoring and supplementation are recommended in IBD patients with a high risk of folate deficiency [68].
Vitamin B12 (cobalamin) and folic acid have significant roles in erythropoiesis and are often associated with anemia in patients with IBD [2][66]. Cobalamin and folate are crucial for nucleic acid synthesis and the process of erythropoiesis [2]. In the course of differentiation, erythroblasts need vitamin B12 and folic acid for proliferation, while their deficiency leads to macrocytosis, the apoptosis of erythroblasts, and anemia [2][66]. According to a previous investigation, the prevalence of vitamin B12 deficiency ranges between 6 and 38% [11][69]. Dietary vitamin B12 binds an intrinsic factor synthesized by the parietal cells in the duodenum for its further absorption in the terminal ileum. Hence, vitamin B12 deficiency is much more frequent in CD than in UC patients [19]. According to Battat et al., the crucial risk factor for vitamin B12 deficiency is an ileal resection of more than 30 cm [69]. Nevertheless, CD with ileal localization is not a risk factor for cobalamin deficiency [69]. A previous investigation determined that UC patients have a vitamin B12 deficiency similar to that of the general population [10]. However, UC patients with ileo-anal J-pouch could have vitamin B12 deficiency due to small bacterial overgrowth [11].
The recent guideline recommendations of the European Crohn’s and Colitis Organization (ECCO) endorsed checking folate and vitamin B12 levels at a minimum of once per year or when macrocytosis is present, especially in IBD patients not receiving thiopurines [70]. Even though folate deficiency and elevated homocysteine levels have been linked to IBD-associated colon cancer, preclinical studies with folic acid supplementation contradict previous published data [2][71].

2.4. Folate-Related Genetics

Besides the adequate intake and absorption of vitamin B9, optimal levels of folate bioactive forms and homocysteine are maintained by folate cycle enzymes and transporters. The activity of those proteins show marked inter-individual differences that depend on genetics. One of the key polymorphic enzymes of the folate cycle is methylenetetrahydrofolate reductase (MTHFR), which provides methyltetrahidrofolate, a bioactive form of vitamin B9 involved in re-methylation pathways. There are two common missense variants of the MTHFR gene that cause the reduced activity of the enzyme: c.677C>T (p.Ala222Val) and c.1298A>C (p.Glu429Ala), which have been extensively studied in IBD and other diseases.
Variant c.677T (rs1801133) causes a 70% reduction in enzyme activity [72]. Each copy of the low-activity T allele causes a greater reduction in folate and a higher level of homocysteine [73][74]. Initial reports found an elevated risk of IBD in carriers of the TT genotype, but the majority of subsequent studies, including high-quality studies, did not corroborate this finding [44][67]; however, further research is needed.
Variant c.1298A>C (rs1801131) causes a 40% reduction in enzyme activity [43], and it is less studied than the c.677C>T variant. The lower-activity c.677T and c.1298C variants very rarely lie on the same chromosome. However, in compound heterozygotes of the c.677C>T and c.1298A>C variants, higher homocysteine levels are expected [74]. Interestingly, a recent meta-analysis associated the presence of the lower-activity C allele of the c.1298A>C variant with a greater risk of UC and IBD [44] (Table 2). The same meta-analysis did not show compelling evidence that the c.677C>T variant is associated with IBD development.
Methotrexate is one of the immune-modulating drugs often prescribed to IBD patients. By inhibiting some of the key involved enzymes, methotrexate disrupts the folate cycle. This results in immune-modulating effects, including higher rates of the apoptosis of the immune cells and elevated levels of adenosine, a natural anti-inflammatory agent [75]. In addition to its therapeutic effects, methotrexate could also exert toxic effects, most notably on GIT, liver and bone marrow [76]. These side effects might be more common in patients with MTHFR variants [45][77], though more research is needed, especially studies involving IBD patients. Variants in other pharmacogenes, such as those involved in folate and methotrexate transport (most notably SLCO1B1 and SLC19A1), might also play a role in response to methotrexate therapy in pediatric IBD patients and rheumatoid arthritis patients [78][79]. Methotrexate side effects can be mitigated by folate supplementation, so identifying patients at risk, such as those who carry unfavorable genetic variants, could be of great benefit.


  1. Sasson, A.N.; Ananthakrishnan, A.N.; Raman, M. Diet in Treatment of Inflammatory Bowel Diseases. Clin. Gastroenterol. Hepatol. 2021, 19, 425–435.e3.
  2. Ghishan, F.K.; Kiela, P.R. Vitamins and Minerals in Inflammatory Bowel Disease. Gastroenterol. Clin. N. Am. 2017, 46, 797–808.
  3. Weisshof, R.; Chermesh, I. Micronutrient deficiencies in inflammatory bowel disease. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 576–581.
  4. Massironi, S.; Rossi, R.E.; Cavalcoli, F.A.; Della Valle, S.; Fraquelli, M.; Conte, D. Nutritional deficiencies in inflammatory bowel disease: Therapeutic approaches. Clin. Nutr. 2013, 32, 904–910.
  5. Benchimol, E.I.; Mack, D.R.; Guttmann, A.; Nguyen, G.C.; To, T.; Mojaverian, N.; Quach, P.; Manuel, D.G. Inflammatory bowel disease in immigrants to Canada and their children: A population-based cohort study. Am. J. Gastroenterol. 2015, 110, 553–563.
  6. Rempel, J.; Grover, K.; El-Matary, W. Micronutrient Deficiencies and Anemia in Children with Inflammatory Bowel Disease. Nutrients 2021, 13, 236.
  7. Cox, S.R.; Clarke, H.; O’Keeffe, M.; Dubois, P.; Irving, P.M.; Lindsay, J.O.; Whelan, K. Nutrient, Fibre, and FODMAP Intakes and Food-related Quality of Life in Patients with Inflammatory Bowel Disease, and Their Relationship with Gastrointestinal Symptoms of Differing Aetiologies. J. Crohns. Colitis 2021, 15, 2041–2053.
  8. Sauk, J. Diet and Microbiome in Inflammatory Bowel Diseases. In Nutritional Management of Inflammatory Bowel Diseases; Springer International Publishing: Cham, Switzerland, 2016; pp. 3–16.
  9. Hart, A.R.; Chan, S.S.M. Dietary Risk Factors for the Onset and Relapse of Inflammatory Bowel Disease. In Nutritional Management of Inflammatory Bowel Diseases; Springer International Publishing: Cham, Switzerland, 2016; pp. 17–28.
  10. Jarmakiewicz-Czaja, S.; Piątek, D.; Filip, R. The Influence of Nutrients on Inflammatory Bowel Diseases. J. Nutr. Metab. 2020, 2020, 2894169.
  11. Battistini, C.; Ballan, R.; Herkenhoff, M.E.; Saad, S.M.I.; Sun, J. Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases. Int. J. Mol. Sci. 2020, 22, 362.
  12. Assa, A.; Vong, L.; Pinnell, L.J.; Rautava, J.; Avitzur, N.; Johnson-Henry, K.C.; Sherman, P.M. Vitamin D deficiency predisposes to adherent-invasive Escherichia coli-induced barrier dysfunction and experimental colonic injury. Inflamm. Bowel Dis. 2015, 21, 297–306.
  13. Trifan, A.; Stanciu, C.; Stoica, O.; Girleanu, I.; Cojocariu, C. Impact of Clostridium difficile infection on inflammatory bowel disease outcome: A review. World J. Gastroenterol. 2014, 20, 11736–11742.
  14. Dionne, S.; Duchatelier, C.-F.; Seidman, E.G. The influence of vitamin D on M1 and M2 macrophages in patients with Crohn’s disease. Innate Immun. 2017, 23, 557–565.
  15. Limketkai, B.N.; Singla, M.B.; Rodriguez, B.; Veerappan, G.R.; Betteridge, J.D.; Ramos, M.A.; Hutfless, S.M.; Brant, S.R. Levels of Vitamin D Are Low After Crohn’s Disease Is Established But Not Before. Clin. Gastroenterol. Hepatol. 2020, 18, 1769–1776.e1.
  16. Ratajczak, A.E.; Szymczak-Tomczak, A.; Rychter, A.M.; Zawada, A.; Dobrowolska, A.; Krela-Kaźmierczak, I. Does Folic Acid Protect Patients with Inflammatory Bowel Disease from Complications? Nutrients 2021, 13, 4036.
  17. Moein, S.; Vaghari-Tabari, M.; Qujeq, D.; Kashifard, M.; Shokri-Shirvani, J.; Hajian-Tilaki, K. Association between serum folate with inflammatory markers, disease clinical activity and serum homocysteine in patients with inflammatory bowel disease. Does folate level have an effect on maintaining clinical remission? Acta Biomed. 2020, 91, e2020106.
  18. Drzewoski, J.; Gasiorowska, A.; Małecka-Panas, E.; Bald, E.; Czupryniak, L. Plasma total homocysteine in the active stage of ulcerative colitis. J. Gastroenterol. Hepatol. 2006, 21, 739–743.
  19. Madanchi, M.; Fagagnini, S.; Fournier, N.; Biedermann, L.; Zeitz, J.; Battegay, E.; Zimmerli, L.; Vavricka, S.R.; Rogler, G.; Scharl, M.; et al. The Relevance of Vitamin and Iron Deficiency in Patients with Inflammatory Bowel Diseases in Patients of the Swiss IBD Cohort. Inflamm. Bowel Dis. 2018, 24, 1768–1779.
  20. Hashemi, J.; Asadi, J.; Amiriani, T.; Besharat, S.; Roshandel, G.R.; Joshaghani, H.R. Serum vitamins A and E deficiencies in patients with inflammatory bowel disease. Saudi Med. J. 2013, 34, 432–434.
  21. Alkhouri, R.H.; Hashmi, H.; Baker, R.D.; Gelfond, D.; Baker, S.S. Vitamin and mineral status in patients with inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 2013, 56, 89–92.
  22. da Rocha Lima, B.; Pichi, F.; Lowder, C.Y. Night blindness and Crohn’s disease. Int. Ophthalmol. 2014, 34, 1141–1144.
  23. Stein, J.; Hartmann, F.; Dignass, A.U. Diagnosis and management of iron deficiency anemia in patients with IBD. Nat. Rev. Gastroenterol. Hepatol. 2010, 7, 599–610.
  24. Vagianos, K.; Bector, S.; McConnell, J.; Bernstein, C.N. Nutrition assessment of patients with inflammatory bowel disease. JPEN J. Parenter. Enter. Nutr. 2007, 31, 311–319.
  25. Siva, S.; Rubin, D.T.; Gulotta, G.; Wroblewski, K.; Pekow, J. Zinc Deficiency is Associated with Poor Clinical Outcomes in Patients with Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2017, 23, 152–157.
  26. Ananthakrishnan, A.N.; Cheng, S.-C.; Cai, T.; Cagan, A.; Gainer, V.S.; Szolovits, P.; Shaw, S.Y.; Churchill, S.; Karlson, E.W.; Murphy, S.N.; et al. Association between reduced plasma 25-hydroxy vitamin D and increased risk of cancer in patients with inflammatory bowel diseases. Clin. Gastroenterol. Hepatol. 2014, 12, 821–827.
  27. Zhang, Y.; Leung, D.Y.M.; Richers, B.N.; Liu, Y.; Remigio, L.K.; Riches, D.W.; Goleva, E. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. 2012, 188, 2127–2135.
  28. Reich, K.M.; Fedorak, R.N.; Madsen, K.; Kroeker, K.I. Vitamin D improves inflammatory bowel disease outcomes: Basic science and clinical review. World J. Gastroenterol. 2014, 20, 4934–4947.
  29. Niforou, A.; Konstantinidou, V.; Naska, A. Genetic Variants Shaping Inter-individual Differences in Response to Dietary Intakes-A Narrative Review of the Case of Vitamins. Front. Nutr. 2020, 7, 558598.
  30. Wang, T.J.; Zhang, F.; Richards, J.B.; Kestenbaum, B.; van Meurs, J.B.; Berry, D.; Kiel, D.P.; Streeten, E.A.; Ohlsson, C.; Koller, D.L.; et al. Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 2010, 376, 180–188.
  31. Ahn, J.; Yu, K.; Stolzenberg-Solomon, R.; Simon, K.C.; McCullough, M.L.; Gallicchio, L.; Jacobs, E.J.; Ascherio, A.; Helzlsouer, K.; Jacobs, K.B.; et al. Genome-wide association study of circulating vitamin D levels. Hum. Mol. Genet. 2010, 19, 2739–2745.
  32. Ramagopalan, S.V.; Heger, A.; Berlanga, A.J.; Maugeri, N.J.; Lincoln, M.R.; Burrell, A.; Handunnetthi, L.; Handel, A.E.; Disanto, G.; Orton, S.-M.; et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res. 2010, 20, 1352–1360.
  33. Wu, S.; Zhang, Y.-G.; Lu, R.; Xia, Y.; Zhou, D.; Petrof, E.O.; Claud, E.C.; Chen, D.; Chang, E.B.; Carmeliet, G.; et al. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut 2015, 64, 1082–1094.
  34. Simmons, J.D.; Mullighan, C.; Welsh, K.I.; Jewell, D.P. Vitamin D receptor gene polymorphism: Association with Crohn’s disease susceptibility. Gut 2000, 47, 211–214.
  35. Martin, K.; Radlmayr, M.; Borchers, R.; Heinzlmann, M.; Folwaczny, C. Candidate genes colocalized to linkage regions in inflammatory bowel disease. Digestion 2002, 66, 121–126.
  36. Xue, L.-N.; Xu, K.-Q.; Zhang, W.; Wang, Q.; Wu, J.; Wang, X.-Y. Associations between vitamin D receptor polymorphisms and susceptibility to ulcerative colitis and Crohn’s disease: A meta-analysis. Inflamm. Bowel Dis. 2013, 19, 54–60.
  37. Dresner-Pollak, R.; Ackerman, Z.; Eliakim, R.; Karban, A.; Chowers, Y.; Fidder, H.H. The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients. Genet. Test. 2004, 8, 417–420.
  38. Pei, F.H.; Wang, Y.J.; Gao, S.L.; Liu, B.R.; Du, Y.J.; Liu, W.; Yu, H.Y.; Zhao, L.X.; Chi, B.R. Vitamin D receptor gene polymorphism and ulcerative colitis susceptibility in Han Chinese. J. Dig. Dis. 2011, 12, 90–98.
  39. Naderi, N.; Farnood, A.; Habibi, M.; Derakhshan, F.; Balaii, H.; Motahari, Z.; Agah, M.R.; Firouzi, F.; Rad, M.G.; Aghazadeh, R.; et al. Association of vitamin D receptor gene polymorphisms in Iranian patients with inflammatory bowel disease. J. Gastroenterol. Hepatol. 2008, 23, 1816–1822.
  40. Xia, S.-L.; Yu, L.-Q.; Chen, H.; Hu, D.-Y.; Shao, X.-X.; Guo, M.-D.; Jiang, L.-J.; Lin, X.-X.; Lin, X.-Q.; Jiang, Y. Association of vitamin D receptor gene polymorphisms with the susceptibility to ulcerative colitis in patients from Southeast China. J. Recept. Signal Transduct. Res. 2015, 35, 530–535.
  41. Gisbert-Ferrándiz, L.; Salvador, P.; Ortiz-Masiá, D.; Macías-Ceja, D.C.; Orden, S.; Esplugues, J.V.; Calatayud, S.; Hinojosa, J.; Barrachina, M.D.; Hernández, C. A Single Nucleotide Polymorphism in the Vitamin D Receptor Gene Is Associated with Decreased Levels of the Protein and a Penetrating Pattern in Crohn’s Disease. Inflamm. Bowel Dis. 2018, 24, 1462–1470.
  42. Bermejo, F.; Algaba, A.; Guerra, I.; Chaparro, M.; De-La-Poza, G.; Valer, P.; Piqueras, B.; Bermejo, A.; García-Alonso, J.; Pérez, M.-J.; et al. Should we monitor vitamin B12 and folate levels in Crohn’s disease patients? Scand. J. Gastroenterol. 2013, 48, 1272–1277.
  43. Weisberg, I.; Tran, P.; Christensen, B.; Sibani, S.; Rozen, R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol. Genet. Metab. 1998, 64, 169–172.
  44. Yang, P.; Wang, L.; Tang, X.; Liang, Y. The methylenetetrahydrofolate reductase 1298 A>C polymorphism is associated with an increased risk of inflammatory bowel disease: Evidence from a meta-analysis. Expert Rev. Clin. Immunol. 2021, 17, 1221–1229.
  45. Shao, W.; Yuan, Y.; Li, Y. Association Between MTHFR C677T Polymorphism and Methotrexate Treatment Outcome in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis. Genet. Test. Mol. Biomark. 2017, 21, 275–285.
  46. Maroni, L.; van de Graaf, S.F.J.; Hohenester, S.D.; Oude Elferink, R.P.J.; Beuers, U. Fucosyltransferase 2: A genetic risk factor for primary sclerosing cholangitis and Crohn’s disease—A comprehensive review. Clin. Rev. Allergy Immunol. 2015, 48, 182–191.
  47. Cheng, S.; Hu, J.; Wu, X.; Pan, J.-A.; Jiao, N.; Li, Y.; Huang, Y.; Lin, X.; Zou, Y.; Chen, Y.; et al. Altered gut microbiome in FUT2 loss-of-function mutants in support of personalized medicine for inflammatory bowel diseases. J. Genet. Genom. 2021, 48, 771–780.
  48. Nongmaithem, S.S.; Joglekar, C.V.; Krishnaveni, G.V.; Sahariah, S.A.; Ahmad, M.; Ramachandran, S.; Gandhi, M.; Chopra, H.; Pandit, A.; Potdar, R.D.; et al. GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians. Hum. Mol. Genet. 2017, 26, 2551–2564.
  49. Borel, P.; Desmarchelier, C. Genetic Variations Associated with Vitamin A Status and Vitamin A Bioavailability. Nutrients 2017, 9, 246.
  50. Fransén, K.; Franzén, P.; Magnuson, A.; Elmabsout, A.A.; Nyhlin, N.; Wickbom, A.; Curman, B.; Törkvist, L.; D’Amato, M.; Bohr, J.; et al. Polymorphism in the retinoic acid metabolizing enzyme CYP26B1 and the development of Crohn’s Disease. PLoS ONE 2013, 8, e72739.
  51. De Falco, L.; Tortora, R.; Imperatore, N.; Bruno, M.; Capasso, M.; Girelli, D.; Castagna, A.; Caporaso, N.; Iolascon, A.; Rispo, A. The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. Am. J. Hematol. 2018, 93, 383–393.
  52. Urbaszek, K.; Drabińska, N.; Szaflarska-Popławska, A.; Jarocka-Cyrta, E. TMPRSS6 rs855791 Polymorphism Status in Children with Celiac Disease and Anemia. Nutrients 2021, 13, 2782.
  53. Collij, V.; Imhann, F.; Vich Vila, A.; Fu, J.; Dijkstra, G.; Festen, E.A.M.; Voskuil, M.D.; Daly, M.J.; Xavier, R.J.; Wijmenga, C.; et al. SLC39A8 missense variant is associated with Crohn’s disease but does not have a major impact on gut microbiome composition in healthy subjects. PLoS ONE 2019, 14, e0211328.
  54. Eloranta, J.J.; Wenger, C.; Mwinyi, J.; Hiller, C.; Gubler, C.; Vavricka, S.R.; Fried, M.; Kullak-Ublick, G.A.; Swiss IBD Cohort Study Group. Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease. Pharmacogenet. Genom. 2011, 21, 559–564.
  55. Lund-Nielsen, J.; Vedel-Krogh, S.; Kobylecki, C.J.; Brynskov, J.; Afzal, S.; Nordestgaard, B.G. Vitamin D and Inflammatory Bowel Disease: Mendelian Randomization Analyses in the Copenhagen Studies and UK Biobank. J. Clin. Endocrinol. Metab. 2018, 103, 3267–3277.
  56. Usategui-Martín, R.; De Luis-Román, D.-A.; Fernández-Gómez, J.M.; Ruiz-Mambrilla, M.; Pérez-Castrillón, J.-L. Vitamin D Receptor (VDR) Gene Polymorphisms Modify the Response to Vitamin D Supplementation: A Systematic Review and Meta-Analysis. Nutrients 2022, 14, 360.
  57. Däbritz, J.; Musci, J.; Foell, D. Diagnostic utility of faecal biomarkers in patients with irritable bowel syndrome. World J. Gastroenterol. 2014, 20, 363–375.
  58. Gioxari, A.; Amerikanou, C.; Papada, E.; Zioga, E.; Georgoulis, A.D.; Bamias, G.; Kaliora, A.C. Serum Vitamins D, B9 and B12 in Greek Patients with Inflammatory Bowel Diseases. Nutrients 2020, 12, 3734.
  59. Kunisawa, J.; Hashimoto, E.; Ishikawa, I.; Kiyono, H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS ONE 2012, 7, e32094.
  60. Samblas, M.; Martínez, J.A.; Milagro, F. Folic Acid Improves the Inflammatory Response in LPS-Activated THP-1 Macrophages. Mediat. Inflamm. 2018, 2018, 1312626.
  61. Burr, N.E.; Hull, M.A.; Subramanian, V. Folic Acid Supplementation May Reduce Colorectal Cancer Risk in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. J. Clin. Gastroenterol. 2017, 51, 247–253.
  62. Piovani, D.; Danese, S.; Peyrin-Biroulet, L.; Nikolopoulos, G.K.; Lytras, T.; Bonovas, S. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology 2019, 157, 647–659.e4.
  63. Zezos, P.; Papaioannou, G.; Nikolaidis, N.; Vasiliadis, T.; Giouleme, O.; Evgenidis, N. Hyperhomocysteinemia in ulcerative colitis is related to folate levels. World J. Gastroenterol. 2005, 11, 6038–6042.
  64. Pan, Y.; Liu, Y.; Guo, H.; Jabir, M.S.; Liu, X.; Cui, W.; Li, D. Associations between Folate and Vitamin B12 Levels and Inflammatory Bowel Disease: A Meta-Analysis. Nutrients 2017, 9, 382.
  65. Oussalah, A.; Guéant, J.-L.; Peyrin-Biroulet, L. Meta-analysis: Hyperhomocysteinaemia in inflammatory bowel diseases. Aliment. Pharmacol. Ther. 2011, 34, 1173–1184.
  66. Jowett, S.L.; Seal, C.J.; Phillips, E.; Gregory, W.; Barton, J.R.; Welfare, M.R. Dietary beliefs of people with ulcerative colitis and their effect on relapse and nutrient intake. Clin. Nutr. 2004, 23, 161–170.
  67. Lambert, K.; Pappas, D.; Miglioretto, C.; Javadpour, A.; Reveley, H.; Frank, L.; Grimm, M.C.; Samocha-Bonet, D.; Hold, G.L. Systematic review with meta-analysis: Dietary intake in adults with inflammatory bowel disease. Aliment. Pharmacol. Ther. 2021, 54, 742–754.
  68. Maaser, C.; Sturm, A.; Vavricka, S.R.; Kucharzik, T.; Fiorino, G.; Annese, V.; Calabrese, E.; Baumgart, D.C.; Bettenworth, D.; Borralho Nunes, P.; et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J. Crohns. Colitis 2019, 13, 144–164.
  69. Battat, R.; Kopylov, U.; Szilagyi, A.; Saxena, A.; Rosenblatt, D.S.; Warner, M.; Bessissow, T.; Seidman, E.; Bitton, A. Vitamin B12 deficiency in inflammatory bowel disease: Prevalence, risk factors, evaluation, and management. Inflamm. Bowel Dis. 2014, 20, 1120–1128.
  70. Dignass, A.U.; Gasche, C.; Bettenworth, D.; Birgegård, G.; Danese, S.; Gisbert, J.P.; Gomollon, F.; Iqbal, T.; Katsanos, K.; Koutroubakis, I.; et al. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J. Crohns. Colitis 2015, 9, 211–222.
  71. Carrier, J.; Medline, A.; Sohn, K.-J.; Choi, M.; Martin, R.; Hwang, S.W.; Kim, Y.-I. Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2- and beta(2)-microglobulin-deficient mice. Cancer Epidemiol. Biomark. Prev. 2003, 12, 1262–1267.
  72. Frosst, P.; Blom, H.J.; Milos, R.; Goyette, P.; Sheppard, C.A.; Matthews, R.G.; Boers, G.J.; den Heijer, M.; Kluijtmans, L.A.; van den Heuvel, L.P. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 1995, 10, 111–113.
  73. Tsang, B.L.; Devine, O.J.; Cordero, A.M.; Marchetta, C.M.; Mulinare, J.; Mersereau, P.; Guo, J.; Qi, Y.P.; Berry, R.J.; Rosenthal, J.; et al. Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: A systematic review and meta-analysis of trials and observational studies. Am. J. Clin. Nutr. 2015, 101, 1286–1294.
  74. Ménézo, Y.; Patrizio, P.; Alvarez, S.; Amar, E.; Brack, M.; Brami, C.; Chouteau, J.; Clement, A.; Clement, P.; Cohen, M.; et al. MTHFR (methylenetetrahydrofolate reductase: EC SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility. J. Assist. Reprod. Genet. 2021, 38, 2383–2389.
  75. Cronstein, B.N.; Aune, T.M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol. 2020, 16, 145–154.
  76. Rosh, J.R. The Current Role of Methotrexate in Patients With Inflammatory Bowel Disease. Gastroenterol. Hepatol. 2020, 16, 43–46.
  77. Herrlinger, K.R.; Cummings, J.R.F.; Barnardo, M.C.N.M.; Schwab, M.; Ahmad, T.; Jewell, D.P. The pharmacogenetics of methotrexate in inflammatory bowel disease. Pharmacogenet. Genom. 2005, 15, 705–711.
  78. Mehta, R.S.; Taylor, Z.L.; Martin, L.J.; Rosen, M.J.; Ramsey, L.B. SLCO1B1 *15 allele is associated with methotrexate-induced nausea in pediatric patients with inflammatory bowel disease. Clin. Transl. Sci. 2022, 15, 63–69.
  79. Li, X.; Hu, M.; Li, W.; Gu, L.; Chen, M.; Ding, H.; Vanarsa, K.; Du, Y. The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: A meta-analysis. Int. Immunopharmacol. 2016, 38, 8–15.
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , , , , , ,
View Times: 438
Revisions: 3 times (View History)
Update Date: 04 Nov 2022