Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling

Critical Reviews in Food Science and Nutrition

Volumn 60, Issue 2, 2020, Pages 244-256

  Kok, Dieuwertje E ^a   Steegenga, Wilma T ^a   Smid, Eddy J ^a   Zoetendal, Erwin G ^a   Ulrich, Cornelia M ^b   Kampman, Ellen ^a  

^a WAGENINGEN UNIVERSITY   (Netherlands)

^b UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

biosynthesis; colon; colorectal cancer; DNA methylation; Folate; intestinal bacteria; one carbon metabolism

Indexed keywords

ALKYLATION; BACTERIA; BIOCHEMISTRY; BIOSYNTHESIS; DIETARY SUPPLEMENTS; DNA; NUTRITION; VITAMINS;

CARBON METABOLISM; COLON; COLORECTAL CANCER; DNA METHYLATION; FOLATE; INTESTINAL BACTERIA;

DISEASES;

FOLIC ACID; VITAMIN B COMPLEX;

BACTERIUM; COLORECTAL TUMOR; DIET; HUMAN; METABOLISM;

BACTERIA; COLORECTAL NEOPLASMS; DIET; FOLIC ACID; HUMANS; VITAMIN B COMPLEX;

EID: 85076455526     PISSN: 10408398     EISSN: 15497852     Source Type: Journal    
DOI: 10.1080/10408398.2018.1522499     Document Type: Review

References (157)

1. Flour Fortification Innitiative (FFI). 2017. Map of Mandatory Cereal Grain Legislation - November Countries with Mandatory Wheat Flour Fortification Regulations. Accessed February 21, 2018. http://www.ffinetwork.org/global_progress/index.php.
2. Asrar, F. M., and D. L., O'Connor. 2005. Bacterially synthesized folate and supplemental folic acid are absorbed across the large intestine of piglets. Journal of Nutrition Biochemistry 16 (10):587–93.
3. Aufreiter, S., J. F., Gregory, 3rd, C. M., Pfeiffer, Z., Fazili, Y. I., Kim, N., Marcon, P., Kamalaporn, P. B., Pencharz, and D. L., O'Connor. 2009. Folate is absorbed across the Colon of adults: evidence from cecal infusion of (13)C-labeled [6S]-5-formyltetrahydrofolic acid. The American Journal of Clinical Nutrition 90 (1):116–23.
4. Aufreiter, S., J. H., Kim, and D. L., O'Connor. 2011. Dietary oligosaccharides increase colonic weight and the amount but not concentration of bacterially synthesized folate in the Colon of piglets. The Journal of Nutrition 141 (3):366–72.
5. Bae, M. G., J. Y., Kim, and J. K., Choi. 2016. Frequent hypermethylation of orphan CpG islands with enhancer activity in cancer. BMC Medical Genomics 9 (S1):38.
6. Bailey, L. B., P. J., Stover, H., McNulty, M. F., Fenech, J. F., Gregory, J. L., Mills, C. M., Pfeiffer, Z., Fazili, M., Zhang, P. M., Ueland, et al. 2015. Biomarkers of nutrition for Development-Folate Review. The Journal of Nutrition 145 (7):1636S–80S.
7. Bailey, S. W., and J. E., Ayling. 2009. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proceedings of the National Academy of Sciences of the United States of America 106 (36):15424–9.
8. Ben-Amor, K., H., Heilig, H., Smidt, E. E., Vaughan, T., Abee, and W. M., de Vos. 2005. Genetic diversity of viable, injured, and dead fecal bacteria assessed by fluorescence-activated cell sorting and 16S rRNA gene analysis. Applied and Environmental Microbiology 71 (8):4679–89.
9. Blount, B. C., M. M., Mack, C. M., Wehr, J. T., MacGregor, R. A., Hiatt, G., Wang, S. N., Wickramasinghe, R. B., Everson, and B. N., Ames. 1997. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proceedings of the National Academy of Sciences of the United States of America 94 (7):3290–5.
10. Blumberg, J. B., R. L., Bailey, H. D., Sesso, and C. M., Ulrich. 2018. The evolving role of multivitamin/multimineral supplement use among adults in the age of personalized nutrition. Nutrients 10 (2):248.
11. Camilo, E., J., Zimmerman, J. B., Mason, B., Golner, R., Russell, J., Selhub, and I. H., Rosenberg. 1996. Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 110 (4):991–8.
12. Chan, Y. M., S., Aufreiter, S. J., O'Keefe, and D. L., O'Connor. 2018. Switching to a fibre-rich and low-fat diet increases colonic folate contents among African Americans. Applied Physiology, Nutrition, and Metabolism.
13. Chen, P., C., Li, X., Li, J., Li, R., Chu, and H., Wang. 2014. Higher dietary folate intake reduces the breast cancer risk: a systematic review and Meta-analysis. British Journal of Cancer 110 (9):2327–38.
14. Chon, J., P. J., Stover, and M. S., Field. 2017. Targeting nuclear thymidylate biosynthesis. Molecular Aspects of Medicine 53:48–56.
15. Chuang, S. C., M., Rota, M. J., Gunter, A., Zeleniuch-Jacquotte, S. J., Eussen, S. E., Vollset, P. M., Ueland, T., Norat, R. G., Ziegler, and P., Vineis. 2013. Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a Meta-analysis based on a flexible Meta-regression model. American Journal of Epidemiology 178 (7):1028–37.
16. Cole, B. F., J. A., Baron, R. S., Sandler, R. W., Haile, D. J., Ahnen, R. S., Bresalier, G., McKeown-Eyssen, R. W., Summers, R. I., Rothstein, C. A., Burke., et al. 2007. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. The Journal of the American Medical Association 297 (21):2351–9.
17. Costa-Pinheiro, P., D., Montezuma, R., Henrique, and C., Jeronimo. 2015. Diagnostic and prognostic epigenetic biomarkers in cancer. Epigenomics 7 (6):1003–15.
18. Cravo, M. l. L., C. M., Albuquerque, L. S., de Sousa, L. S. M., Glória, P., Chaves, A. D., Pereira, C. N., Leitão, M. G., Quina, and F. C., Mira. 1998. Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation. The American Journal of Gastroenterology 93:2060–64.
19. Czeizel, A. E., I., Dudas, and J., Metneki. 1994. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Archives of Gynecology and Obstetrics 255 (3):131–9.
20. Crittenden, R. G., N. R., Martinez, and M. J., Playne. 2003. Synthesis and utilisation of folate by yoghurt starter cultures and probiotic bacteria. International Journal of Food Microbiology 80:217–22.
21. D'Aimmo, M. R., P., Mattarelli, B., Biavati, N. G., Carlsson, and T., Andlid. 2012. The potential of bifidobacteria as a source of natural folate. Journal of Applied Microbiology 112 (5):975–84.
22. D'Aimmo, M. R., M., Modesto, P., Mattarelli, B., Biavati, and T., Andlid. 2014. Biosynthesis and cellular content of folate in bifidobacteria across host species with different diets. Anaerobe 30:169–77.
23. Darcy-Vrillon, B., J., Selhub, and I. H., Rosenberg. 1988. Analysis of sequential events in intestinal absorption of folylpolyglutamate. The American Journal of Physiology 255 (3 Pt 1):G361–6.
24. De-Regil, L. M., J. P., Pena-Rosas, A. C., Fernandez-Gaxiola, and P., Rayco-Solon. 2015. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Systematic Review. Cd007950.
25. de Crécy-Lagard, V., B., El Yacoubi, R. D., de la Garza, A., Noiriel, and A. D., Hanson. 2007. Comparative genomics of bacterial and plant folate synthesis and salvage: predictions and validations. BMC Genomics 8 (1):245.
26. de Vries, M. C., E. E., Vaughan, M., Kleerebezem, and W. M., de Vos. 2006. Lactobacillus plantarum—survival, functional and potential probiotic properties in the human intestinal tract. International Dairy Journal. 16 (9):1018–28.
27. den Boer, E., M. C., de Rotte, S. M., Pluijm, S. G., Heil, J. M., Hazes, and R., de Jonge. 2014. Determinants of erythrocyte methotrexate polyglutamate levels in rheumatoid arthritis. The Journal of Rheumatology 41 (11):2167–78.
28. den Hoed, M. A., E., Lopez-Lopez, M. L., Te Winkel, W., Tissing, J. D., de Rooij, A., Gutierrez-Camino, A., Garcia-Orad, E., den Boer, R., Pieters, S. M., Pluijm., et al. 2015. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. The Pharmacogenomics Journal 15 (3):248–54.
29. DeVos, L., A., Chanson, Z., Liu, E. D., Ciappio, L. D., Parnell, J. B., Mason, K. L., Tucker, and J. W., Crott. 2008. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations. The American Journal of Clinical Nutrition 88 (4):1149–58.
30. Divya, J. B., K. K., Varsha, and K. M., Nampoothiri. 2012. Newly isolated lactic acid bacteria with probiotic features for potential application in food industry. Biotechnology and Applied Biochemistry 167:1314–24.
31. Ducker, G. S., and J. D., Rabinowitz. 2017. One-Carbon metabolism in health and disease. Cell Metabolism 25 (1):27–42.
32. Dudeja, P. K., S. A., Torania, and H. M., Said. 1997. Evidence for the existence of a carrier-mediated folate uptake mechanism in human colonic luminal membranes. American Journal of Physiology 272 (6):G1408–15.
33. Duthie, S. J. 2011. Folate and cancer: how DNA damage, repair and methylation impact on Colon carcinogenesis. Journal of Inherited Metabolic Disease 34 (1):101–9.
34. Eden, A., F., Gaudet, A., Waghmare, and R., Jaenisch. 2003. Chromosomal instability and tumors promoted by DNA hypomethylation. Science (New York, N.Y.) 300 (5618):455.
35. EFSA-report. 2014. Scientific opinion on dietary reference values for folate. EFSA Journal 12 (2):3580.
36. Esteller, M. 2008. Epigenetics in cancer. The New England Journal of Medicine 358 (11):1148–59.
37. Estrada, A., D. L., Wright, and A. C., Anderson. 2016. Antibacterial antifolates: From development through resistance to the next generation. Cold Spring Harbor Perspectives in Medicine 6 (8):a028324.
38. Fallingborg, J., L. A., Christensen, M., Ingeman-Nielsen, B. A., Jacobsen, K., Abildgaard, and H. H., Rasmussen. 2007. pH-profile and regional transit times of the normal gut measured by a radiotelemetry device. Alimentary Pharmacology & Therapeutics 3 (6):605–13.
39. Feinberg, A. P. 2018. The key role of epigenetics in human disease prevention and mitigation. The New England Journal of Medicine 378 (14):1323–34.
40. Feinberg, A. P., and B., Vogelstein. 1983. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301 (5895):89–92.
41. Ferreira, H. J., and M., Esteller. 2018. CpG islands in cancer: Heads, tails, and sides. In CpG islands. Methods in molecular biology, ed. T., Vavouri, M., Peinado, vol 1766. New York, NY: Humana Press.
42. Flood, A., J. B., Mason, Z., Liu, B. D., Cash, A., Schatzkin, P. S., Schoenfeld, and A. J., Cross. 2011. Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps. Gut 60 (1):66–72.
43. Galeone, C., V., Edefonti, M., Parpinel, E., Leoncini, K., Matsuo, R., Talamini, A. F., Olshan, J. P., Zevallos, D. M., Winn, V., Jayaprakash, et al. 2015. Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the International Head and Neck Cancer Epidemiology Consortium. International Journal of Cancer 136 (4):904–14.
44. Ganji, V., and M. R., Kafai. 2006. Trends in serum folate, RBC folate, and circulating total homocysteine concentrations in the United States: analysis of data from National Health and Nutrition Examination Surveys, 1988–1994, 1999–2000, and 2001–2002. The Journal of Nutrition 136 (1):153–8.
45. Ganji, V., and M. R., Kafai. 2009. Hemoglobin and hematocrit values are higher and prevalence of anemia is lower in the post-folic acid fortification period than in the pre-folic acid fortification period in US adults. The American Journal of Clinical Nutrition 89 (1):363–71.
46. Gaudet, F., J. G., Hodgson, A., Eden, L., Jackson-Grusby, J., Dausman, J. W., Gray, H., Leonhardt, and R., Jaenisch. 2003. Induction of tumors in mice by genomic hypomethylation. Science (New York, N.Y.) 300 (5618):489–92.
47. Greppi, A., F., Saubade, C., Botta, C., Humblot, J.-P., Guyot, and L., Cocolin. 2017. Potential probiotic pichia kudriavzevii strains and their ability to enhance folate content of traditional cereal-based African fermented food. Food Microbiology 62:169–77.
48. Haffner, M. C., A., Chaux, A. K., Meeker, D. M., Esopi, J., Gerber, L. G., Pellakuru, A., Toubaji, P., Argani, C., Iacobuzio-Donahue, W. G., Nelson., et al. 2011. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2 (8):627–37.
49. Hanks, J., I., Ayed, N., Kukreja, C., Rogers, J., Harris, A., Gheorghiu, C. L., Liu, P., Emery, and M., Pufulete. 2013. The association between MTHFR 677C > T genotype and folate status and genomic and gene-specific DNA methylation in the Colon of individuals without colorectal neoplasia. The American Journal of Clinical Nutrition 98 (6):1564–74.
50. Herceg, Z., A., Ghantous, C. P., Wild, A., Sklias, L., Casati, S. J., Duthie, R., Fry, J. P., Issa, R., Kellermayer, I., Koturbash, et al. 2018. Roadmap for investigating epigenome deregulation and environmental origins of cancer. International Journal of Cancer 142 (5):874–82.
51. Hoey, L., H., McNulty, N., Askin, A., Dunne, M., Ward, K., Pentieva, J. J., Strain, A. M., Molloy, C. A., Flynn, and J. M., Scott. 2007. Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults1–3. The American Journal of Clinical Nutrition 86 (5):1405–13.
52. Honein, M. A., L. J., Paulozzi, T. J., Mathews, J. D., Erickson, and L. Y., Wong. 2001. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285 (23):2981–6.
53. Hsu, C. Y., S. W., Chiu, K. S., Hong, J. L., Saver, Y. L., Wu, J. D., Lee, M., Lee, and B., Ovbiagele. 2018. Folic acid in stroke prevention in countries without mandatory folic acid food fortification: A meta-analysis of randomized controlled trials. Journal of Stroke 20 (1):99–109.
54. Hugenholtz, J., J., Hunik, H., Santos, and E., Smid. 2002. Nutraceutical production by propionibacteria. Le Lait 82 (1):103–12.
55. Institute of Medicine. 1998. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: The National Academies Press.
56. Jaenisch, R., and A., Bird. 2003. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genetics 33 (3s):245–54.
57. Jia, M., X., Gao, Y., Zhang, M., Hoffmeister, and H., Brenner. 2016. Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: A systematic review. Clinical Epigenetics 8 (1):25.
58. Joubert, B. R., H. T., den Dekker, J. F., Felix, J., Bohlin, S., Ligthart, E., Beckett, H., Tiemeier, J. B., van Meurs, A. G., Uitterlinden, A., Hofman, et al. 2016. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide Meta-analysis of newborns. Nature Communications 7:10577.
59. Kanwal, R., and S., Gupta. 2012. Epigenetic modifications in cancer. Clinical Genetics 81 (4):303–11.
60. Kennedy, D. A., S. J., Stern, M., Moretti, I., Matok, M., Sarkar, C., Nickel, and G., Koren. 2011. Folate intake and the risk of colorectal cancer: A systematic review and Meta-analysis. Cancer Epidemiol 35 (1):2–10.
61. Kim, D. H., S. A., Smith-Warner, D., Spiegelman, S. S., Yaun, G. A., Colditz, J. L., Freudenheim, E., Giovannucci, R. A., Goldbohm, S., Graham, L., Harnack, et al. 2010. Pooled analyses of 13 prospective cohort studies on folate intake and Colon cancer. Cancer Causes & Control 21 (11):1919–30.
62. Kim, T. H., J., Yang, P. B., Darling, and D. L., O'Connor. 2004. A large Pool of available folate exists in the large intestine of human infants and piglets. The Journal of Nutrition 134 (6):1389–94.
63. Kim, Y.-I. 2018. Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde? The American Journal of Clinical Nutrition 107 (2):139–42.
64. Kim, Y.-I., K., Fawaz, T., Knox, Y.-M., Lee, R., Norton, E., Libby, and J. B., Mason. 2001a. Colonic mucosal concentrations of folate are accurately predicted by blood measurements of folate status among individuals ingesting physiologic quantities of folate. Cancer Epidemiology Biomarkers & Prevention 10:715–9.
65. Kim, Y. I. 2004. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Preview 13:511–9.
66. Kim, Y. I. 2008. Folic acid supplementation and cancer risk: point. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 17 (9):2220–5.
67. Kim, Y. I., H. W., Baik, K., Fawaz, T., Knox, Y. M., Lee, R., Norton, E., Libby, and J. B., Mason. 2001b. Effects of folate supplementation on two provisional molecular markers of Colon cancer: A prospective, randomized trial. The American Journal of Gastroenterology 96 (1):184–95.
68. Kleerebezem, M., J., Boekhorst, R., van Kranenburg, D., Molenaar, O. P., Kuipers, R., Leer, R., Tarchini, S. A., Peters, H. M., Sandbrink, M. W., Fiers, et al. 2003. Complete genome sequence of Lactobacillus plantarum WCFS1. Proceedings of the National Academy of Sciences of the United States of America 100 (4):1990–5.
69. Kok, D. E., R. A., Dhonukshe-Rutten, C., Lute, S. G., Heil, A. G., Uitterlinden, N., van der Velde, J. B., van Meurs, N. M., van Schoor, G. J., Hooiveld, L. C., de Groot, et al. 2015. The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clinical Epigenetics 7:121.
70. Kok, D. E., W. T., Steegenga, and J. A., McKay. 2018. Folate and epigenetics: why we should not forget bacterial biosynthesis. Epigenomics In press. Accepted for publication on 27th of July 2018.
71. Konings, E. J., H. H., Roomans, E., Dorant, R. A., Goldbohm, W. H., Saris, and P. A., van den Brandt. 2001. Folate intake of the dutch population according to newly established liquid chromatography data for foods. The American Journal of Clinical Nutrition 73 (4):765–76.
72. Krause, L. J., C. W., Forsberg, and D. L., O'Connor. 1996. Feeding human milk to rats increases bifidobacterium in the cecum and Colon which correlates with enhanced folate status. The Journal of Nutrition 126 (5):1505–11.
73. Kulis, M., A. C., Queiros, R., Beekman, and J. I., Martin-Subero. 2013. Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochimica et Biophysica Acta 1829 (11):1161–74.
74. Kumar, C. K., M. P., Moyer, P. K., Dudeja, and H. M., Said. 1997. A protein-tyrosine kinase-regulated, pH-dependent, carrier-mediated uptake system for folate in human normal colonic epithelial cell line NCM460. Journal of Biological Chemistry 272 (10):6226–31.
75. Laiño, J. E., M., Juarez del Valle, G., Savoy de Giori, and J. G. J., LeBlanc. 2014. Applicability of a Lactobacillus amylovorus strain as co-culture for natural folate bio-enrichment of fermented milk. International Journal of Food Microbiology 191:10–6.
76. Lakoff, A., Z., Fazili, S., Aufreiter, C. M., Pfeiffer, B., Connolly, J. F., Gregory, P. B., Pencharz, and D. L., O’Connor. 2014. Folate is absorbed across the human Colon: evidence by using enteric-coated caplets containing 13C-labeled [6S]-5-formyltetrahydrofolate. The American Journal of Clinical Nutrition 100 (5):1278–86.
77. LeBlanc, J. G., J. E., Laino, M. J., del Valle, V., Vannini, D., van Sinderen, M. P., Taranto, G. F., de Valdez, G. S., de Giori, and F., Sesma. 2011. B-group vitamin production by lactic acid bacteria–current knowledge and potential applications. Journal of Applied Microbiology 111 (6):1297–309.
78. LeBlanc, J. G., W., Sybesma, M., Starrenburg, F., Sesma, W. M., de Vos, G. S., de Giori, and J., Hugenholtz. 2010. Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats. Nutrition (Burbank, Los Angeles County, Calif.) 26 (7–8):835–41.
79. LeBlanc, J. G., D., Van Sinderen, J., Hugenholtz, J.-C., Piard, F., Sesma, and G., Savoy de Giori. 2010. Risk assessment of genetically modified lactic acid bacteria using the concept of substantial equivalence. Current Microbiology 61 (6):590–5.
80. Li, P., Q., Zhou, and Q., Gu. 2016. Complete genome sequence of Lactobacillus plantarum LZ227, a potential probiotic strain producing B-group vitamins. Journal of Biotechnology 234:66–70.
81. Lin, M. Y., and C. M., Young. 2000. Folate levels in cultures of lactic acid bacteria. International Dairy Journal 10 (5–6):409–13.
82. Liu, J., L. B Hesson, A. P. Meagher, M. J. Bourke, N. J. Hawkins, K. N. Rand, P. L. Molloy, J. E. Pimanda, and R. L. Ward. 2012. Relative Distribution of Folate Species Is Associated with Global DNA Methylation in Human Colorectal Mucosa. Cancer Prevention Research 5:921–29.
83. Llinàs-Arias, P., and M., Esteller. 2017. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: An update. Open Biology 7 (9):170152.
84. Magnusdottir, S., D., Ravcheev, V., de Crecy-Lagard, and I., Thiele. 2015. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Frontiers in Genetics 6:148.
85. Marco, M. L., T. H., Peters, R. S., Bongers, D., Molenaar, S., van Hemert, J. L., Sonnenburg, J. I., Gordon, and M., Kleerebezem. 2009. Lifestyle of Lactobacillus plantarum in the mouse caecum. Environmental Microbiology 11 (10):2747–57.
86. Mason, J. B., and S. Y., Tang. 2017. Folate status and colorectal cancer risk: A 2016 update. Molecular Aspects of Medicine 53:73–9.
87. McDougall, C. J., R., Wong, P., Scudera, M., Lesser, and J. J., DeCosse. 1993. Colonic mucosal pH in humans. Digestive Diseases and Sciences 38 (3):542–5.
88. McGlynn, A. P., G. R., Wasson, S. L., O'Reilly, H., McNulty, C. S., Downes, C. K., Chang, L., Hoey, A. M., Molloy, M., Ward, J. J., Strain, et al. 2013. Low colonocyte folate is associated with uracil misincorporation and global DNA hypomethylation in human colorectum. The Journal of Nutrition 143 (1):27–33.
89. McNulty, H., and K., Pentieva. 2010. Folate in health and Disease - Chapter 2: Folate bioavailability. Edited by L. B., Bailey. Boca Raton: CRC Press Taylor & Francis Group.
90. Meenan, J., E., O'Hallinan, S., Lynch, A., Molloy, J., McPartlan, J., Scott, and D. G., Weir. 1996. Folate status of gastrointestinal epithelial cells is not predicted by serum and red cell folate values in replete subjects. Gut 38 (3):410–3.
91. Meenan, J., E., O'Hallinan, J., Scott, and D. G., Weir. 1997. Epithelial cell folate depletion occurs in neoplastic but not adjacent normal Colon mucosa. Gastroenterology 112 (4):1163–8.
92. Melse-Boonstra, A., A., De Bree, P., Verhoef, A. L., Bjørke-Monsen, and W. M., Monique Verschuren. 2002. Dietary monoglutamate and polyglutamate folate are associated with plasma folate concentrations in Dutch men and women aged 20–65 years. The Journal of Nutrition 132 (6):1307–12.
93. Milani, C., G. A., Lugli, S., Duranti, F., Turroni, F., Bottacini, M., Mangifesta, B., Sanchez, A., Viappiani, L., Mancabelli, B., Taminiau, et al. 2014. Genomic encyclopedia of type strains of the genus bifidobacterium. Applied and Environmental Microbiology 80 (20):6290–302.
94. Miller, J. W., and C. M., Ulrich. 2013. Folic acid and cancer-where are we today? Lancet (London, England) 381 (9871):974–6.
95. Moazzen, S., R., Dolatkhah, J. S., Tabrizi, J., Shaarbafi, B. Z., Alizadeh, G. H., de Bock, and S., Dastgiri. 2017. Folic acid intake and folate status and colorectal cancer risk: a systematic review and Meta-analysis. Clinical Nutrition.
96. Molloy, A. M. 2010. Folate in health and Disease - Chapter 15: Folate–vitamin B12 Interrelationships - Links to disease risk. Edited by L. B., Bailey. 2nd ed. Boca Raton, FL: CRC press, Taylor and Francis Group.
97. Murtha, M., and M., Esteller. 2016. Extraordinary cancer epigenomics: Thinking outside the classical coding and promoter box. Trends Cancer 2 (10):572–84.
98. Neuhouser, M. L., H. F., Nijhout, J. F., Gregory, M. C., Reed, S. J., James, A., Liu, B., Shane, and C. M., Ulrich. 2011. Mathematical modeling predicts the effect of folate deficiency and excess on cancer related biomarkers. Cancer Epidemiol Biomarkers Preview 20 (9):1912–7.
99. Nijhout, H. F., M. C., Reed, and C. M., Ulrich. 2008. Chapter 2 mathematical models of folate‐mediated one‐carbon metabolism. Vitamins & Hormones 79:45–82.
100. Odin, E., Y. Wettergren, G. Carlsson, and B. Gustavsson. 2013. Determination of reduced folates in tumor and adjacent mucosa of colorectal cancer patients using LC-MS/MS. Biomedical Chromatography 27:487–95.
101. O'Reilly, S. L., A. P., McGlynn, H., McNulty, J., Reynolds, G. R., Wasson, A. M., Molloy, J. J., Strain, D. G., Weir, M., Ward, G., McKerr, et al. 2016. Folic acid supplementation in postpolypectomy patients in a randomized controlled trial increases tissue folate concentrations and reduces aberrant DNA biomarkers in colonic tissues adjacent to the former polyp site. The Journal of Nutrition 146 (5):933–9.
102. Pauwels, S., M., Ghosh, R. C., Duca, B., Bekaert, K., Freson, I., Huybrechts, S., Langie, G., Koppen, R., Devlieger, and L., Godderis. 2017. Dietary and supplemental maternal methyl-group donor intake and cord blood DNA methylation. Epigenetics 12 (1):1–10.
103. Pfeiffer, C. M., S. P., Caudill, E. W., Gunter, J., Osterloh, and E. J., Sampson. 2005. Biochemical indicators of B vitamin status in the US population after folic acid fortification: Results from the National Health and Nutrition Examination Survey 1999–2000. The American Journal of Clinical Nutrition 82 (2):442–50.
104. Pokusaeva, K., G. F., Fitzgerald, and D., van Sinderen. 2011. Carbohydrate metabolism in bifidobacteria. Genes Nutrition 6 (3):285–306.
105. Pompei, A., L., Cordisco, A., Amaretti, S., Zanoni, D., Matteuzzi, and M., Rossi. 2007. Folate production by bifidobacteria as a potential probiotic property. Applied and Environmental Microbiology 73 (1):179–85.
106. Pompei, A., L., Cordisco, A., Amaretti, S., Zanoni, S., Raimondi, D., Matteuzzi, and M., Rossi. 2007. Administration of folate-producing bifidobacteria enhances folate status in Wistar rats. The Journal of Nutrition 137 (12):2742–6.
107. Porter, K., L., Hoey, C. F., Hughes, M., Ward, and H., McNulty. 2016. Causes, consequences and public health implications of low B-Vitamin Status in ageing. Nutrients 8:E725.
108. Powers, H. J., M. H., Hill, M., Welfare, A., Spiers, W., Bal, J., Russell, Y., Duckworth, E., Gibney, E. A., Williams, and J. C., Mathers. 2007. Responses of biomarkers of folate and riboflavin status to folate and riboflavin supplementation in healthy and colorectal polyp patients (the FAB2 study). Cancer Epidemiology Biomarkers & Prevention 16 (10):2128–35.
109. Protiva, P., J. B., Mason, Z., Liu, M. E., Hopkins, C., Nelson, J. R., Marshall, R. W., Lambrecht, S., Pendyala, L., Kopelovich, M., Kim, et al. 2011. Altered folate availability modifies the molecular environment of the human colorectum: Implications for colorectal carcinogenesis. Cancer Prevention Research 4 (4):530–43.
110. Qiu, A., M., Jansen, A., Sakaris, S. H., Min, S., Chattopadhyay, E., Tsai, C., Sandoval, R., Zhao, M. H., Akabas, and I. D., Goldman. 2006. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127 (5):917–28.
111. Quinlivan, E. P., and J. F., Gregory, 3rd. 2003. Effect of food fortification on folic acid intake in the United States. The American Journal of Clinical Nutrition 77 (1):221–5.
112. Reidy, J. A. 1988. Role of deoxyuridine incorporation and DNA repair in the expression of human chromosomal fragile sites. Mutation Research 200 (1–2):215–20.
113. Rivière, A., M., Selak, D., Lantin, F., Leroy, and L., De Vuyst. 2016. Bifidobacteria and Butyrate-Producing Colon bacteria: Importance and strategies for their stimulation in the human gut. Frontiers in Microbiology 7:979.
114. Rong, N., J., Selhub, B. R., Goldin, and I. H., Rosenberg. 1991. Bacterially synthesized folate in rat large intestine is incorporated into host tissue folyl polyglutamates. The Journal of Nutrition 121 (12):1955–9.
115. Rossi, M., A., Amaretti, and S., Raimondi. 2011. Folate production by probiotic bacteria. Nutrients 3 (1):118–34.
116. Rossi, M., S., Raimondi, L., Costantino, and A., Amaretti. 2016. Folate: Relevance of chemical and microbial production. In: Industrial Biotechnology of Vitamins, Biopigments, and Antioxidants, eds. E. J. Vandamme and J. L. Revuelta, Chapter 5, 103–128. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co.
117. Said, H. M. 2013. Recent advances in transport of water-soluble vitamins in organs of the digestive system: A focus on the Colon and the pancreas. American Journal of Physiology Gastrointestinal and Liver Physiology 305 (9):G601–10.
118. Said, H. M., and Z. M., Mohammed. 2006. Intestinal absorption of water-soluble vitamins: an update. Current Opinion in Gastroenterology 22 (2):140–6.
119. Santos, F., A., Wegkamp, W. M., de Vos, E. J., Smid, and J., Hugenholtz. 2008. High-Level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112. Applied and Environmental Microbiology 74 (10):3291–4.
120. Saubade, F., Y. M., Hemery, J. P., Guyot, and C., Humblot. 2017. Lactic acid fermentation as a tool for increasing the folate content of foods. Critical Reviews in Food Science and Nutrition 57 (18):3894–910.
121. Sawaengsri, H., J., Wang, C., Reginaldo, J., Steluti, D., Wu, S. N., Meydani, J., Selhub, and L., Paul. 2016. High folic acid intake reduces natural killer cell cytotoxicity in aged mice. The Journal of Nutritional Biochemistry 30:102–7.
122. Scott, J. M. 1999. Folate and vitamin B12. The Proceedings of the Nutrition Society 58 (2):441–8.
123. Sepehr, E., R. W., Peace, K. B., Storey, P., Jee, B. J., Lampi, and S. P., Brooks. 2003. Folate derived from cecal bacterial fermentation does not increase liver folate stores in 28-d folate-depleted male Sprague-Dawley rats. The Journal of Nutrition 133 (5):1347–54.
124. Smith, A. D., and H., Refsum. 2016. Homocysteine, B vitamins, and cognitive impairment. Annual Review of Nutrition 36:211–39.
125. Steegers-Theunissen, R. P., S. A., Obermann-Borst, D., Kremer, J., Lindemans, C., Siebel, E. A., Steegers, P. E., Slagboom, and B. T., Heijmans. 2009. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 4(11):e7845.
126. Strozzi, G. P., and L., Mogna. 2008. Quantification of folic acid in human feces after administration of bifidobacterium probiotic strains. Journal of Clinical Gastroenterology 42 (Suppl 3 Pt 2):S179–S84.
127. Sugahara, H., T., Odamaki, N., Hashikura, F., Abe, and J. Z., Xiao. 2015. Differences in folate production by bifidobacteria of different origins. Bioscience of Microbiota, Food and Health 34 (4):87–93.
128. Sybesma, W., J., Hugenholtz, W. M. D, Vos, and E. J., Smid. 2006. Safe use of genetically modified lactic acid bacteria in food. Bridging the gap between consumers, green groups, and industry. Electronic Journal of Biotechnology 9 (4):12.
129. Sybesma, W., M., Starrenburg, M., Kleerebezem, I., Mierau, W. M., de Vos, and J., Hugenholtz. 2003. Increased production of folate by metabolic engineering of Lactococcus lactis. Applied Environmental Microbiology 69 (6):3069–76.
130. Sybesma, W., M., Starrenburg, L., Tijsseling, M. H. N., Hoefnagel, and J., Hugenholtz. 2003. Effects of cultivation conditions on folate production by lactic acid bacteria. Applied and Environmental Microbiology 69 (8):4542–8.
131. Thoma, C., T. J., Green, and L. R., Ferguson. 2003. Citrus pectin and oligofructose improve folate status and lower serum total homocysteine in rats. International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- Und Ernahrungsforschung. Journal International de Vitaminologie et de Nutrition 73 (6):403–9.
132. Tomar, S. K., N., Srivatsa, R., Iyer, and R., Singh. 2009. Estimation of folate production by Streptococcus thermophilus using modified microbiological assay. Milchwissenschaft 64:260–3.
133. Troen, A. M., B., Mitchell, B., Sorensen, M. H., Wener, A., Johnston, B., Wood, J., Selhub, A., McTiernan, Y., Yasui, E., Oral, et al. 2006. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. The Journal of Nutrition 136 (1):189–94.
134. Ulrich, C. M. 2007. Folate and cancer prevention: A closer look at a complex picture. The American Journal of Clinical Nutrition 86 (2):271–3.
135. Ulrich, C. M., and J. D., Potter. 2007. Folate and cancer-timing is everything. JAMA 297 (21):2408–9.
136. van den Donk, M., L., Pellis, J. W., Crott, M., van Engeland, P., Friederich, F. M., Nagengast, J. D., van Bergeijk, S. Y., de Boer, J. B., Mason, F. J., Kok, et al. 2007. Folic acid and vitamin B-12 supplementation does not favorably influence uracil incorporation and promoter methylation in rectal mucosa DNA of subjects with previous colorectal adenomas. The Journal of Nutrition 137 (9):2114–20.
137. Verhoef, H., J., Veenemans, M. N., Mwangi, and A. M., Prentice. 2017. Safety and benefits of interventions to increase folate status in malaria-endemic areas. British Journal of Haematology 177 (6):905–18.
138. Vesa, T., P., Pochart, and P., Marteau. 2000. Pharmacokinetics of Lactobacillus plantarum NCIMB 8826, Lactobacillus fermentum KLD, and Lactococcus lactis MG 1363 in the human gastrointestinal tract. Aliment Pharmacology & Therapeutics 14:823–8.
139. Visentin, M., N., Diop-Bove, R., Zhao, and I. D., Goldman. 2014. The intestinal absorption of folates. Annual Review of Physiology 76:251–74.
140. Wang, Z. M., B., Zhou, Z. L., Nie, W., Gao, Y. S., Wang, H., Zhao, J., Zhu, J. J., Yan, Z. J., Yang, and L. S., Wang. 2012. Folate and risk of coronary heart disease: a Meta-analysis of prospective studies. Nutrition, Metabolism, and Cardiovascular Diseases 22 (10):890–9.
141. Waterland, R. A., and R. L., Jirtle. 2003. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology 23 (15):5293–300.
142. WCRF/AICR. 2017. World Cancer Research Fund/American Institute for Cancer Research. The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer Continuous Update Project and Systematic Literature Review for Colorectal Cancer. Available at https://www.wcrf.org/dietandcancer/colorectal-cancer. Date revised 06/09/2017. Accessed at June 22, 2018.
143. Weber, M., J. J., Davies, D., Wittig, E. J., Oakeley, M., Haase, W. L., Lam, and D., Schubeler. 2005. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genetics 37 (8):853–62.
144. Wegkamp, A., W. M., De Vos, and E. J., Smid. 2009. Folate overproduction in Lactobacillus plantarum WCFS1 causes methotrexate resistance. FEMS Microbiology Letters 297 (2):261–5.
145. Wegkamp, A., A. E., Mars, M., Faijes, D., Molenaar, R. C. H., de Vos, S. M. J., Klaus, A. D., Hanson, W. M., de Vos, and E. J., Smid. 2010. Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1. Microbial Cell Factories 9 (1):100.
146. Wegkamp, A., M., Starrenburg, W. M., de Vos, J., Hugenholtz, and W., Sybesma. 2004. Transformation of folate-consuming Lactobacillus gasseri into a folate producer. Applied and Environmental Microbiology 70 (5):3146–8.
147. Wegkamp, A., W., van Oorschot, W. M., de Vos, and E. J., Smid. 2007. Characterization of the role of Para-aminobenzoic acid biosynthesis in folate production by Lactococcus lactis. Applied and Environmental Microbiology 73 (8):2673–81.
148. WHO. 2012. WHO. Serum and red blood cell folate concentrations for assessing folate status in populations. Vitamin and mineral nutrition information system. Geneva: World Health Organization, 2012. http://apps.who.int/iris/bitstream/handle/10665/75584/WHO_NMH_NHD_EPG_12.1_eng.pdf;sequence=1. Accessed June 1, 2018.
149. Williams, E. A., M., Welfare, A., Spiers, M. H., Hill, W., Bal, E. R., Gibney, Y., Duckworth, H. J., Powers, and J. C., Mathers. 2013. Systemic folate status, rectal mucosal folate concentration and dietary intake in patients at differential risk of bowel cancer (the FAB2 study). European Journal of Nutrition 52 (7):1801–10.
150. Winkels, R. M., I. A., Brouwer, E., Siebelink, M. B., Katan, and P., Verhoef. 2007. Bioavailability of food folates is 80% of that of folic acid. The American Journal of Clinical Nutrition 85 (2):465–73.
151. Wolff, T., C. T., Witkop, T., Miller, and S. B., Syed. 2009. Folic acid supplementation for the prevention of neural tube defects: An update of the Evidence for the U.S. Preventive Services Task Force. Annals of Internal Medicine 150 (9):632–9.
152. Wright, A. J., P. M., Finglas, J. R., Dainty, D. J., Hart, C. A., Wolfe, S., Southon, and J. F., Gregory. 2003. Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of folate bioavailability studies. British Journal of Nutrition 90 (2):363–71.
153. Yan, M., C., Ho, E., Winquist, D., Jonker, D., Rayson, L., Stitt, S., Tokmakejian, A., Tomiak, and M. D., Vincent. 2016. Pretreatment serum folate levels and toxicity/efficacy in colorectal cancer patients treated with 5-Fluorouracil and folinic acid. Clinical Colorectal Cancer 15 (4):369–76.e363.
154. Yang, Q., L. D., Botto, J. D., Erickson, R. J., Berry, C., Sambell, H., Johansen, and J. M., Friedman. 2006. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113 (10):1335–43.
155. Yeung, L., Q., Yang, and R. J., Berry. 2008. Contributions of total daily intake of folic acid to serum folate concentrations. JAMA 300 (21):2486–7.
156. Yu, M. B., A., Firek, and W. H. R., Langridge. 2018. Predicting methotrexate resistance in rheumatoid arthritis patients. Inflammopharmacology 26 (3):699–708.
157. Zhao, R., S., Aluri, and I. D., Goldman. 2017. The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption. Molecular Aspects of Medicine 53:57–72.