High-Dose Folic Acid Supplementation and its Impact on the Gut Normal Flora
Keywords:
Folic acid supplementation, High-dose folate, Gut microbiota, Dysbiosis, Microbial diversityAbstract
Due to its therapeutic and preventive uses, especially in the treatment of chronic illnesses and during pregnancy, high-dose folic acid supplementation has drawn attention from all over the world. Despite being widely regarded as safe, high folic acid consumption has sparked growing concerns about possible impacts upon the usual bacteria in the stomach. Because it aids in immunological regulation, food metabolism, and pathogen defense, the gut microbiota is vital to human health. The research that is now available, however, indicates that this balance might be upset by supraphysiological folic acid intake. High doses of folic acid have been shown in both clinical and experimental investigations to suppress beneficial bacterial species like Lactobacillus and Bifidobacterium, decrease microbial diversity, and increase dysbiosis. Intestinal barrier function, host-microbe interactions, and disease susceptibility may all be affected by such changes. However, high-dose supplementation may be beneficial for some pathological diseases, such as cardiovascular illnesses, pregnancy-related difficulties, and folate insufficiency. This duality emphasizes how folic acid interacts with the gut microbiota to shape host health in a complicated way. Given how common fortified foods and supplements are, more research is desperately needed to understand dose-dependent effects, determine safe supplementation limits, and investigate the long-term impacts of changes in the gut microbiota.References
[1] Wang, P., Zhang, X., Zheng, X., Gao, J., Shang, M., Xu, J., & Liang, H. (2022). Folic acid protects against hyperuricemia in C57BL/6J mice via ameliorating gut–kidney axis dysfunction. Journal of Agricultural and Food Chemistry, 70(50), 15787-15803. [HTML]
[2] Mölzer, C., Wilson, H. M., Kuffova, L., & Forrester, J. V. (2021). A Role for Folate in Microbiome‐Linked Control of Autoimmunity. Journal of Immunology Research, 2021(1), 9998200. wiley.com
[3] J. Henry, C., Nemkov, T., Casás-Selves, M., Bilousova, G., Zaberezhnyy, V., C. Higa, K., J. Serkova, N., C. Hansen, K., D’Alessandro, A., & DeGregori, J. (2017). Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis. ncbi.nlm.nih.gov
[4] Chen, S., Yang, M., Wang, R., Fan, X., Tang, T., Li, P., ... & Qi, K. (2022). Suppression of high-fat-diet-induced obesity in mice by dietary folic acid supplementation is linked to changes in gut microbiota. European Journal of Nutrition, 61(4), 2015-2031. [HTML]
[5] Institute of Medicine (IOM). (1998). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academies Press. https://doi.org/10.17226/6015
[6] Bailey, R. L., Fulgoni, V. L., Keast, D. R., & Dwyer, J. T. (2010). Dietary supplement use is associated with higher intakes of minerals from food sources. American Journal of Clinical Nutrition, 91(2), 535–546. https://doi.org/10.3945/ajcn.2009.28339
[7] World Health Organization (WHO). (2015). Guideline: Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects. Geneva: World Health Organization.
[8] Spreadbury, J. (2013). Folic Acid and Its Receptors. [PDF]
[9] Hafiza, U., Ahmad, W., Hina, N., Shoaib, A. M., Saleem, K. M., & Muhammad, W. (2024). Association of vitamin deficiency with the progression of anaemia. The Egyptian Journal of Haematology, 49(2), 115-120. lww.com
[10] Thabit, J. A., & Almzaiel, A. J. (2023). Emerging Role of Folate-Mediated One Carbon Metabolism in Leukemia: A Review. Egyptian Academic Journal of Biological Sciences. C, Physiology and Molecular Biology, 15(2), 215-229. ekb.eg
[11] Bai, Y., Herforth, A., & Masters, W. A. (2022). Global variation in the cost of a nutrient-adequate diet by population group: an observational study. The Lancet Planetary Health. thelancet.com
[12] Maynard, C., Cummins, I., Green, J., & Weinkove, D. (2018). A bacterial route for folic acid supplementation.. [PDF]
[13] Van Hul, M., Cani, P. D., Petitfils, C., De Vos, W. M., Tilg, H., & El-Omar, E. M. (2024). What defines a healthy gut microbiome? Gut, 73(11), 1893-1908. bmj.com
[14] He, Q. & Li, J. (2023). The evolution of folate supplementation–from one size for all to personalized, precision, poly-paths. Journal of Translational Internal Medicine. degruyterbrill.com
[15] Zheng, X., Xia, C., Liu, M., Wu, H., Yan, J., Zhang, Z., ... & Li, P. (2024). Role of folic acid in regulating gut microbiota and short-chain fatty acids based on an in vitro fermentation model. Applied Microbiology and Biotechnology, 108(1), 40. springer.com
[16] van der Windt, M., Schoenmakers, S., van Rijn, B., Galjaard, S., Steegers-Theunissen, R., & van Rossem, L. (2021). Epidemiology and (patho) physiology of folic acid supplement use in obese women before and during pregnancy. Nutrients, 13(2), 331. mdpi.com
[17] Rudzka, A., Kapusniak, K., Zielińska, D., Kołożyn-Krajewska, D., Kapusniak, J., & Barczyńska-Felusiak, R. (2024). The Importance of Micronutrient Adequacy in Obesity and the Potential of Microbiota Interventions to Support It. Applied Sciences, 14(11), 4489. mdpi.com
[18] Megala, G. & Kavitha, M. (2025). Folate from probiotic bacteria and its therapeutic applications. Archives of Microbiology. [HTML]
[19] Choi, J. H., Yates, Z., Veysey, M., Heo, Y. R., & Lucock, M. (2014). Contemporary Issues Surrounding Folic Acid Fortification Initiatives. ncbi.nlm.nih.gov
[20] Oliver, A., B. Chase, A., Weihe, C., B. Orchanian, S., F. Riedel, S., L. Hendrickson, C., Lay, M., Massimelli Sewall, J., B. H. Martiny, J., & Whiteson, K. (2021). High-Fiber, Whole-Food Dietary Intervention Alters the Human Gut Microbiome but Not Fecal Short-Chain Fatty Acids. ncbi.nlm.nih.gov
[21] Sun, X., Wen, J., Guan, B., Li, J., Luo, J., Li, J., ... & Qiu, H. (2022). Folic acid and zinc improve hyperuricemia by altering the gut microbiota of rats with high-purine diet-induced hyperuricemia. Frontiers in microbiology, 13, 907952. frontiersin.org
[22] Wan, Z., Zheng, J., Zhu, Z., Sang, L., Zhu, J., Luo, S., ... & He, H. (2022). Intermediate role of gut microbiota in vitamin B nutrition and its influences on human health. Frontiers in nutrition, 9, 1031502. frontiersin.org
[23] T. Otten, A., R. Bourgonje, A., Peters, V., Z. Alizadeh, B., Dijkstra, G., & J. M. Harmsen, H. (2021). Vitamin C Supplementation in Healthy Individuals Leads to Shifts of Bacterial Populations in the Gut—A Pilot Study. ncbi.nlm.nih.gov
[24] Dricot, C. E., Erreygers, I., Cauwenberghs, E., De Paz, J., Spacova, I., Verhoeven, V., ... & Lebeer, S. (2024). Riboflavin for women’s health and emerging microbiome strategies. npj Biofilms and Microbiomes, 10(1), 107. nature.com
[25] Ma, H., Liu, H., Yang, Y., Han, M., & Jiang, C. (2025). The effect of folate deficiency and different doses of folic acid supplementation on liver diseases. British Journal of Nutrition. [HTML]
[26] Liu, Y., Yang, J., Liu, X., Liu, R., Wang, Y., Huang, X., ... & Yang, X. (2023). Dietary folic acid addition reduces abdominal fat deposition mediated by alterations in gut microbiota and SCFA production in broilers. Animal Nutrition, 12, 54-62. sciencedirect.com
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