Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) and MTHFR

Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) and MTHFR

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder
Last updated:
IBS, IBD and MTHFR | MTHFR | Methyl-Life® Supplements Source: YouTube.com

What is IBS?

Irritable bowel syndrome (IBS) is a functional bowel disorder that causes abdominal pain and changes in bowel function. People with IBS may experience diarrhea, constipation, or both1. IBS is one of the most common gastrointestinal disorders, affecting around 7-16% of the US population2. Symptoms can have a significant impact on daily life if not managed.

What is IBD?

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract that involves recurring episodes of intestinal inflammation.

IBD predominantly comprises two different conditions: ulcerative colitis (UC) and Crohn's disease (CD).
IBD is complex and can be influenced by a wide range of factors, including genetic predisposition, immune dysregulation, microbiome imbalances, diet, and downstream processes related to micronutrient deficiencies and impaired homocysteine metabolism3.

Folate deficiency and IBD

People with IBD (both Crohn’s disease and ulcerative colitis) are often lower in folate than healthy individuals. 

There may be several causes for this, including impaired absorption due to intestinal damage; reduced intake of folate (avoiding foods such as legumes, fruits, and green vegetables) and inflammation, which can deplete folate stores faster. 

The medication sulfasalazine is a first-line treatment for ulcerative colitis but inhibits folate absorption. This inhibition has been shown to lead to folate deficiency in patients that consequently increases risk of megaloblastic anemia, as well as neural defects in children.
For this reasons, sulfasalazine is prescribed alongside folic acid, usually in elevated doses of 1–5 mg/day (compared to standard recommended intake of 0.4 mg/day)4. IBD patients taking sulfasalazine should monitor their folate levels regularly.

Methotrexate (MTX) (for rheumatoid arthritis), can also inhibit folate absorption5. Methotrexate also exerts its anticancer effects by inhibiting dihydrofolate reductase (DHFR), thereby disrupting folate metabolism.

Connection between MTHFR and bowel diseases

Several studies have investigated whether a link between MTHFR variants and IBD exists, but findings are inconsistent.

One study reported an increased risk of Crohn’s disease in certain Jewish populations, while another study in Moroccan populations found no significant link6,7.

Older studies have found a higher prevalence of the MTHFR C677T mutation in people with IBD, as well as lower folate and B12, and higher homocysteine levels8.

However, a 2021 meta-analysis found that the MTHFR A1298C variant was associated with IBD, but not MTHFR C677T. This meta-analysis also found that A1298C appeared to be linked to a higher risk of developing ulcerative colitis rather than Crohn’s9. 

It should be noted that hyper-homocysteinemia and folate deficiency are both found to be common in IBD and MTHFR. High homocysteine is linked to oxidative stress, poor antioxidant capacity and endothelial damage, which can lead to inflammation and damage to the intestinal barrier10.

Can methylfolate be a treatment for bowel diseases?

Studies have indicated that folate deficiency is common in patients with Crohn’s disease, along with B12 deficiency. This may be due to malabsorption in the intestine, intestinal bacterial overgrowth, reduced vitamin intake and increased demand11. Methotrexate is often prescribed for IBD patients, which inhibits folate metabolism. 

Folate plays an important role in the bowel as it is required for nucleic acid production, protein synthesis, and amino acid conversion, all of which are involved in the growth and regulation of cell functions12.

Folate is also shown to help control the chronic inflammation in IBD by decreasing the expression of major inflammatory proteins in the bod.13. A meta-analysis found that supplementation of folic acid may play a protective role against the development of colorectal cancer. However, it is important to note that the use of folic acid in preventing cancer in IBD patients has not been substantiated in large studies, and the European Crohn's and Colitis Organisation does not recommend folic acid as a preventative measure14. Folic acid is poorly metabolized in people with MTHFR genetic variants (up to 60% of the US population). The only form of folate that can bypass the MTHFR variant is the active form, methylfolate, which is available in supplements15.

Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) and MTHFR

Key takeaways

  • Icon IBD is a chronic inflammatory disease affecting the bowel and includes ulcerative colitis (UC) and Crohn's disease (CD).
  • Icon Folate deficiency is common in people with IBD due to malabsorption disorders (such as celiac disease) diet, and medications.
  • Icon Although methylfolate supplementation for IBD has not been studied, folic acid has been shown to reduce inflammation.

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Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) and MTHFR

Frequently Asked Questions about MTHFR and bowel diseases

Can MTHFR mutation cause IBS?

No, there is no evidence to suggest that MTHFR mutations directly cause IBS. However, MTHFR mutations can lead to reduced folate and B12 levels, which can then increase the risk of inflammatory conditions due to higher homocysteine and poor methylation. Inflammation may play a role in the development of IBS16.
It is also worth noting that serotonin is considered one of the main pathophysiological factors for IBS, as enteric serotonin is responsible for gut motility, visceral hypersensitivity, and inflammation17. The MTHFR variant can lead to reduced levels of serotonin, which may indirectly link MTHFR to IBS.

Can methylfolate help with IBS issues?

Studies involving methylfolate and IBS are currently limited. However, some research has shown that supplementation of folic acid (along with other methyl donors) may help in modulating inflammation. Methylfolate is the bioavailable form of folic acid and is immediately absorbed by the body, while folic acid must undergo a conversion process. A significant percentage of individuals with IBS also experience anxiety or depression, and L-methylfolate is found to be an effective adjunctive for enhancing the effects of antidepressants and the production of serotonin18. This may be helpful for IBS patients, even if they have to purchase methylfolate OTC.

Can low folate cause IBS?

While low folate is not shown to cause IBS, people with IBS are found to have low folate levels. This is usually due to malabsorption in the intestines, poor dietary intake, and certain medications. European Crohn's and Colitis Organisation guidelines recommend that IBD patients taking methotrexate should supplement with folate every 2-3 days to reduce the risk of deficiency.

References

  1. Gerald J Holtmann, Alexander C Ford, Nicholas J Talley; "Pathophysiology of irritable bowel syndrome"; The lancet. Gastroenterology & hepatology; 2016 Oct

    https://pubmed.ncbi.nlm.nih.gov/28404070/

  2. Ami D Sperber, Shrikant I Bangdiwala, Douglas A Drossman, Uday C Ghoshal, Magnus Simren, Jan Tack, William E Whitehead, Dan L Dumitrascu, Xuicai Fang, Shin Fukudo, John Kellow, Edith Okeke, Eamonn M M Quigley, Max Schmulson, Peter Whorwell, Timothy Archampong, Payman Adibi, Viola Andresen, Marc A Benninga, Bruno Bonaz, Serhat Bor, Luis Bustos Fernandez, Suck Chei Choi, Enrico S Corazziari, Carlos Francisconi, Albis Hani, Leonid Lazebnik, Yeong Yeh Lee, Agata Mulak, M Masudur Rahman, Javier Santos, Mashiko Setshedi, Ari Fahrial Syam, Stephen Vanner, Reuben K Wong, Aurelio Lopez-Colombo, Valeria Costa, Ram Dickman, Motoyori Kanazawa, Ammar Hassanzadeh Keshteli, Rutaba Khatun, Iradj Maleki, Pierre Poitras, Nitesh Pratap, Oksana Stefanyuk, Sandie Thomson, Judith Zeevenhooven, Olafur S Palsson; "Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study"; Gastroenterology; 2021 Jan

    https://pubmed.ncbi.nlm.nih.gov/32294476/

  3. M Chen, B Xia, R M Rodriguez-Gueant, M Bigard, J-L Gueant; "Genotypes 677TT and 677CT+1298AC of methylenetetrahydrofolate reductase are associated with the severity of ulcerative colitis in central China"; Gut; 2005 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC1774509/

  4. Mario-Livio Jeličić, Edvin Brusač, Stanislav Kurajica, Matija Cvetnić, Daniela Amidžić Klarić, Biljana Nigović, Ana Mornar; "Drug–Drug Compatibility Evaluation of Sulfasalazine and Folic Acid for Fixed-Dose Combination Development Using Various Analytical Tools"; Pharmaceutics; 2021 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8002613/

  5. Xiaojuan Li, Yedong Hu MD, Xiaodan Shi, Xinyan Zhu, Fei Liu; "Prevalence and relevant factors of micronutrient deficiencies in hospitalized patients with inflammatory bowel disease"; Nutrition; 2022

    https://linkinghub.elsevier.com/retrieve/pii/S0899900722000831

  6. Amir Karban, Tzah Feldman, Matti Waterman, Ronit Leiba Edna Efrati, Ingrid Arijs; "The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population"; 2016 Dec

    https://journals.lww.com/md-journal/fulltext/2016/12230/the_association_of_the_mthfr_c677t_polymorphism.20.aspx

  7. Nezha Senhaji, Nadia Serbati, Brehima Diakité, Sofia Arazzakou, Khalil Hamzi, Wafaa Badre, Sellama Nadifi; "Methylenetetrahydrofolate reductase C677T variant in Moroccan patients with inflammatory bowel disease"; Gene; 2013 May

    https://www.sciencedirect.com/science/article/abs/pii/S0378111913002965

  8. N Mahmud, A Molloy, J McPartlin, R Corbally, A S Whitehead, J M Scott, D G Weir; "Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications"; Gut; 1999 Sep

    https://pubmed.ncbi.nlm.nih.gov/10446107/

  9. M Chen, B Xia, R M Rodriguez-Gueant, M Bigard, J-L Gueant; "Genotypes 677TT and 677CT+1298AC of methylenetetrahydrofolate reductase are associated with the severity of ulcerative colitis in central China"; Gut; 2005 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC1774509/

  10. Tanmoy Rana; "Influence and Implications of the Molecular Paradigm of Nitric Oxide Underlying Inflammatory Reactions of the Gastrointestinal Tract of Dog: A Major Hallmark of Inflammatory Bowel Disease"; Inflammatory bowel diseases; 2022 Aug

    https://pubmed.ncbi.nlm.nih.gov/35312776/

  11. Fakhira Hassan Nazki, Aga Syed Sameer, Bashir Ahmad Ganaie; "Folate: Metabolism, genes, polymorphisms and the associated diseases"; Gene; 2014 Jan

    https://www.sciencedirect.com/science/article/abs/pii/S0378111913012687

  12. Alicja Ewa Ratajczak, Aleksandra Szymczak-Tomczak, Anna Maria Rychter, Agnieszka Zawada, Agnieszka Dobrowolska, Iwona Krela-Kaźmierczak; "Does Folic Acid Protect Patients with Inflammatory Bowel Disease from Complications?"; Nutrients; 2021 Nov

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8618862/

  13. Mirian Samblas, J. Alfredo Martínez, Fermín Milagro; "Folic Acid Improves the Inflammatory Response in LPS-Activated THP-1 Macrophages"; Mediators of Inflammation; 2018 July

    https://onlinelibrary.wiley.com/doi/full/10.1155/2018/1312626

  14. Shaji Sebastian, Hernandez Vincent Hernández, Pär Myrelid, Revital Kariv, Epameinondas Tsianos, Murat Toruner, Marc Marti-Gallostra, Antonino Spinelli, Andrea E. van der Meulen-de Jong, Elif Sarıtas Yuksel, Christoph Gasche, Sandro Ardizzone, Silvio Danese; "Colorectal cancer in inflammatory bowel disease: Results of the 3rd ECCO pathogenesis scientific workshop"; Journal of Crohn's and Colitis; 2014 Jan

    https://academic.oup.com/ecco-jcc/article-abstract/8/1/5/1820999

  15. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine; 2022 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836

  16. Qin Xiang Ng, Alex Yu Sen Soh, Wayren Loke, Donovan Yutong Lim, Wee-Song Yeo; "The role of inflammation in irritable bowel syndrome (IBS)"; Journal of inflammation research; 2018 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6159811/

  17. Ilmaben S Vahora, Nicholas Tsouklidis, Rajat Kumar, Ravi Soni, Safeera Khan; "How Serotonin Level Fluctuation Affects the Effectiveness of Treatment in Irritable Bowel Syndrome"; Cureus; 2020 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7505258/

  18. Vladimir Maletic, Richard Shelton, Valerie Holmes; "A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder"; The primary care companion for CNS disorder; 2023 May

    https://pubmed.ncbi.nlm.nih.gov/37192264/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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