MTHFR and gut health

MTHFR and gut health

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - BSN, RN

Edited By:

Kari Asadorian - BSN, RN

Updated On:

March 22, 2025

MTHFR and gut health

Your gut microbiome influences almost every system in your body, from your digestion and metabolism to your immune system, skin health and even your mood.

Impaired methylation due to low folate levels may be linked to poor gut health.

How does the MTHFR gene affect the gut?

The MTHFR enzyme is essential for producing methylfolate, which is then required for converting homocysteine to methionine and enabling DNA methylation.


Methylation plays a vital role in gut health by regulating processes such as gene expression in cells lining the gut, immune responses and availability of key nutrients - all of which may affect the composition and function of the gut microbiota.


When MTHFR isn’t functioning efficiently - as is the case with common C677T or A1298C genetic mutations - methylation is impaired. MTHFR gene mutations are well-studied and have been linked to elevated plasma homocysteine levels and decreased capacity for folate regeneration in its active form.1


This can affect many downstream processes linked to the gut, including:

  • Repair and maintenance of the gut lining
    Altered methylation patterns may affect the development and function of gastrointestinal cells, as well as the ability of the gut lining to repair itself. Many gastrointestinal conditions- including inflammatory bowel diseases (IBD), certain colorectal cancers, and other dysfunctions in the gastrointestinal tract - have been indirectly linked to irregular DNA methylation.2

  • Dysbiosis
    Folate deficiency can disrupt the balance of gut microbiota by impairing the growth and activity of folate-dependent or folate-producing bacteria.
    Studies show that low folate levels are linked to gut dysbiosis in conditions such as inflammatory bowel disease. Folate deficiency can lead to diminished populations of beneficial folate-producing microbes such as Streptococcus and Lactococcus, which can then affect the overall balance of the microbiome. Dysbiosis (an imbalance of healthy bacteria) can increase oxidative stress and inflammation.
    However, restoring folate levels - either through diet or supplements - may help to restore microbial balance and normalize folate and homocysteine levels.3

  • Inflammation and Oxidative Stress
    The MTHFR genetic mutation can lead to a reduction in S-adenosylmethionine (SAMe) and an increase in homocysteine, which can then increase levels of oxidative stress.4 Vitamin B12 and methionine synthase may also be impaired or inactivated by oxidative stress, which further compromises methylation.5 Imbalances in the microbiome may also affect the synthesis of glutathione, the body’s major antioxidant and another nutrient involved in gut health.6 Glutamine is required for enterocyte proliferation, regulation of tight junction proteins, suppressing inflammatory processes and protecting intestinal cells against apoptosis and cellular stress.7

MTHFR and leaky gut

Although MTHFR is not directly associated with causing leaky gut syndrome, some research has shown that MTHFR-related conditions can lead to increased intestinal permeability.


Elevated homocysteine is a common consequence of MTHFR mutations due to low folate levels and poor methylation.8 Studies have shown that  high homocysteine can increase inflammatory processes, leading to injury of the intestinal barrier and intestinal permeability.9

Recent research in lupus patients shows that increased intestinal permeability is associated with widespread changes in DNA methylation at genes involved in supporting gut integrity, cell adhesion and immune regulation.10 Tight junction proteins including occludin and zonulin - which are responsible for maintaining gut barrier integrity - are regulated by methylation, and may be affected by reduced methylation capacity.11

Other digestive issues related to MTHFR

Inflammatory bowel disorders

Elevated homocysteine has been linked to inflammation and dysfunction of blood vessels in the intestines. Hyperhomocysteinemia is also known to increase the risk of developing inflammatory bowel disease (IBD).12

Impaired nutrient absorption

Compromised methylation in people with MTHFR mutations may be worsened by poor digestive function.Folate and B12 are cofactors for methylation, and both are produced (and influenced) by gut bacteria. Only certain strains are capable of producing vitamin B12. In humans, dietary B12 is absorbed in the distal ileum, where it is absorbed by specific receptors after binding to intrinsic factor. Inflammation and/or oxidative stress in the gut - which is common in MTHFR mutations - may further impair B12 absorption, compounding methylation issues.13

Things to do for your gut if you have MTHFR

Increase intake of fiber and fermented foods

Prebiotics are a type of dietary fiber that acts as fuel for healthy bacteria, supporting their growth and function. Prebiotics are fermented (broken down) by gut bacteria to provide short-chain fatty acids that have numerous benefits for the body, including intestinal epithelial function. This is essential for maintaining the defense barrier against invading pathogens, and also for nutrient absorption.14

Good sources of prebiotics include ginger, asparagus, beets, garlic, onion, Jerusalem artichoke, chicory, whole grains, unripe bananas, barley, rye, soybeans, raw milk, peas, beans and some seaweeds.

Fermented foods contain live microorganisms similar to those living in our own gut. Eating probiotic foods and/or taking probiotic gut health supplements can improve the composition of the microbiome by increasing levels of ‘good’ bacteria, which reduce populations of pathogenic (harmful) bacteria. Good bacteria also help in building a healthy intestinal mucosa protective layer and enhancing the immune system.15

Food sources of probiotics include yogurt, kefir, kimchi, sauerkraut, miso, tempeh and natto.

Adding a probiotic supplement to your health regime can help maximize the delivery of live probiotics to your digestive system. A spore-based probiotic such as RestorFlora™ (which also contains the beneficial yeast saccharomyces boulardii) is ideal. RestorFlora™ can also be taken alongside antibiotics.

Take digestive enzymes

Digestive enzymes help your body to break down the food you eat. Different types of enzymes are required to metabolize fats, proteins and carbohydrates and to assist with the absorption of nutrients. A supplement such as Gut Health is a great option here because it contains prebiotics, probiotics and postbiotics. Taking it together with digestive enzymes can help to maximize the breakdown and absorption of food.

Stay hydrated

Adequate water intake is essential for maintaining healthy microbial balance and immune function in the gut, helping to support your defenses against harmful pathogens.16

Prioritize sleep

Sleep has a major influence on immune functions. Sleep supports the release of growth hormone and prolactin, which in turn support immune interactions and balance.17

Sleep deprivation and chronic stress can trigger inflammation and an increased risk for chronic illnesses, including cardiometabolic, autoimmune and neurodegenerative diseases.18

Manage stress for gut health

The gut-brain axis is a bi-directional communication between the central nervous system and enteric nervous system. Chronically elevated cortisol may lead to impaired digestive function, including leaky gut, impaired nutrient absorption, abdominal pain or discomfort and gut inflammation. Stress management such as meditation and yoga help to lower stress levels, reduce overeating, and switch off the ‘fight or flight’ stress response, which impairs digestion.19

Avoid antibiotics when possible

Although antibiotics are sometimes necessary to treat bacterial infection, they are often prescribed too readily. Some studies have demonstrated a direct link between antibiotic use and poor gut bacteria, including changes in the gut microbiota that may affect normal immune function.20
If you do need to take antibiotics, take a probiotic alongside it. Check that the strains within the probiotic formula are resistant to antibiotics - for example, Saccharomyces boulardii.

Regular exercise for gut health

Exercising at a moderate to high-intensity level for 30-90 minutes at least three times per week (or 150-270 minutes per week) can improve gut microbiota. Exercise appears to be effective in enhancing the diversity and quantity of gut bacteria, especially aerobic exercise combined with resistance training.21

Product Recommendations

TrioBiotic Restore - Full-Spectrum Microbiome Support

TrioBiotic Restore - Full-Spectrum Microbiome Support

$45.00

  • Enzymes to Break Down & Aid Digestion
  • Probiotics to Populate the Microbiome
  • Prebiotics to Feed the Probiotics for Max Survival
  • Postbiotics to Increase the Effects on the Gut

Product Recommendations

Chewable Digestive Enzymes

Chewable Digestive Enzymes

$46.00

  • Ease Your Belly from Post Meal Discomfort
  • Assists Breakdown of Proteins, Carbohydrates, Lipids, Gluten & Dairy
  • Tastes like a natural, after-dinner mint
  • 3rd-Party Tested, Non-GMO, Gluten-Free, 90 Vegan Tablets

Frequently Asked Questions about MTHFR and gut health

Does MTHFR cause gut issues?

MTHFR may not directly cause gut issues, but mutations such as C677T or A1298C reduce methylation capacity, potentially compromising gut cell renewal, immune function and microbial balance. This may contribute to problems that affect gut function. For example, low folate and high homocysteine may increase inflammation and reduce the body’s ability to repair the gut lining, which can lead to increased intestinal permeability.22

What foods should you avoid with MTHFR mutation?

High consumption of processed food can change the gut microbiota and trigger inflammation. There is no regulation for the testing of the effects of food additives on gut microbiota, and many can alter the composition of the microbiota and lead to gut inflammation, which may increase the risk of many inflammatory diseases.

Why is dairy bad for MTHFR?

There is no solid evidence that dairy is specifically harmful for people with MTHFR variants, unless it contains synthetic folic acid. Fermented dairy products (when tolerated) may actually be beneficial, as they are typically lower in immunogenic proteins, for supporting the gut microbiome and providing a natural source of calcium.
Rather, dairy may be an issue for individuals who develop FRAAs (Folate receptor autoantibodies) or who consume dairy products fortified with synthetic folic acid, which relies on efficient folate metabolism.
Studies indicate that cow’s milk intake may promote the formation of folate receptor alpha autoantibodies (FRAAs), which can impair folate transport. Higher serum FRAA levels have been observed in individuals with regular milk consumption and tend to decrease when dairy is eliminated from the diet. These findings suggest a diet- and immune-mediated effect rather than a direct consequence of MTHFR genetic variation.23

How to fix methylation in the gut?

If you are affected by a MTHFR mutation, you can improve methylation by supplementing with methylfolate (bioactive folate) and active B12. These nutrients are required for the methylation of homocysteine to methionine, as well as many other processes involved in maintaining gut health.

References

  1. Massimo De Martinis, Maria Maddalena Sirufo, Cristina Nocelli, Lara Fontanella, Lia Ginaldi; "Hyperhomocysteinemia is Associated with Inflammation, Bone Resorption, Vitamin B12 and Folate Deficiency and MTHFR C677T Polymorphism in Postmenopausal Women with Decreased Bone Mineral Density"; International journal of environmental research and public health; 2020 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7345373/

  2. Brian G Jorgensen, Seungil Ro; "Role of DNA Methylation in the Development and Differentiation of Intestinal Epithelial Cells and Smooth Muscle Cells"; Journal of neurogastroenterology and motility; 2019 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6657918/

  3. Adil Mardinoglu, Hao Wu, Elias Bjornson, Cheng Zhang, Antti Hakkarainen, Sari M. Räsänen, Sunjae Lee, Rosellina M. Mancina, Mattias Bergentall, Kirsi H. Pietiläinen, Sanni Söderlund, Niina Matikainen, Marcus Ståhlman, Per-Olof Bergh, Martin Adiels, Brian D. Piening, Marit Granér, Nina Lundbom, Kevin J. Williams, Stefano Romeo, Jens Nielsen, Michael Snyder, Mathias Uhlén, Göran Bergström, Rosie Perkins, Hanns-Ulrich Marschall, Fredrik Bäckhed, Marja-Riitta Taskinen, Jan Borén; "An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans"; Clinical and Translational Report; 2018 Mar

    https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30054-8

  4. Merrill F Elias, Craig J Brown; "New Evidence for Homocysteine Lowering for Management of Treatment-Resistant Hypertension"; American journal of hypertension; 2021 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8976174

  5. Erik E van de Lagemaat, Lisette CPGM de Groot, Ellen GHM van den Heuvel; "Vitamin B12 in Relation to Oxidative Stress: A Systematic Review"; Nutrients; 2019 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6412369/

  6. Yin Yuan, Jing Yang, Aoxiang Zhuge, Lanjuan Li, Shuo Ni; "Gut microbiota modulates osteoclast glutathione synthesis and mitochondrial biogenesis in mice subjected to ovariectomy"; Cell proliferation; 2022 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8891549

  7. Min-Hyun Kim, Hyeyoung Kim; "The Roles of Glutamine in the Intestine and Its Implication in Intestinal Diseases"; International journal of molecular sciences; 2017 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC5454963/

  8. National Library of Medicine; "MTHFR methylenetetrahydrofolate reductase [Homo sapiens (human)]"; 2026 Feb

    https://www.ncbi.nlm.nih.gov/gene/4524

  9. Hao Ding, Qiao Mei, Hui-Zhong Gan, Li-Yu Cao, Xiao-Chang Liu, Jian-Ming Xu; "Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism"; Gastroenterology report; 2014 Aug

    https://pubmed.ncbi.nlm.nih.gov/24787389/

  10. Mckenna M Bowes, Desiré Casares-Marfil, Amr H Sawalha; "Intestinal permeability correlates with disease activity and DNA methylation changes in lupus patients"; Clinical immunology: The Official Journal of the Clinical Immunology Society; 2024 May

    https://pubmed.ncbi.nlm.nih.gov/38460891/

  11. Alessio Fasano; "Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer"; Physiological Reviews; 2011

    https://journals.physiology.org/doi/full/10.1152/physrev.00003.2008

  12. S Givvimani, C Munjal, N Narayanan, F Aqil, G Tyagi, N Metreveli, S C Tyagi; "Hyperhomocysteinemia decreases intestinal motility leading to constipation"; American journal of physiology. Gastrointestinal and liver physiology; 2012 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3423105/

  13. Sabrina Giammarco, Patrizia Chiusolo, Roberto Maggi, Monica Rossi, Gessica Minnella, Elisabetta Metafuni, Francesco D’Alò, Simona Sica; "MTHFR polymorphisms and vitamin B12 deficiency: correlation between mthfr polymorphisms and clinical and laboratory findings"; Annals of hematology; 2024 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11512882/

  14. Dorna Davani-Davari, Manica Negahdaripour, Iman Karimzadeh, Mostafa Seifan, Milad Mohkam, Seyed Jalil Masoumi, Aydin Berenjian, Younes Ghasemi; "Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications"; Foods; 2019 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6463098/

  15. Xinzhou Wang, Peng Zhang, Xin Zhang; "Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity"; Molecules; 2021 Oct

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8512487/

  16. Kensuke Sato, Mariko Hara-Chikuma, Masato Yasui, Joe Inoue, Yun-Gi Kim; "Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination"; iScience; 2024 Jun

    https://www.sciencedirect.com/science/article/pii/S2589004224011258

  17. Michael R Irwin, Mark R Opp; "Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity"; Neuropsychopharmacology; 2016 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC5143488/

  18. Sergio Garbarino, Paola Lanteri, Nicola Luigi Bragazzi, Nicola Magnavita, Egeria Scoditti; "Role of sleep deprivation in immune-related disease risk and outcomes"; Communications biology; 2021 Nov

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8602722/

  19. Christine E Cherpak; "Mindful Eating: A Review Of How The Stress-Digestion-Mindfulness Triad May Modulate And Improve Gastrointestinal And Digestive Function"; Integrative medicine; 2019 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7219460/

  20. Skye R S Fishbein, Bejan Mahmud, Gautam Dantas; "Antibiotic perturbations to the gut microbiome"; Nature reviews. Microbiology; 2025 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC12087466

  21. Alexander N Boytar, Tina L Skinner, Ruby E Wallen, David G Jenkins, Marloes Dekker Nitert; "The Effect of Exercise Prescription on the Human Gut Microbiota and Comparison between Clinical and Apparently Healthy Populations: A Systematic Review"; Nutrients; 2023 Mar

    https://pubmed.ncbi.nlm.nih.gov/36986264/

  22. Hao Ding, Qiao Mei, Hui-Zhong Gan, Li-Yu Cao, Xiao-Chang Liu, Jian-Ming Xu; "Effect of homocysteine on intestinal permeability in rats with experimental colitis, and its mechanism"; Gastroenterology report; 2014 Aug

    https://pubmed.ncbi.nlm.nih.gov/24787389/

  23. Ai Shi, Di Liu, Huiwen Wu, Rui Zhu, Ying Deng, Lulu Yao, Yaqian Xiao, George H. Lorimer, Reza A. Ghiladi, Xinjie Xu, Rong Zhang, Haiqing Xu, Jun Wang; "Serum binding folate receptor autoantibodies lower in autistic boys and positively-correlated with folate"; Biomedicine & Pharmacotherapy; 2024 Mar

    https://www.sciencedirect.com/science/article/pii/S0753332224000726

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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