MTHFR Gene Mutation: The Gene's Role in Gut Health and Immune Function

MTHFR Gene Mutation: The Gene's Role in Gut Health and Immune Function

Katie Stone - Naturopath

Written By:

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

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 22, 2025

Table of Contents

    MTHFR Gene Mutation: The Gene's Role in Gut Health and Immune Function

    Fact: your gut microbiome influences almost every system in the body. Especially your immune system!


    The bacteria in your intestines are absolutely vital when it comes to detecting threats and protecting you from disease. That’s why any imbalance in the gut - known as dysbiosis - can have quite a significant impact on the rest of the body.


     

    And, while the development of dysbiosis is most commonly linked to lifestyle factors, research suggests that the MTHFR gene mutation may also play a part.


    The MTHFR mutation affects the conversion of folate into its active form in the body. It is estimated that around 25% of the world’s population are carriers of the C677T MTHFR mutation, while another 25% have the A1298C MTHFR mutation.  [1] This means that a significant proportion of the world’s population may be at risk of poor gut health and reduced immune function.


    Those with an MTHFR mutation are commonly low in folate, which can have a major impact on gut health.


    This article will discuss the effects of the MTHFR gene on gut health and immunity, and what this can mean for someone who has been diagnosed with a MTHFR mutation. We will also explain how to improve gut health, support your immune system, and optimize overall wellbeing.  

    Effects on gut health

    B vitamins play crucial roles in shaping the diversity and richness of the gut microbiota1. Folate - aka vitamin B9 - is usually obtained through the diet, and partially by gut microbiota.2 Folate is an essential methyl donor nutrient involved in one-carbon metabolism. It is required for synthesizing S-adenosylmethionine (SAM), cellular biosynthesis, and DNA methylation


    Folate is also necessary for regenerating the lining of the intestine.3


    Some studies indicate that a significant proportion of patients with inflammatory bowel disorders such as Crohn's disease suffer from vitamin B12 and/or folate deficiency. Crohn's disease usually affects the small intestine, which is also where vitamin B12 and folate are absorbed.4


    Other symptoms of folate deficiency regarding the gastrointestinal tract include glossitis (”burning tongue”), and cheilitis, along with nonspecific symptoms such as abdominal pain, dyspepsia, nausea, vomiting, diarrhea and disturbances in intestinal functioning.5

    Effects on immune function

    Gut microbiome has considerable control over immune function and susceptibility to autoimmune and autoinflammatory diseases, such as inflammatory bowel disease (IBD) and many other chronic illnesses. This is partly due to the direct effects of the microbiome on gastrointestinal function and nutrient transport, but also its effects on immune cells. A balanced microbiome with adequate folate and micronutrient production is vital for maintaining overall homeostasis.6


    Low folate levels can significantly disrupt the diversity of gut microbiome. Studies in folate-deficient mice found that the populations of healthy bacteria (Bacteroidales and Clostridiales) decreased, as well as a decrease in overall bacterial diversity.7

    Increased risk of developing leaky gut

    The GI tract has a defensive barrier to prevent substances from entering the bloodstream. When this is compromised, the barrier becomes more permeable - or a condition known as ‘leaky gut’8.


    Low folate has been shown to cause an increase in the depth between intestinal villi in the duodenum and jejunum, resulting in reduced villi function. Folate deficiency in mice is also shown to affect intestinal cell health.9 This means that substances in the intestine can pass through the villi into systemic circulation, causing leaky gut. This, in turn, can lead to various health disorders. 10]

    Higher likelihood of inflammation

    Some studies on the role of MTHFR in inflammatory bowel diseases (IBD)11 have shown that increased levels of homocysteine are more common in those with IBD. It is also noted that the MTHFR gene is located on chromosome 1, a locus found to be associated with IBD risk.12


    One study found that 17.5% of patients with ulcerative colitis and 16.8% with Crohn's disease also had the C677T MTHFR mutation, compared with 7.3% of patients who had neither condition.13

    Digestive diseases may be more common

    Along with poor intestinal integrity, folate deficiency has been associated with gastrointestinal symptoms such as persistent diarrhea.14


    Folate deficiency is also known to significantly alter the shape, structure, form, and size of intestinal cells, and may increase the risk of intestinal carcinogenesis. 15


    The MTHFR C677T polymorphism may increase the risk for developing gastric lesions, including in patients who are negative for Helicobacter pylori.16

    Possible increased stress and faster aging

    Those with genetic disorders such as MTHFR mutations are at a higher risk of elevated homocysteine levels.17 High homocysteine has been linked to significant oxidative stress and proinflammatory effects in the body, which in turn can speed the aging process.18

    Risk of autoimmune disease

    Immune dysfunction and dysbiosis is often a factor in both autoimmune diseases and inflammatory diseases. Folate is required for the generation and maintenance of T-cells, which play a central role in the regulation of the immune system. Researchers have suggested that one mechanism for the development of autoimmune disease is through the induction of T regulatory cells in the gastrointestinal tract, a process that involves both the microbiome and folate.19

    Potential issues with Vitamin B12 absorption

    Intestinal absorption of vitamin B12 is genetically associated with the MTHFR C677T variant. It has been shown that individuals with the MTHFR C677T variant are also more likely to have vitamin B12 deficiency.20


    While it’s not yet certain how the metabolic factors of B12 deficiency and MTHFR are linked, some researchers have suggested that it may be due to abnormal homocysteine metabolism caused by impaired MTHFR enzyme function.21


    Strategies to improve your gut health and immune function if you have MTHFR mutations

    Incorporate probiotic and prebiotic foods

    If you’ve done some research on how to heal your gut, you’ve probably heard of probiotics.


    Probiotic 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 prevent pathogenic (bad) bacteria from spreading in the intestine. Good bacteria also help in building a healthy intestinal mucosa protective layer and enhancing the immune system.22


    Food sources of probiotics include yogurt, kefir, kimchi, sauerkraut, miso, tempeh, and natto.23


    Prebiotics are special types of fiber that act 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 development.24


    Good sources of prebiotics include asparagus, beets, garlic, onion, Jerusalem artichoke, chicory, wholewheat, unripe bananas, barley, rye, soybean, raw milk, peas, beans, and some seaweeds.25


    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 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 4-in-1 is a great option here because it contains prebiotics, probiotics, and postbiotics together with digestive enzymes, maximising the breakdown and absorption of food.

    Stay hydrated for digestive health

    Drinking plenty of water throughout the day helps to maintain the health of the digestive system. Those who drink less water are found to have poorer gut microbiota composition than those who drink more. The source of the water is also important. Drinking tap water is found to increase the amount of bacteria associated with antibiotic resistance compared with sterilized water.26

    Prioritize sleep for immune health

    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.


    Sleep deprivation and chronic stress can trigger inflammation and weak immune responses.27

    Limit intake of processed foods

    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.28

    Practice mindful eating

    Stress is linked to many gastrointestinal disorders such as irritable bowel syndrome (IBS) and functional dyspepsia. Mindful-eating practices can improve digestion by inducing “rest and digest”, which reduces the stress response and helps to regulate the nervous system. Studies have shown that encouraging mindfulness while eating has a positive effect on both gastrointestinal and neuro-endocrine-immune signaling due to the link between the gut and the brain.29

    Follow a personalized diet plan

    Everyone’s health needs are different. A personalized diet plan can improve gut health by tailoring your food choices according to your dietary needs (such as sensitivities and intolerances) while optimizing digestive function and the growth of beneficial gut bacteria. A tailored plan can also help in managing specific digestive issues or conditions such as IBS or leaky gut.

    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.30

    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.31

    Regular exercise for gut health

    Research shows that exercising at a moderate to high-intensity level for 30–90 min at least three times per week (or 150–270 min 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.32

    The takeaway

    The MTHFR gene mutation has been linked to gastrointestinal disorders, digestive issues, and reduced immune function. These conditions may be linked to folate deficiency that results from MTHFR dysfunction, as well as disruptions in DNA or RNA synthesis, repair, and chromosomal damage.


    If you have an MTHFR mutation, the first step in supporting your gut health and immune function should be a healthy diet and lifestyle practices. If you struggle with this, it’s a good idea to seek advice from a qualified practitioner. 

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    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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