Methylation and the gut: what you need to know

Methylation is a process your body relies on every day — from supporting your mood and energy to helping you detoxify, this tiny but powerful biochemical process deserves a closer look. In this article, I’ll discuss what methylation is, why it matters, and how to support it for a healthy gut.

What is methylation?

Methylation is a biochemical process in the body that involves the transfer of a methyl group—one carbon atom and three hydrogen atoms—to various molecules. This process happens in every cell of your body. It can regulate gene expression and has a major influence on numerous cellular functions, including:

1. DNA and Gene Regulation

   Methylation can silence or activate genes, helping control how cells grow, divide, and respond to stress or other stimuli.

2. Neurotransmitter Production

   Methylation assists in producing neurotransmitters like serotonin, dopamine, and epinephrine, which affect mood, energy, brain function, and gut motility.

3. Detoxification

   The body relies on methylation to remove harmful substances, including environmental toxins and metabolic byproducts.

4. Hormone Metabolism

   Proper methylation supports the processing of hormones like estrogen, contributing to hormonal balance.

Poor methylation may contribute to health challenges because the body might struggle with detoxification, maintaining proper gene expression, or synthesizing crucial molecules. This can result in neurological and mood issues, hormone imbalances, a higher body burden of toxins, reduced cellular repair, and immune dysregulation, all of which can negatively impact gut health.

Key Nutrients for Methylation

Here is an image showing the methylation cycle. You can see that there are multiple pathways involved in recycling homocysteine back into methionine or converting it into other molecules like cysteine. Each step relies on enzymes that require cofactors such as B vitamins to supply or transfer methyl groups. The cycle also has some built-in redundancy, so if one pathway is temporarily weakened, another route can help compensate. However, if several pathways become compromised—due to nutrient deficiencies or genetic variations—homocysteine may build up, or crucial metabolic processes may slow down.

Adapted from Taylor et al. Nutrients (2018).

Several nutrients serve as either “methyl donors” (providing the methyl group) or “cofactors” (supporting enzymes that transfer methyl groups). The primary players include:

1. Folate (Vitamin B9) – Critical for forming methyl groups and converting homocysteine to methionine.

2. Vitamin B12 (Cobalamin) – Works closely with folate to support the final step of homocysteine recycling.

3. Vitamin B6 (Pyridoxine) – Important for converting homocysteine to cysteine and overall amino acid metabolism.

4. Riboflavin (Vitamin B2) – Helps activate folate and vitamin B6.

5. Choline – Can be converted into betaine, a methyl donor.

6. Betaine (Trimethylglycine) – Directly donates methyl groups, assisting homocysteine conversion.

7. Magnesium – A cofactor in many enzymes, including those involved in methylation.

Gut Microbes Produce Small Amounts of B Vitamins

Several common gut tests, like Thorne and Nirvanabiome, include an estimate of your gut microbiome’s capacity to produce different vitamins. While some gut bacteria can synthesize key methylation nutrients like B12, folate, B2, and B6, the overall contribution to human B vitamin status is likely pretty low. This is because B vitamin absorption primarily occurs in the small intestine, whereas most of the vitamin-producing microbes reside in the colon.

Still, gut microbiota-derived B vitamins may have benefits for the colon. Research suggests that such microbially produced B vitamins may play a role in maintaining mucosal integrity or modulating the local immune response, even if they don’t substantially raise systemic B vitamin levels. One study found that microbial B vitamin production is reduced by stress and boosted by fiber intake.

Gut Conditions: Methylation in IBS, IBD, and more

While it is often overlooked, methylation may play a contributing role in both IBS and IBD, and gut conditions can also affect the absorption of key methylation-related nutrients.

Longstanding research shows folate deficiency is common in IBD, and recent studies indicate that low folate and B12 status may correlate with worsened gut inflammation, higher homocysteine levels, and poor cellular repair. B12 deficiency in Crohn’s disease is not only tied to decreased absorption but also to greater disease activity and complications such as strictures. Magnesium and B6 levels can also be affected.

Though IBS is typically less inflammatory than IBD, research suggests that IBS patients commonly show deficiencies in riboflavin (B2) and B6, key cofactors in homocysteine metabolism. The dysbiosis and altered gut motility in IBS can impair nutrient uptake, making it harder to maintain adequate B vitamin levels that support robust methylation.

Proton pump inhibitors, common medications for acid reflux, and chronic gastritis can also increase the risk of B12 deficiency.

Genetic testing: What about MTHFR?

There is a lot of hype about testing for MTHFR (methylenetetrahydrofolate reductase). Gene variants of this enzyme can determine how efficiently your body converts folate into its active forms.

In his eye-opening presentation, “Lies, Damn Lies, and Genetics”, Dr. Tommy Wood unpacked the original data around MTHFR, finding that despite commonly cited enzyme-activity reductions, these common variants explain only about 1 percent of the variation in homocysteine levels across the population. Even someone with the “worst” (677TT) genotype has only an 8 percent higher likelihood of having elevated homocysteine compared to someone with the “best” genotype — and this small effect could be offset by ensuring adequate intake of riboflavin (B2).

Overall, the takeaway is you don’t need to know your genetics to improve your methylation and your overall health. You’re much better off assessing your phenotype — the things we can directly measure about how your body is functioning now — and focusing on fixing your inputs, like diet and lifestyle.

Assessing Methylation Status

Monitoring certain markers and nutrient levels can give insights into how well the methylation cycle is functioning, and whether it could be impacting your gut and overall health:

1. Homocysteine: A great overall marker of methylation status. Levels between 5-8 umol/L are ideal. Elevated levels suggest possible deficiencies in B12, folate, B6, or other methylation-related nutrients.

2. Folate (Vitamin B9): Can be measured as RBC folate in blood, or urinary FIGlu on organic acids testing.

3. Vitamin B12: Ideally measured as serum or urine methylmalonic acid.

4. Vitamin B6 (PLP): Measured in plasma.

5. Vitamin B2, Betaine, & Choline: Assessed less commonly, though some specialized labs may be able to measure these.

How to Support Optimal Methylation & Gut Health:

To support optimal methylation:

1. Eat beef, liver, and eggs (B vitamins, choline)

2. Eat some leafy greens (folate) and dark chocolate (magnesium).

3. Test your homocysteine and B vitamin status, and increase dietary intake or supplement accordingly. Sublingual forms may be ideal for those with active gut inflammation.

4. Take creatine! Creatine synthesis can use up to half of daily methylation capacity, so supplementing can spare methyl donors for other processes.

5. Reduce stress. Stress-related pathways demand more methyl donors. Practices like mindfulness, meditation, and regular exercise can help with stress management.

6. Sweat. Sauna and exercise can encourage toxin excretion via sweating, potentially easing the overall load on methylation-driven detox pathways.

That’s all for now. Let me know your thoughts in the comments!