Chronic Fatigue Starts in the Gut: How Microbes Impact Energy and Brain Health

In this article I will discuss the problem of fatigue in people with multiple sclerosis (MS) and other neurological disorders. I’ll share my personal experiences with fatigue, explain some of the underlying biological factors that contribute to fatigue, and highlight the essential role B vitamins play in supporting mitochondrial function. You’ll also learn practical ways to increase your intake of B vitamins through food and supplements.

Fatigue and Brain Fog: Top Drivers of Job Loss 

Fatigue is one of the most common reasons people with MS—as well as those with systemic autoimmune diseases, Parkinson’s, and other neurodegenerative diseases—leave the workforce. Cognitive decline is the next most frequent cause.

The longer someone has MS, the more likely they are to experience worsening fatigue and brain fog. These issues often intensify over time, beginning in the mid-40s. At present, we have not identified the specific biological or metabolic pathways that cause MS-related fatigue, and as of this writing there is not a specific way to test for this.

That said, chronic fatigue and brain fog likely result from a complex intersection of many different biological, metabolic, and mitochondrial dysfunctions. I believe mitochondrial efficiency is a key factor in both.

My fatigue Journey: How I Restored My Energy

My first neurological symptoms began when I was 25, with severe electrical face pain that would later be diagnosed as trigeminal neuralgia. Then when I was 32, I had an episode of dim vision, which would later be diagnosed as my first episode of optic neuritis.

Twenty years later (at age 45) I was finally diagnosed with MS. Within 3 years of my diagnosis, I had to get a tilt/recline wheelchair, and I was experiencing severe fatigue that kept getting worse.

My neurologist gave me Provigil® to treat the fatigue. It provided a small level of improvement, but I was still exhausted by 10AM. Still, I was definitely more exhausted without the Provigil, so I kept taking it.

Looking for answers, I turned to PubMed.gov to read the available scientific articles concerning Parkinson’s, Alzheimer’s, and the progressive forms of MS. I was seeking any science I could find that would explain the severity and persistence of my worsening fatigue.

That’s when I discovered several studies showing that the B family of vitamins are critical in the generation of adenosine triphosphate (ATP), the main energy molecule produced in the mitochondria.

I had long suspected that mitochondrial strain was an important driver of my disability, including severe fatigue. I began taking lipoic acid, coenzyme Q, and B vitamins. But because I did not see much change in my energy levels, I stopped my cocktail of supplements after about six months.

That’s when I had my “aha” moment.

About 36 hours after stopping the supplements, I was too fatigued to get out of bed and go to work. At 72 hours, my wife Jackie suggested I restart them—so I did. The next morning, I woke up with my usual energy and was able to return to work.

I was excited (and curious)—so two weeks later, I repeated the experiment. Once again, 36 hours after stopping the supplements, I was too exhausted to function. At the 72-hour mark, I restarted them—and by the next morning, my energy and mental clarity had returned.

That experience convinced me I was on the right track. I returned to the scientific literature and continued tinkering with ways to support my mitochondria.

That was 2008. In the 17 years since, I’ve learned a great deal about B vitamin pathways, genetic variants, and homocysteine metabolism—and I’ve used that knowledge to help many patients restore their energy and mental clarity. I haven’t used my wheelchair since January of 2008. That is 17 years ago.

How B Vitamins Support Mitochondrial Function, Health, And Vitality

B vitamins work together synergistically to support the health and proper functioning of your cells. One of their most critical roles is in the production of adenosine triphosphate (ATP), the energy molecule used by every cell in your body. ATP is made inside the mitochondria—your cells' power plants—and B vitamins are required at multiple steps in the chemical pathways that create it.^{[1, 2]}

Without adequate B vitamin levels, your mitochondria can't efficiently generate energy, which can contribute to fatigue and cognitive decline.

Unfortunately, many common foods are low in B vitamins. White flour, for example, has been stripped of its natural B vitamin content during processing. To compensate, synthetic versions are added back in—but these are not always as effective. For instance, folic acid (a synthetic form of folate) is commonly used to fortify white flour and reduce the risk of neural tube defects. However, folic acid may interfere with the body’s use of natural folate and has been associated with an increased risk of certain cancers.^{[3, 4]}

High Homocysteine Is A Problem (Here’s Why)

Homocysteine is a compound that your body produces as it breaks down proteins. In small amounts, it's a normal part of your metabolism. But when homocysteine levels become too high, it can damage brain^{[1, 2]} and retinal^{[3, 4]} cells, increase oxidative stress, and contribute to inflammation—all of which are linked to a higher risk of heart disease, stroke, Alzheimer’s, and other neurodegenerative conditions. Elevated homocysteine is also a marker of insufficient intracellular B vitamin levels, which can contribute to the development of heart disease, brain related problems, and eye disease. ^{[2, 5]}

To keep homocysteine in check, your body relies on several B vitamins—especially B6 (pyridoxine), B9 (folate), and B12 (cobalamin). These vitamins help recycle homocysteine back into methionine, an amino acid the body can reuse. If you're low in these B vitamins (either due to poor diet, poor absorption, or genetic factors), homocysteine can build up in your bloodstream.

In my clinical practice, I routinely check homocysteine levels. Ideally, they should be between 5 and 7 μmol/L. If they’re elevated, I address that with diet, lifestyle changes, and targeted supplementation. In most cases, correcting vitamin B deficiencies brings homocysteine back into the healthy range—and patients often report better energy and clearer thinking when it does.

The conventional cut off for elevated homocysteine is 15 μmol/L,
though some labs place the upper level at 10 μmol/L.
A mild elevation is 8-15 mmol/L;
moderate elevation is 16-30 μmol/L;
severe elevation is 31-60 μmol/L;
and very severe elevation is > 60 μmol/L.

I talk more about recommended labs below.

Questions I Ask My Fatigued Patients

When a single nucleotide in your DNA is swapped for a different one, it is called a single nucleotide polymorphism (SNP). Some SNPs can interfere with how efficiently your mitochondria use B vitamins—which may make it harder for your brain and body to produce enough ATP.

This can lead to fatigue, brain fog, mood problems, and worsening disability. It can also increase the risk of heart disease, neurodegenerative conditions, and certain eye diseases.

To assess the risk for having these problem SNPs, I always ask my patients these questions:

Do you have a family history of any of the following?

• Eye diseases (such as age-related macular degeneration)
• Mental health issues (anxiety, depression, bipolar, schizophrenia, etc.)
• Neurological issues (MS, Parkinson’s, or Alzheimer’s)
• Cardiovascular disease (stroke or heart disease)

The more family members affected by these types of issues, the more likely you are to carry SNPs that affect B vitamin pathways.

In my case, I have multiple aunts and uncles with a variety of these conditions. That means I probably carry multiple genetic variants that affect how my cells manage their B vitamin pathways.

How to Increase Your Intake of B Vitamins Naturally

I encourage everyone to focus on improving their nutrition first. This is the most important way to increase your intake of naturally occurring B vitamins (as opposed to the synthetic forms).

Here are my top recommendations:

• Avoid white flour-based products like bread and pasta. 
• Be mindful about how you cook your food—B vitamins are water-soluble and can be lost if you cook your food in water that you subsequently discard. 
• Meat, dairy, and eggs are great sources of cobalamin (B12). Although certain bacteria in the colon can produce vitamin B12, we can’t absorb it there. That’s because vitamin B12 (also called cobalamin) must bind to a protein called intrinsic factor in the stomach. This binding is essential for B12 to be absorbed later in the small intestine.
• Eat more green leafy vegetables, which are rich in folate and riboflavin. 
• Legumes are rich in vitamin B1, B3 and B9. 
• Meat is an excellent source for all of the B vitamins, with organ meat being an especially good source. 
• Vegetarians and vegans are at higher risk of being low in B12 and having elevated homocysteine levels.

Activated B Vitamins Can Bypass SNPs & Improve Absorption

I recommend that my patients take a supplement that contains the activated forms of B vitamins, which bypass problem SNPs. The activated forms of vitamin B12 (methylcobalamin), B9, (methylfolate) and B6 (pyridoxal-5-phosphate) help reduce homocysteine to more optimal levels.

I also recommend taking activated vitamin B1 (benfotiamine), which supports brain,^[5] retinal.^{[6, 7]} and heart health,^[8] as well as activated vitamin B2 (riboflavin 5 phosphate) for those with migraine and chronic headache.^{[9, 10]}

Other activated B vitamins that may be useful include niacin and niacinamide, which have also been helpful in migraine and chronic headache^[11]; choline, an important nutrient for cognition and mental health,^{[12, 13]}; and biotin, which is involved the production of myelin.^[14]

The Laboratory Tests I Check in My Patients

In addition to checking for homocysteine levels, I also check my patients’ basic primary care labs (complete blood count, kidney function, liver function, and metabolic health).

You can ask your medical team to monitor your B vitamins and homocysteine. If you are unable to obtain these types of tests through your medical team, it may be possible to obtain homocysteine and other nutrient assessments at Yourlabwork.

Additional Supplementation to Support Healthy Homocysteine Levels

People who have mild homocysteine elevation are often able to correct their homocysteine with one capsule each day of Activated B vitamins. Those with moderate elevations are sometimes able to correct their homocysteine with two capsules per day.

Those with severe and very severe elevations of homocysteine are more likely to need significantly higher doses of activated folate, activated cobalamin, and other activated B vitamins, as well as closer monitoring. They are more likely to benefit from MTHFR Complete.

Summary

Years ago, I resolved my own fatigue, and since then, I’ve helped thousands of others do the same using diet, lifestyle, and targeted supplements. For people facing brain, heart, or eye issues, optimizing B vitamin pathways is often a key part of their self-care strategy.

The process starts with food. I encourage patients to increase their intake of naturally occurring B vitamins and avoid synthetic forms. I also check their homocysteine levels—a key marker of B vitamin status. If levels are elevated, I recommend activated B vitamins and retest in three months, adjusting as needed. Supporting my mitochondria with both food-based and activated B vitamins has made a profound difference in my health, and it can do the same for others.

Citations

1. Ansari, R., et al., Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol, 2014. 10(4): p. 281-8.
2. Obeid, R., A. McCaddon, and W. Herrmann, The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med, 2007. 45(12): p. 1590-606.
3. Elsherbiny, N.M., et al., Homocysteine Induces Inflammation in Retina and Brain. Biomolecules, 2020. 10(3).
4. Ola, M.S., et al., Neurodegeneration and neuroprotection in diabetic retinopathy. Int J Mol Sci, 2013. 14(2): p. 2559-72.
5. Dardiotis, E., et al., Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis. Mult Scler Relat Disord, 2017. 17: p. 190-197.
6. Chakrabarti, R., et al., Preventive effects of benfotiamine in chronic diabetic complications. J Diabetes Investig, 2011. 2(2): p. 123-31.
7. Cinici, E., et al., The Protective Effect of Thiamine Pryophosphate Against Sugar-Induced Retinal Neovascularisation in Rats. Int J Vitam Nutr Res, 2018. 88(3-4): p. 137-143.
8. Wong, E.K.C., et al., High-Dose Thiamine Supplementation in Older Patients With Heart Failure: A Pilot Randomized Controlled Crossover Trial (THIAMINE-HF). CJC Open, 2022. 4(6): p. 532-539.
9. Grech, L., et al., Management of Osteoporosis, Fracture and Falls in People with Multiple Sclerosis: Systematic Review of Guidelines. Calcif Tissue Int, 2024. 114(3): p. 201-209.
10. Lisicki, M. and J. Schoenen, Metabolic treatments of migraine. Expert Rev Neurother, 2020. 20(3): p. 295-302.
11. Fila, M., et al., Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine. Nutrients, 2021. 13(12).
12. Freedman, R., et al., Choline, folic acid, Vitamin D, and fetal brain development in the psychosis spectrum. Schizophr Res, 2021.
13. Gonzalez, H.F. and S. Visentin, Micronutrients and neurodevelopment: An update. Arch Argent Pediatr, 2016. 114(6): p. 570-575.
14. Sedel, F., et al., High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord, 2015. 4(2): p. 159-69.