Let’s Talk About Fatigue (part 3)

Here we are. We’ve arrived at the end of my series of posts for why most people feel fatigued.

So far, we’ve discussed why hormones could be at the root of your fatigue, and why oxidative stress could be at the root of your fatigue.

Now, its time to explore reasons why nutrient deficiencies could be at the root of your fatigue.

But first, let’s take a step back and define what a nutrient deficiency is really fast.

What is a nutrient deficiency?

A nutrient deficiency happens when you don’t have enough of a nutrient to perform all of the required tasks that nutrient is needed for. The demand outweighs the supply.

Nutrients include both micronutrients and macronutrients.

Micronutrients include:

  • vitamins
  • minerals
  • plant-derived polyphenols
  • co-factors for chemical reactions

Macronutrients include:

  • Carbohydrates
  • Proteins / amino acids
  • Fats (also referred to as lipids)
  • Fiber
  • Alcohol (we won’t discuss this one in context of fatigue, because there is no known condition of ‘alcohol deficiency’, even if you want that to be the case)

Micronutrients and Fatigue

Because it is much more likely, in my clinical experience, that a nutrient-deficiency of micronutrients will lead to fatigue than a macronutrient deficiency, let’s start here.

I’m going to remind you that when I refer to ‘energy’ and ‘fatigue,’ I’m speaking in very broad terms of how we feel like we have low energy, such as climbing a flight of stairs is difficult for us, or we struggle to get through even the most basic of physical tasks, or perhaps we even struggle to wake up and get out of bed in the morning.

We should also differentiate here that fatigue is not the same thing as feeling sleepy or being sleep-deprived. Restorative sleep will fix sleep deprivation, but will do little for fatigue.

The first thing to consider with micronutrients is that a deficiency of any of these will affect cellular energy very dramatically, but can also affect the availability of other biological chemicals such as hormones, neurotransmitters, cell signaling molecules, and more.

Cellular energy, occurs in the form of a molecule called adenosine triphosphate (ATP). ATP is manufactured and then used to create heat energy or fuel cell operations.

ATP is generated through a couple of pathways.

The first is referred to as glycolysis. The diagram below seems very complex, but as far as nutrients that are involved, you need carbohydrate in the form of glucose (this is what carbohydrates in your blood are referred to as), niacin (NAD, NADH, and NADPH), and phosphate (taken from an ATP molecule).

image from “Review of aerobic glycolysis and its key enzymes—New targets for lung cancer therapy” – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Schematic-diagram-of-glycolysis_fig1_264781897

This is the process by which your body ‘burns’ carbohydrates for energy. It requires available carbohydrate in your blood, from muscle stores, or liver stores.

Most of us are doing this all day without realizing it. We also do this during short, intense bursts of movement, such as HIIT training, weight lifting, or sprinting.

Glycolysis happens in the ‘cytosol,’ which means the substance outside and surrounding our cells, but not inside our cells.

This energy generation cycle requires these nutrients to work: glucose (usually from carbohydrates and/or fats we eat), phosphate, NADH (niacin, aka vitamin B3).

It is not the body’s preferred method of generating energy over longer periods of movement. That method is referred to as oxidative phosphorylation, or the electron transport chain.

image from “Toxin-Induced Hyperthermic Syndromes” – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Uncoupling-Process-of-uncoupling-of-oxidative-phosphorylation-In-normal-oxidative_fig2_7539438

Oxidative phosphorylation takes cofactors like NADH and ‘oxidizes’ them, which means they lose or donate an electron, in the diagram above, a hydrogen atom.

It is this donating of electrons many times over that generates heat, as well as additional ATP, our cellular energy source, back and forth over our cell membranes.

Oxidative phosphorylation generates significantly more energy in the form of ATP than does glycolysis, or our last method of generating energy, the Krebs cycle.

The nutrients this cycle needs are: NADH (niacin), O2 (from the air we breath), and phosphate.

We also use the Krebs cycle, also called the Citric Acid cycle, to generate energy inside our cells.

image from “15.2: The Citric Acid Cycle” – LibreTexts: Chemistry – Contributed by Allison Soult, University of Kentucky. Last updated: Jun 5, 2019. https://chem.libretexts.org/Courses/University_of_Kentucky/UK%3A_CHE_103_-Chemistry_for_Allied_Health(Soult)/Chapters/Chapter_15%3A_Metabolic_Cycles/15.2%3A_The_Citric_Acid_Cycle

Super involved stuff going on in that diagram, right? Don’t freak out.

If you’ve never had to memorize this in at least one biology or organic chemistry or biochem class in high school or college, the gist is that this cycle takes acetyl CoA, which is produced in glycolysis, which we already discussed, and through a series of oxidation and reduction reactions, turns it into ATP.

As far as nutrients go, it requires NADH (niacin), FADH2 (riboflavin), water, and CO2 (from the air we breath).

Here’s how all of these cycles tie together, in case you need a visual:

image from: “An Introduction to Cellular Respiration” – A Level Biology. https://alevelbiology.co.uk/notes/cellular-respiration/

So far, you’re probably going, okay, so we need a lot of niacin, some riboflavin, a lot of phosphate, some water, and air. Big deal.
We all know that.

Right, but, here’s where things get much more complex: these three energy generating cycles above rely on there always being enough of these building blocks available to continue to operate.

Apart from the obvious players involved in the actual cycle, any other nutrient deficiency can lead to a secondary deficiency of the above nutrients.

Let’s discuss.

Indirect nutrient deficiencies lead to fatigue

Say you have some regular digestive problems, namely diarrhea. Diarrhea, if it goes on for a while, usually leads to malabsorption of one or more nutrients, such as fat-soluble vitamins (A, D, E, and K).

If you have persistent diarrhea, and have trouble absorbing these vitamins, two of which are primary antioxidants (A and E), you’re now lacking a couple critical antioxidants that would otherwise ‘mop up’ free radicals.

Remember the previous post on free radicals and oxidative stress?

Now we have a situation where a nutrient deficiency because of diarrhea is causing oxidative stress.

Or, perhaps you have a genetic mutation that leaves you unable to efficiently convert a nutrient to its active form.

Mutations on the MTHFR genes, 677 and 1298, are common. They are not problematic until they are actually expressed, or ‘active,’ and begin to affect your ability to perform normal cellular functions.

In this situation, the genetic mutation makes it more difficult for you to convert folate or folic acid to its active form, 5-methylenetetrahydrofolate.

Big word, but also a big player, as you can see below.

image from: “What is Methylation?” MTHFR and Beyond.net

Now, there’s a super massive amount of stuff going on in this diagram, and all of it is directly related to energy and fatigue potential.

Its also related to whether we can make enough neurotransmitters to feel ‘happy’ or mentally energized.

Its also related to how well our cells can detoxify waste.

Its also related to how we regulate blood pressure.

And how we produce antioxidants like glutathione.

And how well we build and replicate our DNA during cell division.

And so much more.

But the bottom line is, look over the far left side of the diagram. What do you see there? Oh shit. Its the Kreb’s cycle, aka Citric acid cycle.

If something produced in one of these methylation cycles becomes deficient, some of the enzymes and cofactors needed for the Krebs cycle are impacted.

See how this is all interconnected? What happens in any one of thousands of other nutrient cycles eventually feeds back into other cycles.

Cool, right?

But also complex. When someone has a micronutrient deficiency, rather than guessing and throwing a bunch of ‘energy boosters’ at them and hoping one works, I prefer to run a super comprehensive test that looks at both extra- and intracellular nutrients.

This is really the only way to tease out a micronutrient deficiency that can be at the root of fatigue.

This patient’s deficiency of intracellular vitamin B1 was due in part to a genetic influence whereby the patient has fewer receptors on the intestinal cell that absorb B1 from the gut, but also due to low intake of B1-containing foods. Deficient K2 was due to reduced intake of K2 from diet, and reduced abundance of bacteria that produce K2 in the gut, e.g. Bacillus species.

The above example illustrates that just a couple missing nutrients can knock out one element in nutrient cycle A, leaving that cycle unable to completely cycle through, and therefore, affecting the nutrient cycle B that needs the products of the cycle A.

Vitamin B1, thiamine, is usually found plentifully in the western diet due to what we call fortification.

This is a process in which food manufacturers add extra synthetic vitamins to a packaged food, because they strip them out during processing.

B vitamins are heavily fortified in grain products in the US.

However, when someone goes gluten-free, or especially grain-free, and does not get enough of the food sources that naturally have that vitamin, they may see a partial or total deficiency of some of those fortified vitamins.

This is in no way a recommendation to not be gluten-free, or vice versa. You just need to know how to incorporate a better variety of substitute foods for the ones you’re ommitting in order to still get your micronutrients.

Such was the case with this patient. She had celiac disease, so could not consume gluten-containing grains, which means virtually no fortified B vitamin sources in her diet.

She also ate very little pork, which is the best dietary source of thiamine, followed by trout, tuna, and black beans. Due to a recent SIBO diagnosis, she was following a low FODMAP diet, so no beans, and just wasn’t regularly eating much seafood, especially the two varieties with the highest thiamin.

Once we figured this out, in terms of the dietary deficiency, we corrected for this by including more thiamine-rich food sources (she preferred bacon and occasional canned tuna).

After a month or so of this, she reported feeling significantly more energy during the day, improved skin color (she had reported her skin appearing ‘pale’), and better mental focus.

All because of just one little vitamin missing.

Macronutrients: Kind of obvious

So, now that we’ve looked at some of the much more complex parts of cellular energy production, it may be much easier to understand why a macronutrient deficiency can lead to fatigue.

Now, I made the comment above that micronutrient deficiencies are, in my clinical experience, much more likely to lead to fatigue than macronutrient deficiencies. And here’s why.

If you live in the U.S., or just, in general, the Western world, and you are reading this, you’re also not likely lacking carbohydrates in your diet.

Carbohydrate deficiency and fatigue

Even if you follow a low carb or keto diet, chances are you still eat plenty of carbohydrates intentionally or unintentionally, or fat, which your body can make carbohydrates out of.

We consume LOADS of carbohydrates, as a ‘western culture diet.’

This includes grains (baked goods, pastries, pasta, bread, rice, quinoa, corn, etc), fruit, sugar, root veggies (yams, potatoes, carrots, turnips, chips, etc), legumes (beans, peas, hummus, veggie burgers, vegan foods) and so on.

So, I will make the statement that chances are, you are not deficient in carbohydrates.

Now, a few exceptions to this rule exist, conditionally.

If you like really intense HIIT type exercise or hypertrophy focused strength training, like CrossFit, Orange Theory, sprinting, bodybuilding, powerlifting, or olympic lifting, your muscles prefer carbohydrates for fuel during these activities.

If you are intentionally or unintentionally restricting carbohydrates, you may feel very fatigued during workouts, because you lack enough of this nutrient to fuel that glycolysis pathway, which your body prefers during those activities.

It is very inefficient for it to generate ATP through the electron transport chain/oxidative phosphorylation cycle and Krebs cycle/citric acid cycle during short intense sets, and those cycles also require oxygen directly or indirectly, which is in short supply during HIIT type training.

This can absolutely make you feel tired and perform poorly. Usually this is easily corrected by consuming carbohydrate foods or drinks before or during a workout, and replenishing them afterward, too.

If that does not fix your fatigue during workouts, your fatigue is likely not due to a macronutrient deficiency, in my experience. You probably need to explore either micronutrient deficiencies or oxidative stress as underlying causes.

You can also feel fatigued when you follow a low carb or keto diet and do not eat enough fat to offset that carb depletion. Your body wants to make energy out of either carbs or fats. If you don’t eat at least one of these, you will feel fatigued.

Now, most people who follow a ‘keto’ diet do it wrong, anyway, and aren’t actually in ketosis at all.

They fail to eat 80% of their calories from fat, because eating pure fat seems unappealing to them, so they just eat a lot of protein, and never really reach ketosis, because the body will actually make glucose, a carbohydrate, out of some amino acids, when there is not enough fat in the diet.

This will leave you feeling tired, and also leave you potentially breaking down your own body’s protein to make glucose, which is a double whammy of fatigue, for reasons we’ll get into below relating to enzymes, carrier proteins, muscle cells, and so forth.

Protein deficiency and fatigue

Another way that a macronutrient deficiency can lead to fatigue is not eating enough protein. If you go back and look at the diagrams above, you’ll notice there are a number of words that end in ‘-ase.’ These are enzymes.

Enzymes are made out of proteins–chains of amino acids. We get proteins from both plant and animal sources, and many of us have no idea how little protein we’re eating, because we eat so much carbohydrate and fat, instead.

I wrote a great article about why you need protein, if you want to go read that just to see how critical it is, and how much of it you’re really not eating.

In addition to not having enough protein building blocks to make critical enzymes for energy reactions, we might also not be able to make enough of the proteins that carry oxygen and/or iron in our blood, like heme.

This can also cause us to feel fatigued and short of breath.

Low protein intake can also impact sex hormone production, which we already discussed in part 1 of this series, as a major cause of fatigue.


Okay, I feel like this deserves a bit of a summary, if you’re still reading.

We went through the super complex concepts of energy production methods in cells, to why a micronutrient that’s not even part of those energy production cycles, might still impact them.

Then we talked about macronutrients that are either directly involved in those cycles, or indirectly feed into them also can leave you feeling tired when they’re lacking.

Nutrient deficiencies cause fatigue directly through not having enough players present to operate energy generating cycles like glycolysis, Krebs cycle, and oxidative phosphorylation.

They also lead to fatigue when micronutrients are missing from those cycles, but also when micronutrients are missing from other critical cycles that feed into those energy-generating cycles.

And then, lastly, macronutrient deficiencies lead to fatigue through either not having enough glucose or fat available to run your direct energy-generating cycles, or secondarily, not enough protein available to make the other players in those cycles, or to carry important nutrients to those cycles in your blood, like oxygen, vitamins, minerals, and so forth.

How do you know if a nutrient deficiency is causing your fatigue?

I already kind of mentioned this, but in case you need to hear it again, get your micronutrients tested and work with someone who has a thorough understanding of how macro- and micronutrients work in metabolism and cellular metabolism.

Rather than just experimenting with potentially hundreds of supplements to see what works, spend some time and money up front to get a very specific answer to your own situation and save yourself the frustration, time, and money wasted down the road of stabbing in the dark.

Whoever you work with needs to also have a thorough understanding of how to assess your dietary intake properly for whether or not this is a primary deficiency (you just don’t eat enough of that nutrient), or a secondary deficiency (you probably eat enough of that nutrient, but somewhere along the line its being stolen, not converted, poorly absorbed, or otherwise just not available to you).

Do you think that a nutrient deficiency is at the root of your fatigue? If you’re interested in exploring this, getting some lab testing done, or working with me on anything else, check out my Work With Me page for more info 🙂


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