Genetics, the mono virus, gut bacteria, and even hormones have each been thought to be causes of chronic fatigue.
Maybe each of these is too specific. Maybe the root cause of fatigue is something more generalized.
Maybe chronic fatigue is a consequence of inflammation. Inflammation that has gotten out of control and is affecting multiple body systems. Nothing at all like the inflammation found in a sports injury.
The last time you sprained your ankle, it became red, hot to touch, swollen, and painful didn’t it?
This is the inflammatory process at work. And when it occurs in a localized area (like an ankle), the process of inflammation works wonders. Inflammation is absolutely essential for your body to heal that ankle sprain. Inflammatory cells (macrophages) release a hormone called insulin-like growth factor 1 (IGF-1). (1) IGF-1 helps your muscles and other damaged tissue in the area to heal. When you ice an ankle sprain, you suppress your body’s ability to heal the injury. This is why I never recommend to ice an injury. New research suggests icing an injury actually makes things worse. (2)
But chronic fatigue syndrome is a much more complex process than an ankle sprain. That complexity allows CFS to affect many different areas of your body. From your brain to your immune system (and everywhere in between) become affected. And inflammation may be what’s at the root cause of all your problems.
What exactly is inflammation?
Inflammation is the complex biological response your body uses to respond to harmful stimuli. (3) When your body gets exposed to a virus, it responds with two different immune systems:
- Innate immune system
- Adaptive immune system
The innate immune system is a much more generic immune system response. Inflammation is a prime example of an innate immune system response. As soon as your immune system identifies an intruder, it looks to create a physical barrier between the introducer and itself. This barrier is created through the process of inflammation. Think of your innate immune system as a shotgun approach. It’s a generalized means to eliminate invaders.
The adaptive immune system is much more specific. Adaptive immunity occurs after your initial exposure to a virus/bacteria/etc. Remember chicken pox (varicella virus)? The reason you never catch that virus any more is because of your adaptive immune system. Your adaptive immune system remembers previous encounters with infectious agents. When you get exposed to them again later in life, the adaptive immune system easily remembers how to neutralize the threat. Thanks to your adaptive immune system, you never get chicken pox again. The adaptive immune system is likened to that of a sniper rifle – a targeted approach to eliminating invaders.
One causal theory of chronic fatigue that is being explored suggests that the innate immune system is unable to turn off. This causes inflammation to run rampant. And as you’ll learn later in this post, there are specific types of inflammatory markers that are strongly linked to chronic fatigue.
The fatigue-inflammation connection
Many chronic fatigue patients report that their symptoms began after infection. Sometimes the infection was a bad flu virus. Others report their fatigue began after catching mono.
As far as inflammation goes, this would make good sense. Flu viruses, mono viruses, and any other infectious agents all require your body to create inflammation in order to neutralize the attack. Could your body’s immune system get stuck in the on position; resulting in a neverending cascade of inflammation?
What confuses most doctors is that conventional inflammatory markers are rarely elevated in chronic fatigue syndrome. (3) These conventional markers include:
- C-reactive protein (CRP)
- Erythrocyte sedimentation rate (ESR)
No wonder your doctor tells you that inflammation isn’t your problem! But CRP and ESR are generalized markers for inflammation. Chronic fatigue syndrome is a sneaky illness. The inflammation found in CFS is not caused by the usual suspects.
- Transforming growth factor beta (TGF-β)
- This marker is commonly elevated in chronic fatigue.
- This marker is commonly lower in chronic fatigue.
Transforming growth factor beta (TGF-β)
It is commonly thought that TGF-β is an anti-inflammatory cytokine. (6) Meaning that when your body is dealing with an infection (or localized inflammatory state), TGF-β would be excreted to help lower the levels of inflammation. This would explain why TGF-β is commonly elevated in CFS – it’s trying to lower inflammation, and there’s a lot of inflammation in CFS. So, TGF-β levels rise.
But new studies are suggesting that TGF-β can alter its role depending on its location in your body. (7) In conditions like inflammatory bowel disease (IBD), TGF-β has been shown to contribute to inflammation in the gut. (8) If this is the case in chronic fatigue as well, TGF-β could be a potential causal agent in relentless levels of inflammation within your body. (9)
Resistan has been shown to have a significant effect on promoting inflammation. (10) That is to say, it is a pro-inflammatory cytokine. You’ll find elevated levels of resistan in autoimmune conditions like lupus (SLE) and Crohn’s disease. (11)
In the context of chronic fatigue, resistan displayed confusing behavior. In patients whose fatigue was mild-moderate, resistan levels increased. But in those with moderate-severe levels of fatigue, resistan levels decreased. (12) At the time of this writing, researchers are unsure why resistan levels fluctuate as chronic fatigue progresses.
Resistan and TGF-β are two of the more commonly elevated inflammatory markers in fatigue. Both have repeatedly been shown to be out of range in chronic fatigue syndrome. But new research has found many more markers of inflammation to be out of range in CFS. With all this inflammation going on, could chronic fatigue syndrome be closely related to an autoimmune condition?
Is chronic fatigue syndrome an autoimmune condition?
The autoimmune-fatigue theory came about by way of a happy accident. In 2008, an oncologist in Norway treated one of his cancer patients with a drug called rituximab. Shortly after receiving rituximab, the patient noted that her chronic fatigue was no longer present. This sparked a small research trial into the effectiveness rituximab was on CFS.
Thirty patients were given either rituximab or a placebo. 67% of chronic fatigue patients that received rituximab experienced a significant self-reported decrease in their fatigue levels (compared to only 13% of those that received a placebo). (13) Rituximab is commonly used to treat autoimmune disorders. It’s effective in the treatment of autoimmunity as it decreases the effectiveness of your immune system.
When this small study was run, the researchers proposed that chronic fatigue syndrome was, in fact, an autoimmune condition. New research was started to investigate CFS under the light of autoimmunity. But when a large scale clinical trial was run, it was found that rituximab offered no long-term benefit to CFS patients. (14) Chronic fatigue syndrome is not an autoimmune disease. At least that’s the general consensus at this time.
Something autoimmune diseases and chronic fatigue do share in common is inflammation. And new research suggests that there are specific markers of inflammation that are strongly correlated with fatigue.
More inflammation, more fatigue?
Thanks to modern testing methods, researchers are now aware of far more inflammatory cytokines than ever before. This means that there are many different variables that can be measured to see if they correlate with fatigue. You no longer have to depend only on c-reactive protein (CRP) and ESR as the only ways to measure inflammation and immune activation. Though these two are still probably all that will be measured at your family doctor’s office.
A recent study tracked 51 different cytokine levels to see if any of them were connected to chronic fatigue syndrome. This study compared cytokine levels of 186 CFS patients to cytokine levels of 388 non-fatigued members of the population. In this study, there were 17 different cytokines that were strongly correlated with fatigue severity. (15) Cytokines are cell signaling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection, and trauma. (16)
Of the 17 different cytokines found to be correlated with chronic fatigue, 13 of them were pro-inflammatory. Meaning that those thirteen cytokines assist your body in increasing inflammation. Odds are high that it’s these cytokines that contribute to a number of the symptoms commonly associated with CFS. The 13 pro-inflammatory cytokines include: (16)
- CL11 (Eotaxin-1)
- CXCL1 (GROα)
- CXCL10 (IP-10)
The above thirteen inflammatory cytokines had a strange connection to chronic fatigue. Common knowledge would lead you to believe that these markers would be elevated in CFS patients and lowered in members of the general population. But that’s not what happened at all.
Those with chronic fatigue that was rated as mild or moderate had levels of the above cytokines statistically lower than members of the general population. (17) But those with severe or debilitating levels of fatigue experienced an elevation of the above cytokines. (18) This is why so many other studies have been unable to find a strong connection between inflammation and chronic fatigue syndrome. (19)
It’s not a simple linear relationship between inflammation and fatigue. More inflammation does not always create more fatigue.
A unified fatigue-inflammation theory
No wonder chronic fatigue syndrome is so complicated. Even inflammatory markers don’t follow a “normal” curve in this condition. But there’s a theory as to why that may be.
Those with CFS may be predisposed with an immune system that functions differently than the general population. Dr. Ritchie Shoemaker believes this genetic difference to be caused by the HLA genes. (20) Approximately 25% of the population possess these genes. And it’s these genes that are thought to be what triggers a chronic inflammatory response within the body.
Chronic fatigue patients could have a genetic preponderance to lowered baseline levels of inflammatory cytokines. This has been illustrated through the above study – in general, CFS patients had lower levels of inflammatory cytokines when compared to the general population. (21) The catch here is that this only occurs when the fatigue is mild.
Once fatigue levels increase, chronic fatigue patients are shown to have strong elevations of inflammatory cytokines. The levels of inflammatory cytokines in CFS patients levels are far higher than that of the general population (but only when fatigue levels are severe). This cyclical nature of inflammation could come about through the immune system acting on an infectious agent(s).
Take mold for example. Mold illness is commonly thought to be a root cause of chronic fatigue. In genetically susceptible individuals, mold (and their mycotoxins) trigger the innate immune system to respond. The response of the innate immune system is always one of inflammation. Those with the HLA genes struggle to expel the mold toxins from their body. This results in a vicious cycle of inflammation. Below, I lay out a proposed mechanism of action:
- Step 1: Immune system is dormant when fatigue levels are moderate
- Possibly why you see low levels of cytokines in CFS patients with mild fatigue levels.
- Step 2: Immune system identifies an infectious agent
- This is the in-between stage. Where in the study inflammatory cytokines were neither high nor low.
- Step 3: Immune system reacts to the infectious agent
- This is when you would see an increase in inflammatory agents in the blood.
- The immune system has identified the infectious agent and is mobilizing a response to fight it off.
- Step 4: Immune system calms down
- After mounting an attack, the immune system down-regulates.
- Step 5: Repeat
- This cycle continues on and on without ever fully resolving the condition.
This cycle of inflammation would explain why your fatigue could be good on some weeks/months (calming of the immune system) yet debilitating the following week/month (activation of the immune system). A more detailed look at the inflammatory process can be found here. And if you want to know more about mold’s connection to chronic fatigue, keep your eye on our site. I should have mold-related articles posted within the next 30 days!
To summarize, inflammation and chronic fatigue are most certainly connected. But exactly how that relationship exists within you needs more research.
Now, I want to hear from you!
What have you noticed negatively affects your energy levels?
Do you think it could be because it raises inflammation in your body?
Let me know in the comments section below!
Also published on Medium.