What is chronic fatigue ? – Understanding the mechanisms of CFS
¿What is chronic fatigue ?
Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a debilitating condition of previously thought to be the unknown cause in which sufferers feel extreme fatigue, muscle and/or joint pain, swollen glands, headaches, gastrointestinal (GI) symptoms, unrefreshing sleep and post-exertional tiredness (PEM) without relief. It is currently diagnosed by the process of exclusion in which all other known fatigue causes are ruled out and there is no widely accepted Western therapy. Over the last few years, several key studies have begun to shed light on this once unknown condition and mechanistic models are now finally providing answers to the questions that the Western health industry has struggled to explain about CFS.
Since 2016 published research looking at differences in people with CFS and those without have been able to paint a much better picture of what the mechanism looks like. Both observational and mechanistic studies from multiple independent research groups have returned favourable results for identifying key markers that can help determine the flow and progression of CFS. We can now much better understand what is chronic fatigue based on 3 key studies outlined below:
-Giloteaux et al. (2016) – In this study researchers profiled gut microbial diversity by sequencing genes from stool samples in 48 patients with CFS and 39 healthy controls. They also examined a set of inflammatory markers in blood from the same patients as a gauge of intestinal damage, gut permeability and internal oxidative and inflammatory stress. All patients with chronic fatigue had increased levels of gut permeability (leaky gut), increased levels of intestinal damage and increased levels of inflammatory and auto-immune activity associated with microbial translocation. Further to this they all had a reduced gut biodiversity measured by bacterial DNA count from fecal samples compared to healthy controls.
Summary: Patients with chronic fatigue have increased bacterial gut permeability, increased incidence of leaky gut and generic gut dysbiosis of the microbiome.
-Montoya et al. (2017)– This study set out to determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration. Cytokines of 192 ME/CFS patients and 392 healthy controls were measured. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity. Of the 17 cytokines that correlated with severity, 13 are pro-inflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease
Summary: There is an immune dysfunctional component linked to the condition, with the severity of symptoms being directly related to the levels of inflammation and auto-immune inflammation. The worse the inflammation the worse the symptoms.
-Blomberg et al. (2018) – This mechanistic evaluation demonstrated that CFS patients with a genetic predisposition and dysbiosis experienced a gradual development of B cell clones that were prone to auto-reactivity. A decisive infectious trigger may then lead to immunization against auto-antigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing post-exertional malaise (PEM) and ME/CFS, affecting both muscle and brain tissue.
These and other studies allow us to better understand the pathophysiology of the condition and create a map of progression. So knowing what we now know about chronic fatigue the overall picture may look a little like this:
The 7 step mechanism of chronic fatigue pathophysiology
The above model represents a good fit for CFS and can be used to help explain many of the non-localized symptoms. Patients complain of extreme fatigue, muscle and/or joint pain, swollen glands, headaches, gastrointestinal (GI) symptoms, unrefreshing sleep, and post-exertional tiredness without relief. The feeling of a low-lying infection, swollen glands, GI upsets, and weakened immunity can be explained by the mechanism of dysbiosis leading to increased gut permeation of biome bacteria and a responding continual low-level immune response. Left unchecked this type of infection can create an immunological dysfunction and possible auto-immunity disrupting the natural stress response via dysregulation of the HPA axis (hypothalamus-pituitary – adrenals). Long-term adrenal dysfunction can explain other symptoms like sleep disruption, anxiety, feelings of burnout, etc. While dysregulation of energy metabolism can lead to symptoms like brain fog, fatigue, and post-exertional malaise (PEM).
The key questions surrounding this process are related to the triggers, i.e why does it happen? and also the step-wise progression, i.e how does it happen? Unfortunately, as everybody is different and no two people with chronic fatigue experience the same symptoms it is hard to create anything definitive as to the cause and progression. But the process itself is likely to follow the inflammatory cascade with 5 key steps:
1. Initiation and primary inflammation – What can ‘spark’ the cascade to CFS?
There are many schools of thought regarding this question, everyone with their own opinion. The organic foodies will say it is the ingestion of sprays and chemicals, the anti-vaxxers will blame vaccines, some groups say it it from antibiotics overuse (particularly in children), others say a shift from natural birthing to cesarian and/or non-breast feeding, fluoride in the water, amalgam fillings in out teeth, glandular fever, CMV or pathogenic diseases, electromagnetic radiation, 5G, over consumption of sugar, refined foods… the list goes on and on. It is risky to try and blame one specific factor and I believe it is multi-faceted. In theory all of the above could contribute, Western living has moved so far away from healthy living that our current lifestyles must be partially to blame. Obviously there is a genetic predisposition but genetics are not the only factors to consider. But once the spark is initiated the cycle begins to slowly grind down the body. We see initial dysbiosis and imbalance of gut microbiota. This is followed by breakdown of the gut lining and increased permeability (leaky gut) as a result of primary inflammation.
2. Secondary inflammation and 3. Immune dysregulation (auto-immunity)
Once bacteria begin to regularly flow through the walls in the gut lining the immune system kicks in and begins to try and keep the infection levels in check. The natural response of macrophage (immune) cells is to ignite enzymes like Myeloperoxidase (MPO) and bombard the site with nasty oxidants like hypochlorite (HOCl) and destroy bacteria that have managed to penetrate the gut lumen. The issue in CFS is that this process seems to become more dysfunctional the longer it is left to continue without healing the gut leakage. The immune cells start to produce too much or too little oxidant and the collateral damage to the gut cells causes a much larger breakdown of gut lining and influx of bacteria. Before you know it you have chronic inflammation and increase in levels of inflammatory signalling molecules like TNF-alpha that ignite an auto-immune type response. Where there was once a dripping tap there is now a fast flowing river.
3. HPA dysregulation (Hypothalamus – Pituitary – Adrenals)
After a continual immune battle stemming from the microbiome permeating the gut lining the natural stress response begins to wear down. The body is in a constant sympathetic ‘fight-flight’ state and pumps out cortisol to try and fire up the immune response to battle the infection. This in turn creates a global inflammatory state and in the case of CFS greatly exacerbates the symptoms of the condition. After continual hammering the HPA axis begins to loose it balance and we see HPA dysregulation, leading to an ineffective stress response that is either hypo – not enough or hyper – too much. This can cause long-term irregularities in hormone production, immune function and finally cellular metabolism.
Dysregulation of the HPA axis causes adrenal dysfunction and chronic inflammation, exacerbating global symptoms.
Chronic inflammation, HPA dysregulation and immune dysfunction leads to interference of energy production, metabolism and PEM.
4. Energy production dysfunction (PEM)
Following long-term dysregulation of the HPA axis the energy production pathways of the body’s cells begin to malfunction, particularly in the gut. There is an inability to smoothly convert glucose to acetyl-co-A and the mitochondria struggles to produce adequate ATP. Furthermore as the dysfunction increases so do the levels of reactive oxygen species (ROS) created as a by-product of ‘unclean’ metabolism. These inflammatory molecules create increased levels of cellular inflammation and cause more dysfunction. In essence metabolising creates more damage and exercise leads to fatigue and exacerbation of symptoms – known as postexertional malaise (PEM). This leaves the person exhausted, foggy, tired and at rock bottom, burning fuel they no longer have.
Following the inflammatory cascade we find a chicken or the egg situation where the tail of one leads to the mouth of the other. The initiation in the gut leads to the dysregulation in the brain and this in-turn returns to initiate more inflammation in the gut.
So regardless on the position a patient begins on the progression once in place the model displays a downward spiral that propagates it’s own demise. This seems to be the reason why people with CFS find it so difficult to recover as working on one aspect of health may be overridden by other multi-faceted dysfunctions pulling the person back into the downward spiral.
Either way the progression the gut leads to the brain and the brain leads to the gut creating a downward spiral of pathophysiology.
Many new studies have begun to unlock the once unknown physiology of chronic fatigue. There are still many questions to answer about the full details but we now have a much clearer model of what is going on than we had even 5 years ago. Understanding some of the key points and processes gives us the ability to focus our attention towards management and recovery plans.
Having personally recovered from chronic fatigue there are many things I wish I had known during my journey as the process could have been much more streamlined using a similar model as the one outlined above. Given no two people are the same and no two chronic fatigues are the same there is no ‘one size fits all’ but there is now at least a framework that can help narrow down opportunities to assist with recovery. I personally believe that recovery is possible for anyone given the right health map, plan, knowledge and mindset. To read more see my journey here and subscribe for more future updates and information on how to create your own health map for recovery.