While most of us have felt a sense of perpetual fatigue at some stage, usually during a stressful period in our lives, there are those amongst us who wake up every day feeling as though they haven’t slept a wink.
To be diagnosed with chronic fatigue syndrome (CFS) a feeling of debilitating exhaustion has to persist for longer than six months and be accompanied by a number of other symptoms varying from cognitive impairment to myalgia and arthralgia.
Since there is no current accepted biomarker for CFS, other possible causes for the symptoms are first investigated and excluded.
Immune dysregulation is commonly observed in patients diagnosed with CFS, however it hasn’t been until recent years that CFS research has increased and investigations are underway as to whether it can be classified as an autoimmune disease.
Autoimmunity has become increasingly prevalent in developed countries, with improved hygiene and decreased gut microbial diversity hypothesised as a primary factor. Other risk factors that may contribute to the development of an autoimmune disease include genetic predisposition, poor diet, psychosocial stress and recurrent viral infections, such as Epstein-Barr virus (EBV).[3,4]
These risk factors correlate with the development of CFS, however correlation does not give us a complete picture and sometimes it’s hard to differentiate what came first, immune dysregulation, EBV or the onset of CFS. Let’s look a little closer at what we do know.
The role of the microbiome in CFS
The most current research assessing gut dysbiosis in CFS is coming out of Columbia University, New York. Findings have been considered a significant breakthrough in establishing biomarkers of disease. The study examined 100 people and showed those with CFS had a decreased microbial diversity and altered metabolic pathways, even in patients who did not display symptoms of IBS.
While this is most definitely not the first time the association has been investigated, it does appear to support and build upon previous research, which is a cause for some form of celebration, considering the heterogeneity of the disease.
IBS as a comorbidity is extremely common, with up to 90% of all patients also being diagnosed with IBS either before or after onset of symptoms of CFS. The research from Columbia University set out to delve further into the already emerging role gut bacteria and their metabolites play in disease progression outside of localised pathology, such as in central nervous system, immune and cognitive dysfunction.
Stool analysis showed the number and diversity of bacterial families Lachnospiracea and Porphyromonadaceae in CFS patients to be decreased, with abundant Clostridiaceae compared with controls. A decreased number of the genera Faecalibacterium and the increased colonisation of Alistipes were found to be predictive of CFS development and increased severity of symptoms.
These findings apply to patients with and without concurrent IBS, however there were additional differences seen in each group of patients. Faecalibacterium prausnitzii in healthy adults is the most abundant and potentially the most important commensal species of bacteria, due to its role in the production of short chain fatty acids (SCFAs), specifically butyrate. Decreased levels have previously been associated with crohn’s disease (an autoimmune condition).
F. prausnitzii has an anti-inflammatory effect on the enterocytes, via the production of microbial anti-inflammatory molecules shown to inhibit nuclear factor-κB (NFkB) and subsequent pro-inflammatory cytokines. NFkB plays an important role in moderating the immune system, with upregulation associated with the production of autoantibodies and development of autoimmunity. This process has also been linked to mitochondrial dysfunction, which is a key contributor to fatigue in CFS patients.
Immune dysregulation in CFS
Pro-inflammatory cytokines linked to CFS include interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), a marker of systemic inflammation usually present only in the acute phase of infection. Chronic elevation of TNF-alpha and T cell activation is linked to other rheumatic autoimmune diseases such as rheumatoid arthritis.
Pro-inflammatory cytokines are commonly observed in the first three years of onset of symptoms of CFS. Following this, they appear to be significantly decreased, sometimes even lower than what is found in healthy individuals, which may be due to an exhaustion of cytokine-producing cells. This is one theory as to why the evidence on the role of cytokines in CFS appears contradictory.
With all this conflicting evidence and hypotheses on the topic, there is one consistent finding we can rely on - reduced natural killer (NK) cell cytotoxic activity. NK cells play an important role in early recognition of viruses and a reduced number of these lymphocytes could be indicative of a recent viral infection, such as may be seen in post-infective CFS diagnosis.
Studies on NK cells have yet to identify whether it is a depleted number of NK cells that leaves the susceptible individual open to, or more specifically to, increased severity of, EBV or human herpes virus 6 (HHV-6) infection, or whether it is the malfunctioning of these cells that is to blame.
Impaired NK cell function has been identified in the development of other disease states, including rheumatoid arthritis and endometriosis. Specific alterations that have been identified include altered perforin and granzyme concentrations, which could merely indicate recent infection.
How about autoantibodies?
Elevated autoantibodies in CFS have been found to target neurotransmitter receptors, specifically beta adrenergic and muscarinic cholinergic receptors. These findings correlate with symptoms of autonomic dysregulation.
In assessing possible treatments for CFS, rituximab was trialled as an immunosuppressive drug intervention, targeting B lymphocytes. Treatment with rituximab resulted in a reduced number of autoantibodies over five months and a reduction in symptoms of CFS. Efficacy of rituximab may also be attributable to the interference of B lymphocytes infected with EBV. The research is preliminary at this stage and mechanism of action is partly speculative, however the findings so far support CFS being categorised as an autoimmune disease.
Another treatment that has shown promising results, however may not be addressing the cause, is targeted antiviral against against EBV and HHV-6.
In looking at the role of EBV in CFS, it appears while current or recurrent infection is commonly observed, and may be a factor in continuation of symptoms, it may not be as specific a predictor as previously thought. Up to 90% of young adults have been exposed to the disease and have EBV antibodies, however many will be asymptomatic and will suffer no consequences as a result. EBV in somebody who already has an immune system which is under stress may act as an opportunistic pathogen in the susceptible individual, rather than being the actual instigator.
From the current research available, it doesn’t appear CFS is able to be placed wholly in the category of autoimmune disease at this stage. Inflammation and gut dysbiosis are likely drivers of the disease, with immune dysregulation precipitating an infection.
Further studies are needed to truly understand the development of the disease and provide insight into how to better prevent and treat the condition in susceptible individuals. Other factors that should be considered in understanding CFS include nutrient deficiencies, antibiotic use, diet and lifestyle choices of the patient.
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