Severe fatigue, associated with chronic fatigue syndrome (CFS) or another disorder, has as a core underlying cause chronic inflammation. A valuable paper recently published in BMC Medicine illuminates the role of immune activation and peripheral inflammation with subsequent neuroinflammation and mitochondrial damage as key clinical features. The authors state:
"The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome."
Fatigue triggered by acute infection or ongoing autoimmunity
In either case, immune cells in the brain are activated and persist as chronic neuroinflammation, the linchpin of fatigue.
"There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue.
They point out that chronic immune activation and systemic inflammation are associated with debilitating fatigue in conditions as diverse as multiple sclerosis, Alzheimer’s and Parkinson’s disease, major depression, systemic lupus erythromatosis (SLE), Sjogren's syndrome, and rheumatoid arthritis.
Elevated cytokines, oxidative and nitrosative stress (O and NS) and NF-kappaB
They note that viral and bacterial infections are not always the trigger, and that other factors including environmental toxins can promote chronic inflammation.
"One of the key drivers in the development of chronic immune activation in the absence of bacteria or virus infection is the development of chronic inflammation as evidenced by elevated levels of cytokines and oxidative and nitrosative stress (O and NS) and characterized by activated NF-kappaB. Indeed, the production of proinflammatory cytokines and other inflammatory molecules by macrophages and other sentinel cells, even in the absence of pathogen invasion, and the subsequent activation of NF-kappaB are early events in the genesis of chronic inflammation. Activation of this transcription factor leads to the upregulation of cytokines and O and NS. These players can engage in a feed-forward manner to maintain and amplify chronic inflammation and immune activation in a TLR radical cycle."
In other words, in many conditions associated with fatigue there is a self-maintaining feedback loop of chronic inflammation that sustains activation of NF-kappaB (nuclear factor kappa beta), thus promoting chronic and persistent inflammatory damage. Hence the great clinical importance of the benign agents available to clinicians that help wind down NF-kappaB activity.
Damaging the intestinal barrier systems
Loss of barrier integrity of the intestinal mucosa (and the blood-brain and respiratory barriers) is a major contributor to the loss of immune tolerance and maintenance of chronic inflammation and associated fatigue.
"Chronically elevated levels of NF-kappaB, proinflammatory cytokines and O and NS, in turn, lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, which can further amplify the TLR-radical cycle by acting as a pathogen-associated molecular pattern (PAMP). Translocation of bacterial lipopolysaccharides (LPS) from the gut and engagement with TLRs, due to a state of increased intestinal permeability driven by the effector molecules of chronic inflammation is another cause of chronic immune activation that may play a role in major depression, CFS, neuro-inflammatory disorders and some systemic autoimmune disorders."
Toll-like receptors (TLR) and fatigue
See a brief animation of the TLR signaling chain in inflammation at the bottom. TLR activation is a key step in inflammation that produces fatigue:
"Given the established association between chronic inflammation and the genesis of incapacitating fatigue, the TLR-radical cycle can potentially explain the development of incapacitating fatigue in patients suffering from these and other illnesses. This association may be explained by chronically increased levels of proinflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) produced by the TLR-radical cycle upon stimulation by PAMPs and DAMPs. We have reviewed previously that some proinflammatory cytokines, including IL-1β, TNF-α and IL-6, and increased O and NS processes may cause fatigue in some vulnerable individuals."
Mitochondrial dysfunction and fatigue
Disruption of the capacity to produce energy at the cellular level and depletion of ATP further contribute to fatigue. Multiple sclerosis offers one example:
"Mitochondrial dysfunction likely plays a major role in the progression of MS. Electron transport chain (ETC) complex I, complex III and complex IV activity is grossly reduced in normal appearing gray matter and in normal tissue within the motor cortex in patients suffering from this illness. There is also direct evidence of globally impaired energy production and longitudinal depletion of ATP levels leads to increased levels of physical disability."
Inflammatory and oxidative damage to mitochondria also figures in chronic fatigue and major depression:
"Multiple lines of evidence demonstrate the existence of mitochondrial dysfunction in many, but by no means all, patients afforded a diagnosis of CFS. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins. Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse. There is also accumulating evidence that inflammation and subsequent mitochondrial dysfunction drive the symptoms of major depression."
Mitochondial dysfunction and glutathione depletion in autoimmunity
Fatigue in autoimmune disorders occurs from neuroinflammation and when the capacity to produce energy is derailed.
"Localized or global mitochondrial dysfunction is also an invariant feature of autoimmune diseases. Persistent mitochondrial membrane hyperpolarization and increased O and NS production combined with depleted levels of glutathione and ATP is an invariant characteristic of T cells in SLE. The release of DAMPS into the systemic circulation, consequent to necrosis, acts as a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation which, in turn, amplifies mitochondrial dysfunction in a vicious feed-forward loop. The association between chronic oxidative stress, systemic inflammation and mitochondrial dysfunction and chronic oxidative stress is also firmly established in Sjogren's syndrome. There is also evidence of widespread nitric oxide (NO)-induced inhibition of complex III and V of the ETC in patients with rheumatoid arthritis. The causative role of chronic inflammation and oxidative stress and mitochondrial dysfunction is explained by the presence of elevated levels of ROS and RNS in such environments. These entities cause damage to proteins, DNA and lipid membranes. NO and peroxynitrite have the capacity to inhibit crucial enzymes within the ETC and can inactivate crucial enzymes in the tricarboxylic acid cycle leading to, often critical, reductions in the generation of ATP. Peroxynitrite, in particular, also has a destructive influence on the mitochondrial membrane leading to the loss of potential difference between the outer and inner membrane needed to manufacture ATP. The products of lipid peroxidation driven by elevated levels of ROS are also toxic to mitochondrial membranes. It is noteworthy that inhibition of the ETC leads to the formation of even higher concentrations of oxygen radical species which, in turn, leads to further impairment of mitochondrial function."
Chronic fatigue syndrome
CFS has multiple causes that combine in varying ways for each individual.
"Pathological levels of fatigue unrelated to activity and not relieved by rest is a mandatory requirement for a diagnosis of chronic fatigue syndrome under the current internationally accepted diagnostic guidelines. The original diagnostic criteria contained another mandatory element, namely a clinical picture whereby the patient’s global symptoms represent a unitary illness with a single pathogenesis and pathophysiology. It is more likely that a diagnosis of CFS represents a spectrum of illnesses where different pathophysiological processes converge to produce a very similar phenotype."
Immune dysregulation and present with different types of imbalances with chronic fatigue:
"Numerous research teams have reported a wide range of peripheral immune abnormalities in people afforded a diagnosis of CFS...now data reveal that while some patients present with a Th2 profile and a preponderance of anti-inflammatory cytokine production, others present with a Th1 or possibly Th17 profile, with the synthesis of proinflammatory cytokines being dominant...We have reviewed previously that patients with CFS and Myalgic Encephalomyelitis (ME) show different cytokine profiles, for example, a Th1-like pattern, with increased levels of IFN-γ, IL-2, IL-12 and IL-2 receptor, or a Th2-like pattern, with increased levels of IL-10, IL-4 and IL-5, or combinations thereof. Two recent studies reported evidence of activated TLR4 receptors. The causative relationship between chronic inflammation and the development of fatigue is perhaps strongest in patients afforded a diagnosis of CFS, with many studies demonstrating a significant positive correlation between surrogate markers of inflammation, oxidative stress and symptom severity."
And addressing these causal patterns can afford relief:
"Miwa and Fujita (2010) demonstrated that a rapid decline in inflammation and oxidative stress of patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile."
Major depression and fatigue
It is now well established that major depression is a disorder characterized by chronic neuroinflammation:
"The existence of increased levels of circulatory proinflammatory cytokines in these patients is now a textbook truism...Fatigue of variable severity occurs in practically 100% of people with a diagnosis of depression. It is worthy of note, however, that a systematic review reported that almost 80% of patients still experienced chronic debilitating levels of exhaustion following treatment of their depression. This is perhaps to be expected given that several studies have now demonstrated that antidepressants have no positive modulatory effects on fatigue."
Chronic inflammation, oxidative damage, intestinal barrier permeability and mitochondrial dysfunction all can contribute to depression:
"There is copious evidence of chronically activated T cells with Th1, Th2 and Th17 patterns of differentiation...Chronic systemic inflammation and oxidative stress play a major role in the etiology of depression. Elevated levels of redox-damaged DAMPs, including oxidized low density lipoprotein, oxidized phospholipids, and malondialdehyde (MDA)-adducts are also consistently found in patients suffering from this illness. Compromised epithelial barrier integrity is also a finding in depression and the resulting bacterial translocation into the systemic circulation is intimately involved in the pathogenesis of the disease. Mitochondrial dysfunction affects neuronal function, synaptic plasticity, energy metabolism and neurotransmitter release and, hence, it is not surprising that there is increasing evidence that mitochondrial dysfunction and inflammation drive the symptoms of major depression. Gardner and Boles highlighted the fact that research has failed to confirm a consistent relationship between serotonin levels and depression and that compromised bioenergetics should become a focus of research into the pathogenesis of the illness."
Inflammation in the periphery can fire up inflammation in the brain
There is cross-talk between the rest of the body and the central nervous system that promotes neuroinflammation and fatigue. As this continues the pathways become primed to maintain dysfunctional inflammation even in the absence of the original triggering stimuli.
"There is now copious evidence that chronic or intermittent inflammation...can worsen or trigger neuroinflammatory or neurodegenerative processes via the induction of primed microglia. Briefly, prolonged or intermittent peripheral inflammation and immune activation act to prime microglia which thereafter become exquisitely sensitive to future inflammatory stimuli. Once microglia have achieved this sensitized status, subsequent peripheral inflammation and proinflammatory cytokine production mediated by a number of insults (for example, biotoxin exposure or pathogen invasion) provokes an exaggerated response from microglia and the production of excessive concentrations of neurotoxic molecules, such as nitric oxide, peroxinitrite, prostaglandins, cyclo-oxygenase 2 and cytokines. The secretion of these neurotoxins and alarmins leads to the activation of astrocytes and the combined activation of these glial cells provokes dysregulation of brain homeostasis, development of chronic neuroinflammation and neurotoxicity."
Neuronal (vagal) and cytokine signaling from the periphery to the brain are involved, with disruption of the blood-brain barrier....
"Both humoral and neuroendocrine routes mediate proinflammatory signaling to the brain. The neural route operates via the dorsal motor nucleus of the afferent vagus nerve. The humoral route is facilitated by circulating proinflammatory cytokines that communicate their presence to the brain via direct and indirect routes. Such pathways involve engagement with specific transporters in the blood brain barrier (BBB)...The cumulative effects of proinflammatory cytokines and activated astrocytes cause disruption of the BBB allowing abnormally high numbers of activated T cells and B-cells to circulate between the peripheral immune system and the brain, acting as more channels of communication between the peripheral and central immune system. It should be noted that cytokines are able to diffuse from the CNS into the bloodstream as well."
Gender, hormones and inflammation
There are important sex-related differences in autoimmune predilection associated with the immunomodulatory roles of sex hormones.
"An increased incidence rate in women is observed in most autoimmune disorders...Estrogen, progesterone and testosterone play important immunomodulatory roles and influence the quantity and pattern of cytokine secretion by antigen presentation cells and T lymphocytes and immunoglobulin production by B cells. Sex hormones also regulate the Th1/Th2 balance of the immune system, the production of regulatory T cells and the functionality of granulocytes and natural killer cells."
Clinicians should remember that, while estrogens are neuroprotective at physiological levels, they can promote autoimmune inflammation when excessive.
"...Thus, excessive estrogens but less androgens may favor activation of B cells, a Th2-like response and increased numbers of autoimmune cells and, thus, autoimmune responses."
Inter-related mechanisms produce fatigue
Clearly, a systems biomedicine perspective is required to grasp the dynamics, and peripheral inflammation plays a key role.
"It is of interest that levels of peripheral inflammation, oxidative stress and TNF-α also display a positive correlation with objective markers of disease activity and disability levels and that levels of proinflammatory cytokines correlate positively with levels of fatigue. The existence of gray matter atrophy before the advent of white matter abnormalities, and the existence of metabolic abnormalities before the advent of gray matter pathology, rather argues against the proposition that the chronic peripheral immune activation and oxidative stress seen in early disease is secondary to the release of inflammatory mediators from the CNS. These observations, coupled with data demonstrating that the severity of neuro-inflammation depends on the level of peripheral immune activation and that inflammation drives the development of disease, emphasizes the likely causative role of peripheral pathology. The strong association between the severity of fatigue and disability and the level and geographical distribution of glucose hypometabolism and gray matter hypoperfusion strongly indicates that these elements are driven by generic rather than disease specific pathology...There is also evidence demonstrating that the severity of fatigue is associated with the degree of white matter hyperintensities in people with SLE and evidence that the neuropathology in Sjogren's syndrome is immune mediated. The widespread mitochondrial dysfunction seen in people with autoimmune diseases could also make a significant contribution to the development of fatigue...Given that many such patients also display evidence of peripheral immune activation, oxidative stress, gray matter pathology, glucose hypometabolism, hypoperfusion and metabolic abnormalities in the prefrontal cortex, basal ganglia and elsewhere, it would seem reasonable to investigate all such patients for the presence of these abnormalities. Standard MRI is unlikely to be helpful but other approaches discussed in the main body combined with serum measures of immune activation and oxidative stress may well bear fruit."
Clinical bottom line
Practitioners need to view the complex and dynamic interactions at play for case analysis and treatment planning.
"..the multifactorial triggers that cause secondary fatigue by activating the networks/pathways in those disorders, including viral and bacterial infections, bacterial translocation, psychosocial stressors, exposure to adjuvants, nicotine dependence, sex- and gender-related factors, and so on. Towards this end, a systems biomedicine approach is essential to delineate the genetic and molecular signature of fatigue in these disorders and the non-linear interactions between the many pathways, networks, and trigger and genetic factors that underpin secondary fatigue."
And the authors conclude by mentioning a short list from among the varied therapeutic resources already in use:
"Multi-targeting these interlinked dysfunctions may show benefit in these diseases. For example, a number of antioxidant compounds have demonstrated efficacy in modifying pathways leading to chronic inflammation, oxidative stress and immune dysregulation at relatively high doses for a long duration. N-acetyl-cysteine is an example of a multi-target therapeutic approach having the capacity to decrease the levels of ROS/RNS, increase the levels of cellular antioxidants, such as reduced glutathione, and normalize the production of proinflammatory cytokines and immune cell functions. This supplement has demonstrated the capacity to improve fatigue and disease activity in SLE, CFS and major and bipolar depression. Omega-3 polyunsaturated fatty acids (PUFAs) and zinc are also very effective antioxidants and anti-inflammatory compounds and supplementation has produced clinical benefit in patients diagnosed with depression and chronic fatigue syndrome...Curcumin, another nutraceutical with anti-inflammatory and antioxidative effects, is useful in the treatment of depression and rheumatoid arthritis. Coenzyme Q10 is another powerful antioxidant and anti-inflammatory compound which also has positive effects on mitochondrial function and which displays disease modifying effects in Parkinson’s disease and produced clinical benefit in patients with a diagnosis of CFS. Other approaches aimed at upregulating antioxidant defenses include N acetylcysteine, methylfolate and dimethyl fumarate, with the latter displaying disease modifying properties in MS . Methylfolate produces a similar quantum of benefit in MDD as antidepressants and can often be effective in treatment-resistant depression."
Of course for these and many more therapies clinicians should shun a 'try this, try that' approach and employ the abundant objective laboratory resources to target specific needs on an individual case basis. The authors conclude:
"It is concluded that there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage."
Toll-Like Receptors Pathway
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