Unexplained chronic fatigue or absolute lack of energy, tenderness in the body, brain fogginess, inability to function efficiently that would last for months or years and all that in the absence of any other organic disease, has long perplexed physicians – it is something that is characteristic of chronic fatigue syndrome (CFS).
Many individuals complain about CFS. In the absence of specific tests that could show the changes in the body, diagnosis of CFS remains difficult. Fortunately, more scientific researches are being conducted to understand the disease processes better.
Researchers now know that chronic inflammation and resulting neural changes are central to the development of CFS, that is why CFS is also called Myalgic Encephalomyelitis.
There are several mechanisms involved in the disease development like immune dysregulation, chronic inflammation, perhaps even changes in the gut microbiota, and much more. In recent year chronic activation of NF-kB has received lots of attention.
Researchers consider that dysregulation of NF-kB has a central role in the development of chronic conditions like CFS/ME and in many other chronic diseases like metabolic disorders, cancers, autoimmune disorders, dementia, to name the few1.
What is NF-kB?
NF-kB (Nuclear Factor- kappa B) is a transcription factor. It is the name for a group of proteins that help in translation of genetic information and thus playing a role in protein synthesis. Transcription factors can be called as mediators that help our cells to read the genetic code and manufacture various proteins as per instructions. There are hundreds or perhaps thousands of transcription factors in human cells, each capable of translating only specific segment of DNA. Thus an excess or a deficit of transcription factors may create protein disbalance and dysregulation of body functions.
NF-kB is known to play a vital role in the regulation of immunity and inflammatory processes. Therefore, it’s over-activation is believed to be implicated in chronic inflammation and related diseases. NF-kB can both upregulate and downregulate inflammation and immune responses, by controlling the gene expression2,3.
Triggers for Chronic NF-kB Activation in CFS/ME & Fibromyalgia
It is well known that ME/CFS and Fibromyalgia often occur after some viral infection or period of prolonged stress/ trauma. Some people fail to regain the previous energy levels after the illness.
It is now well known that NF-kB has an important role in immune and inflammatory responses. NF-kB activation is triggered by both the infective agents or inflammatory mediators like cytokines resulting in cell proliferation, and initiation of further immune and inflammatory responses4.
A. Latent Virus Activation – Epstein Barr
Viral infections are especially known to cause malaise, muscular pain, changes in immunity and even provoke some type of cancers. It is true for both acute viral infections or activation of latent viruses. There are many types of viruses that live in our body without causing any illness. However, they may become activated and lead to diseases under certain circumstances. Some viral families are well known to behave in this manner. Example of one such notorious virus is Epstein Barr virus. It is now known that viruses like Epstein Barr may cause long-lasting health conditions through the activation of NF-kB, directly5.
Viruses may also activate NF-kB through induction of inflammatory substances like cytokines, IL-1beta IL-6, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma, secondarily. These inflammatory responses play a critical role in the development of immunity towards viral infections6. Nonetheless, they also lead to chronic activation of NF-kB (thus persistent inflammation), which explains the long-lasting malady after viral infections.
Another way by which viral infections affect the host immune and inflammatory responses are via induction of nitric oxide synthase (iNOS). iNOS leads to increased production of nitric oxide (NO). NO is useful in protecting the body from the bacterial infections, but in viral infections, there is over-production of NO, which is damaging and is immunomodulatory too.
High levels of NO in viral infections generate potent oxidant called peroxynitrite. Peroxynitrite, in turn, depletes anti-oxidants, causes tissue injury, and alters immune responses7.
B. Prolonged Psychological Stress
Prolonged psychological stress is another factor associated with chronic activation of NF-kB and resulting changes in immune responses, and prevalence of chronic inflammation8.
Other conditions well-known to be associated with chronic inflammation, reduced immunity, metabolic disorders are chronic bacterial and fungal infections, increased oxidative stress for any reason, disruption in circadian rhythm (mainly because of sleep disorders).
Effects of chronic NF-kB activation
Impact on the Immune System
NF-kB is the essential part of immunity, as inflammatory responses are necessary to defend and repair the body. However, once the pathogens have been neutralized and repair is done, these responses need to be down-regulated. If this down-regulation does not work, then this defensive mechanism may become damaging in itself. It is what happens in the chronic activation of NF-kB. NF-kB controls the inflammatory responses through gene transcription and production of various inflammatory substances (like cytokines). Dysregulation of NF-kB and resulting dysregulation of the immune system results in the diseases of the liver, central nervous system, various chronic metabolic disorders.
NF-kB also plays a vital role in the activation of macrophages and initiation of the inflammatory cascade. Activated macrophages help fight infections, clear body from the debris. Termination of macrophage activation in a timely manner is necessary for the good health. Chronic activation of NF-kB means that this termination of macrophage activity does not occur properly, and is thought to be behind the diseases like type 2 diabetes, rheumatoid arthritis, diseases of blood vessels, and probably behind CFS and fibromyalgia.
Suppression of these immune and inflammatory responses occur due to various factors outside and inside the body cells. External cellular factors are like the short life of cytokines and clearance of debris by macrophages. Internal cellular factors are specific compounds that suppress the NF-kB activity; one such factor is an inhibitor of κB kinase (IKK)3.
Leaky gut is another term for gut inflammation. Chronic gut inflammation may lead to CFS, while CFS may worsen the gut inflammation. NF-kB plays a vital role in gut immunity9 and the development or persistence of leaky gut. Gut has evolved in a way to keep the dirty and unneeded things outside, while at the same time accepting the necessary nutrients. It occurs with the help of tightly bound epithelial cells that form the mucosal barrier. Hyper-activation of intestinal NF-kB means chronic inflammation, malfunctioning of the mucosal barrier.
Association between the leaky gut and CFS is apparent from the number of studies that show a higher prevalence of various gut diseases in CFS. Thus people living with CFS are more probable to report inflammatory bowel syndrome (IBS)10, one of the common problems of the gut. Further, studies have shown relations between the gut microbiota and chronic activation of NF-kB in the gut. Lipopolysaccharide (LPS) is known to activate gut NF-kB, thus causing inflammation and leaky gut. Studies have shown that Bifidobacterium and Lactobacilli may reduce the gut LPS levels and thus suppress the NF-kB and related inflammation. It demonstrates the possible role of probiotics in the treatment of leaky gut and CFS11.
Mitochondria are cellular furnaces; they produce energy for the functioning of body cells. Brain cells and muscle cells have a high number of mitochondria to fulfill the energy needs. Mitochondria dysfunction is thought to be behind any disease that is characterized by the lack of energy and feeling of fatigue. NF-kB overactivity leads to overproduction of cytokines, interleukin-1, tumor necrosis factor and other inflammatory mediators; it causes a mitochondrial shutdown. Lower levels of Coq10, Zinc, and other antioxidants may further aggravate the condition12.
When the body cells are short of ATP (energy produced by mitochondria), they start using alternative pathways to fulfill the energy needs, which only worsen the things. One alternative path is by directly converting glucose to lactic acid (which produces the just tiny amount of energy). However, the buildup of lactic acid is bad for wellbeing; it causes soreness in muscles, pain, heaviness, and tiredness. Lactic acidosis may damage the muscle and nerve fibers. It could explain why people living with CFS have difficulty in doing exercise and staying fit. A higher level of lactic acid in muscles of those living with CFS has been confirmed by biochemical tests. Similarly, biopsy has shown that in CFS there is an abnormal mitochondrial generation. Further, it has been demonstrated that severity of CFS correlates to the gravity of mitochondrial dysfunction11.
Although it is now well accepted that chronic inflammation causes changes in the brain, and leads to deviations in the working of nervous system13, nevertheless, researchers have found it hard to explain the underlying mechanism of CFS or fibromyalgia due to the complexity of the nervous system. Even so, it is well accepted that fatigue, brain fogginess, high sensitivity to pain have to do with the alterations in the brain.
NF-kB has different roles in the various cells of the brain, and in different parts of the nervous system. It explains why the researchers find it so challenging to define the role of NF-kB in the nervous system. Accordingly, activation of NF-kB would improve memory, while its suppression would worsen it. At the same time, the higher amount of NF-kB would lead to brain inflammation and cell death, thus leading to encephalomyelitis, dementia, and other disorders. Despite all the contraindications, it is clear that brain needs NF-kB in the right and balanced amount, and any dysfunction of NF-kB would worsen the functioning of mind and thus contribute to CFS and fibromyalgia14.
How to Inhibit NF-kB – Health Tips & Recommendation for CFS/ME
At present, no single drug can cure the CFS in short duration, though drug therapy may help. However, considering the low effectiveness of modern drug treatment and the necessity to take these medications for long, and high risk of side effects, it is better to consider the natural remedies. Below are some of the most effective natural remedies to help in CFS.
Consume more of NF-kB inhibitors
A wide range of natural compounds have NF-kB inhibitory activity, thus choose food items and supplements that are rich in them. Science has shown that lignans, sesquiterpenes, diterpenes, polyphenols (resveratrol, quercetin), etc. may help15.
- Beta-Glucans– they are dietary fibers that may help to reduce hyperactivity of NF-kB. It is a glucose polymer found primarily in cereals. Thus eat more of oats, barley (and other grains), specific type of yeasts, seaweed, and algae. They are also found in a smaller amount in wheat and rye.
- Sulforaphane– many vegetables are rich in it and may help to overcome CFS. So eat more of broccoli, cauliflower, Brussels sprout, cabbage, and collards.
- Resveratrol – naturally occurring compound, a powerful antioxidant that is also an NF-kB inhibitor. It not only protects various cells but also helps them to regenerate. Some of the food items rich in resveratrol are the skin of red grapes, red wine, raw cocoa, dark berries (blueberries, mulberries, cranberries), and pistachios.
- Terpenoids– are another class of natural products supported by sufficient scientific research, they have anti-inflammatory action and are inhibitors of NF-kB16. Diterpenes are especially useful for NF-kB inhibition and carrots, spinach, broccoli, pumpkin, cherries, cabbage, lettuce, and watermelon are some of its natural sources.
Correct mitochondrial dysfunction
There is a large number of natural products that can help to correct the mitochondrial dysfunction, some of the commonly used groups are17:
- Vitamins– Vitamin C, D, and E, thiamine, riboflavin
- Minerals– Magnesium, calcium, phosphate
- Lipids– unsaturated fatty acids, membrane phospholipids
- Metabolites– Creatine, Pyruvate
- Cofactors– CoQ10, alpha-lipoic acid, NADH, nicotinic acid
- Transporters– L-carnitine, membrane phospholipids
- Antioxidants– Coq10, alpha-lipoic acid, NADH, glutathione
- Enzyme inhibitors– alpha-lipoic acid, dichloroacetate
- Herbs– Curcumin, schisandrin
Taurine is an amino acid that is abundant in the body is also beneficial for mitochondrial functioning; it helps maintain membrane potential and protects mitochondria from oxidative damage by suppressing superoxide synthesis in excess18.
Sleep disorders are widely prevalent and are often associated with mood disorders and a higher risk of dementia. Thus seek medical attention for sleep-related issues. Sleep disorder is not just about insomnia; it is also about obstructive sleep disorder and insufficient sleep. Sleep is the best treatment for many ailments as it stimulates regenerative processes.
Finally, to avoid overactivity of NF-kB better avoid some of the things like smoking, psychological stress, treat blood pressure, manage diabetes, follow a daily routine to prevent circadian rhythm disruptions, avoid sugary drinks and fatty food items.
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- Römkens TEH, Pinxteren van V, W.j M, et al. High prevalence of fatigue in inflammatory bowel disease: A case control study. J Crohns Colitis. 2011;5(4):332-337. doi:10.1016/j.crohns.2011.02.008
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