Chronic Fatigue Syndrome: does the cure lie within nutritional interventions?

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, is a complex disease that can significantly reduce quality of life, productivity and overall happiness. Diagnosis of the disease remains controversial due to the fact that it is characterized by a broad range of symptoms, and the criteria depends on where you are located. The main symptom includes extreme fatigue after merely minor activities, such as simple mental tasks, over a period of at least 6 months that is not mains unresolved even with rest ^{[1, 2]}. This crippling disease can seriously hinder the ability to perform routine tasks, even sitting or standing upright can be a challenge for individuals. Other symptoms may include:

• Decreased pain threshold ^[3]
• Chronic pain – muscle or joint ^{[1, 2]}
• Sleep disturbances
• Cognitive dysfunction – difficulties concentrating and impaired working memory ^{[1, 3]}
• Lack of revitalizing effects of physical exertion ^{[1, 3]}
• Tender lymph nodes ^[1]
• Recurrent sore throat ^{[1, 2]}
• Gastrointestinal issues

Diving into the body on a molecular level, this disease is correlated with a poorly regulated immune system which leads to widespread inflammation, impaired cellular energy production and a dysregulated central nervous system. Other biological abnormalities include:

• Decreased blood flow/volume ^[3]
• Impaired oxygen delivery to muscles ^[3]
• Increased inflammatory signals after exertion ^[3]
• Cardiovascular irregularities ^[3]
• Dysfunctional mitochondria (powerhouse of the cell)
• Lower antioxidant levels
• Intracellular inflammation

The onset of CFS is typically between the ages of 20 to 35 and tends to affect three females for every one male ^[3]. CFS is diagnosed based on exclusion, meaning that other medical conditions with similar symptoms must be ruled out first because there is no simple diagnostic test available. Other illnesses where fatigue is a symptom do not usually have the same severity of tiredness that goes hand-in-hand with CFS. Additionally, a key point is that the exhaustion cannot be relieved by rest. A large portion of CFS patients are able to identify a specific point in time where they contracted an acute illness that preceded the onset of extreme fatigue, whereas others can have difficulty pinpointing the onset of the fatigue. It is estimated to affect between 0.8 to 3.3 % of the global population, although most have not been identified ^[4].

Unfortunately, to date, there is no known treatment for CFS.

The conditions of patients may improve or even recover over time but others will continue to be affected over extended periods. The focus of treatment has largely been targeting symptom relief rather than the cause of the illness. Treatments may include anti-inflammatories, anti-depressants, drugs that suppress pain or muscle spasms. In some cases, psychotherapy and meditation may be used as a method of coping. However, these symptom treatment strategies are not long-term solutions. There is a pressing need for therapeutic treatment to cure this devastating disease.

The underlying cause of this disease remains largely unknown, but CFS may be correlated to a combination of different factors including:

• bacteria,
• viruses,
• hormonal imbalances,
• environmental factors and/or
• a dysregulated immune system ^[1].

More recently, CFS is being linked to a spectrum of diseases including irritable bowel syndrome (IBS) and fibromyalgia ^{[1, 5]}. For example, individuals with CFS have reduced diversity and changes in the gut microbiota populations which may result in gut inflammation ^{[2, 6, 7]}. The increased gut inflammation in CFS patients can lead to “leaky gut” and “microbial translocation”, meaning that the intestinal bacteria migrate through the gut into the bloodstream. The bacteria are recognized in blood circulation by the immune system, and an inflammatory is launched leading to even higher levels of pro-inflammatory markers in the blood. This type of immune system activation is common in patients with liver diseases, IBS and HIV infection ^{[1, 2]}. One hypothesis is that CFS may be self-perpetuating due to the interlocking of continuous circles of disease that result in chronic inflammatory conditions ^[1]. The vicious cycle of microbial translocation and immune activation reduces the ability of the gut to take up several important nutrients, which leads to vitamin deficiencies resulting in various infections, further reducing the quality of life. Importantly, with this disease hypothesis in mind, therapeutic intervention would need to attempt to break multiple circles with a multifactorial intervention ^[1].

The importance of nutrition in disease prevention is becoming more and more appreciated among the medical community. Thus, nutritional intervention studies for CFS treatment are becoming more common place but due to the complexity of the disease, it is difficult to draw concrete conclusions. Most of the nutrition therapy studies on CFS are observational, and those studies that do use a dietary intervention only use a single nutrient, when in reality, this is a multifactorial disease, so a combination approach should be taken ^[1]. In addition, unfortunately there are few of the gold standard studies, randomized controlled trials, meaning that one group receives a placebo and the other a treatment. However, a few examples of potentially effective interventions outlined below had a significant impact on reducing fatigue.

Chocolate

Just what you wanted to hear right? But seriously, cocoa contains important molecules called polyphenols of which flavonoids are especially bioactive. Studies have demonstrated that these flavonoids can prevent cancers, diabetes, cardiovascular disease and neurodegenerative disease ^[8]. Polyphenol rich chocolate (85% cocoa solids) has been shown to significantly improve fatigue and London Handicap Scores (which assesses activities of daily living, functional mobility, life participation, occupational performance, quality of life and social relationships) in patients with CFS. Bring on the dark chocolate!

Coenzyme Q₁₀ & NADH

Nicotinamide adenine dinucleotide (NADH) and Coenzyme Q₁₀ (also known as CoQ₁₀ or ubiquinone) play an important role in generating approximately 95% of energy required for the body to function. They are also involved in regulating cellular metabolisms and providing antioxidant protection within cells. NADH supplementation treatment for CFS patients reduces anxiety and decreases maximum heart rate after stress tests ^[9]. Various studies demonstrated that after merely 8 weeks of co-supplementation with NADH and CoQ₁₀, CFS patients reported a significant improvement in their fatigue levels ^{[10, 11]}. On a molecular level, the blood cells from the treated patients produced significantly higher levels of energy compared to blood cells from the placebo group. In addition, the treated group reduced oxidative stress damage, meaning less DNA damage. These supplements are proving to be safe and effective therapeutic to reduce fatigue, increase cellular energy production and decrease oxidative damage ^[10]. Because CoQ₁₀ is found ubiquitously in every living cell, there are foods that contain high levels that may be important to include in a diet for CFS patients (see the table below). Further, niacin (vitamin B3) increases your body’s endogenous production of NADH, thus it would also be important to eat foods high in Niacin.

Probiotics

The gut microbiota composition in patients with CFS was similar to that of other IBD patients. For example, similar ro IBD (Crohn’s) patients, CFS patients have lower levels of Firmicutes, which are the most abundance bacterial species in healthy human adults. Proteobacteria is higher in CFS patients and individuals with IBD compared to healthy populations ^[2]. These bacteria feed on the products of the activated host immune system which provides them with the ideal environment to continue to grow and flourish, which in turn leads to more inflammation.

Other populations of bacteria which produce anti-inflammatory molecules are reduced in CFS, IBD and ulcerative colitis patients. Low levels of Bifidobacterium are found across the board in patients with CFS, IBD and type II diabetes ^[2]. Although there is not a specific change of species of gut microbiota across patients, there is a dysregulation and a lack of diversity. Thus, increasing research is investigating the use of diet and nutritional interventions as therapeutic treatment for CFS ^[2]. To increase bacterial diversity, it is recommended to eat a plant-rich diet.

Interestingly, treatment of CFS with a prebiotic, a strain of Bifidobacterium infantis (35624) reduced inflammatory markers in patients with CFS. Targeting the gut microbiota represents a promising therapeutic to break one of the ongoing circles of disease to prevent leaky gut and thus reduce inflammation.

Transfer factor

Transfer factor was initially developed to treat Epstein-Barr virus (EBV). It has been shown to be effective in treating multiple viruses included cytomegalovirus and herpes virus-6. Because some cases of CFS are associated with EBV, Transfer Factor is a promising therapeutic supplement. The rapid viral response immune cells, natural killer cells, from women with CFS taking the Transfer Factor Multi-Immune™ had significantly higher immune cell related activities after just 30 days of supplementation. Depending on the root cause of CFS, this supplement may be very beneficial to those patients with viral infections.

Vitamin B12

In patients with CFS, the genes associated with immune regulation in their immune cells have less regulatory compounds known as methyl groups. The reason for the lack of these methyl groups is unknown, but vitamin B12 and folate play a vital role in providing methyl groups. These supplements also have antioxidant properties. Frequent high-dose vitamin B12 injections, nasal drops and oral folic acid pills have been shown to be effective in treating the symptoms of subsets of patients with CFS ^[1]. However, when stopping the injections, it seems that the ameliorated quality of life begins to deteriorate ^[1].

Mitoprotective diets

As described above CFS patients have impaired mitochondria function. With mitochondria being the powerhouse of the cell, it is an important target for nutritional therapy strategies. Caloric restriction and fasting have been shown to improve mitochondria function ^[12]. Other dietary restrictions improving mitochondrial function include carbohydrate restriction, alternate day fasting or methionine restriction ^[13]. In a small study, to treat patients with CFS and fibromyalgia caloric restriction for only two weeks already demonstrated mood benefits. Although when performing any of these diets it is important to consult with your doctor first.

Summary of Treatments

Current dietary trends used by CFS patients to manage or reduce symptoms are extremely difficult to follow. Food sensitivities vary from patient to patient. Broadly speaking, self-reports have found that certain foods can exacerbate fatigue, such as dairy, sugars, alcohol, gluten-containing grains, or all grain products, which are all known to induce inflammation, even in healthy individuals. It is therefore necessary to tailor diets to each individual. By keeping a food diary and track of symptoms, a food scientist would be able to adjust individual diets to reduce symptoms, improve quality of life and potentially break some of the vicious cycles that these patients find themselves within. This is a multifactorial disease and it requires multifactorial treatment with a tailored diet and supplement regimen to each individual.

References:

1.    Bjørklund G, Dadar M, Pen JJ, Chirumbolo S, Aaseth J: Chronic fatigue syndrome (CFS): Suggestions for a nutritional treatment in the therapeutic approach. Biomedicine & Pharmacotherapy 2019, 109:1000-1007.

2.    Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, Hanson MR: Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome 2016, 4(1):30.

3.    Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles ACP, Speight N, Vallings R et al: Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine 2011, 270(4):327-338.

4.    Johnston S, Brenu EW, Staines D, Marshall-Gradisnik S: The prevalence of chronic fatigue syndrome/ myalgic encephalomyelitis: a meta-analysis. Clin Epidemiol 2013, 5:105-110.

5.    Hanevik K, Wensaas K-A, Rortveit G, Eide GE, Mørch K, Langeland N: Irritable Bowel Syndrome and Chronic Fatigue 6 Years After Giardia Infection: A Controlled Prospective Cohort Study. Clinical Infectious Diseases 2014, 59(10):1394-1400.

6.    Frémont M, Coomans D, Massart S, De Meirleir K: High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe 2013, 22:50-56.

7.    Sheedy JR, Wettenhall REH, Scanlon D, Gooley PR, Lewis DP, Mcgregor N, Stapleton DI, Butt HL, De Meirleir KL: Increased D-Lactic Acid Intestinal Bacteria in Patients with Chronic Fatigue Syndrome. In Vivo 2009, 23(4):621-628.

8.    Sathyapalan T, Beckett S, Rigby AS, Mellor DD, Atkin SL: High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome. Nutrition Journal 2010, 9(1):55.

11.  Castro-Marrero J, Sáez-Francàs N, Segundo MJ, Calvo N, Faro M, Aliste L, Fernández de Sevilla T, Alegre J: Effect of coenzyme Q₁₀ plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome – A randomized, controlled, double-blind trial. Clinical Nutrition 2016, 35(4):826-834.

9.    Alegre J, Rosés JM, Javierre C, Ruiz-Baqués A, Segundo MJ, Fernández de Sevilla T: Nicotinamida adenina dinucleótido (NADH) en pacientes con síndrome de fatiga crónica. Revista Clínica Española 2010, 210(6):284-288.

10.  Castro-Marrero J, Cordero MD, Segundo MJ, Sáez-Francàs N, Calvo N, Román-Malo L, Aliste L, Fernández de Sevilla T, Alegre J: Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal 2015, 22(8):679-685.

12.  Longo Valter D, Mattson Mark P: Fasting: Molecular Mechanisms and Clinical Applications. Cell metabolism 2014, 19(2):181-192.

13. Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries C-G: Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia. PloS one 2015, 10(4):e0124648.

14.  Ruetenik A, Barrientos A: Dietary restriction, mitochondrial function and aging: from yeast to humans. Biochimica et Biophysica Acta (BBA) – Bioenergetics 2015, 1847(11):1434-1447.