Possible Causes of Chronic Fatigue Syndrome

Chronic Fatigue Syndrome is a complex condition involving multiple processes and pathways in the body. There are many theories involving a single cause. However, we propose that there are multiple root causes which compound and reinforce each other, leading to the viscous cycle of CFS.

Bile Acids and the Liver

Bile Acids are crucial to health, without a proper release of bile a whole host of health problems can ensue. Bile has many uses, one commonly known use is to emulsify fats in the small intestine. Another less known yet crucial role of bile is to provide defense against microbes in the small intestine. In the absence of Bile, bacteria and other microbes such as yeasts and fungi are able to flourish. Bile has a Bactericidal effect which helps to keep the small intestine somewhat sanitized.(4)

When bacteria is comes into contact with bile for a long enough period of time it is killed. When bacteria is cultured in taurocholate(a component of bile) there is almost complete death after 24 hours. (5) Bile plays an important role in protecting the small intestine from microbial overgrowth. If the liver and gallbladder are functioning properly it will be hard to reach high levels of microbial overgrowth in the small intestine. There are a few possible ways the release of bile can malfunction, or be ineffective.

1. The bile ducts/gallbladder are partially blocked and bile cannot be excreted sufficiently

2. There is no trigger for the release of bile due to low stomach acid or a low fat diet(most likely caused by hypochlorhydria, H.Pylori, pellagra, pernicious anemia, atrophic gastritis or of stomach cancer.)

3. Bile concentration is weak(most likely due to low electrolytes and dehydration)

4. Constipation and slow transit time don’t allow bile to effectively flow through the small intestine

5. Metabolic rate decreasing due to low thyroid issues.

6. Autoimmune disorders where the immune system attacks it’s own parietal cells which are responsible for producing gastric acid.

7. Sulfate deficiency.

When bile is not being released properly, liver health will suffer. The liver processes all sorts of toxins, and excretes them as bile is released. Some of these toxins include xenobiotic chemicals, carcinogens, pharmaceuticals, and heavy metals. Low cholesterol levels often lead to low production of bile.(6)

The Livers cytochrome p450 detox system is also very important. When this system is not working properly a buildup of toxins can occur, which will poison and further weaken the mitochondria. The liver uses up 27% of the bodies energy.(7) In CFS/ME energy production is impaired, this results in a poor ability to detox. There are a few reasons why the p450 system may not work properly.

Sulfur, Sulfate, and Sulphide

Many people with CFS have issues with the PST(phenol-sulfotransferase) enzyme. PST is a Phase II enzyme which is responsible for the detoxification of many compounds, some of which are phenols, amines, and toxic molecules. This enzyme is also responsible for the oxidization of sulfur to sulfate.(18)

Another condition that can contribute to trouble processing phenols is Gilbert’s Syndrome.

Following ingestion phenols undergo first-pass metabolism and are conjugated with glucuronic acid and sulphate. The glucuronidation pathway is impaired in Gilbert’s syndrome. This is often manifested with symptoms of malaise, fatigue, and loss of appetite.(19)

Sulfate is incredibly important for many reasons, and ties into almost all issues associated with CFS.

Sulfate is essential to every cell in the body, it is one of the most important macronutrients.(20)

When there is an issue with the PST enzyme not enough sulfate is made available. In order to break the viscous cycle of leaky gut, SIBO, hypochlohydria, and bile acid insufficiency we must supply adequate sulfate to our cells. Sulfate is also necessary for the production of protective mucus throughout the body, and especially in the stomach. Mucus traps microorganisms, and by doing so protects the reproductive, digestive, respiratory and urinary systems. An enzyme in mucus, saliva, and tears called lysozyme kills bacteria.(21)

Sulfate is also involved in forming the extracellular matrix. Formation of this matrix is necessary for factors such as growth, and wound healing(including healing a leaky gut).(22)

Viruses can also impede sulphation by creating inflammation in the liver and kidneys.(23)

Viruses such as EBV and Coxsackie are highly implicated in CFS. A study done on CFS patients found VP1, RNA and non-cytopathic viruses in the stomach through biopsy.(23.1)

Another study found that 13% of subjects with chronic fatigue housed enterovirus RNA in their muscle tissue, compared to 0% in the healthy controls.(23.2)

Coxsackievirus B can split into two different forms: The normal enterovirus (which convirussists of viral particles, ie, virions), and the non-cytopathic enterovirus. The non-cytopathic enterovirus is very different, consisting only of strands of dsRNA and no viral shell (virion) at all. These strands of dsRNA live purely inside cells, and most regular antivirals will not touch them.(23.3)

Enteroviruses can also be responsible for many chronic diseases besides CFS/ME, some examples are arthritis, coronary heart disease, and encephalitis.(23.4)

Another major cause of sulfate insufficiency is sulfate reducing bacteria. In many cases of SIBO, there is an overgrowth of sulfate reducing bacteria. These bacteria use up our vitally important sulfate, and release a toxin known as hydrogen sulfide. Hydrogen sulfide is toxic to the nervous system and mitochondria, leading to chronic fatigue symptoms. (24)

Major strains responsible include Streptococcus, Enterococcus, and Prevotella.(25)

The byproducts of these bacteria can also impair oxidative phosphorylation and ATP production. Hydrogen sulphide can also bind to the mitochondrial enzyme cytochrome c oxidase, which is part of the electron transport chain. (26)

These bacteria can produce tryptophanase which digests tryptophan, the main building block for serotonin and ultimately melatonin.(27) When this occurs levels of both of these hormones can become low, which in turn lead to sleep disturbances, mitochondrial impairment, and oxidative stress as well as muscle fatigue. (28)

The main focus is to prevent Apoptosis (cell death). It’s imperative that we start mitochondria supportive therapy and identify and treat gut imbalances, as well as intracellular deficiencies.

Heavy metals and enteroviruses can impair kidney and liver function, limiting sulfate transportation.(9.4) They create high levels of inflammation in both the kidneys and the liver.(29)

Lack of sulfate contributes to leaky gut. Many studies have been done on autistic individuals showing that they commonly have leaky gut and very low serum sulphate. This loss of sulphate causes, and is caused by leaky gut as sulfate leaks through the intestines. (30)

Hydrochloric Acid

Hydrochloric Acid(HCL) is essential for many reasons, one of which is triggering the release of digestive enzymes such as bile. Without adequate HCL the stomach will not break down food properly, this is problematic for multiple reasons. Without food being broken down properly it will easily provide food for microbes living in the small intestine. When these microbes are fed food that has not been broken down in the stomach they will multiply exponentially. HCL and fats also trigger the release of bile and other digestive enzymes. Without this trigger there will be no/minimal release of digestive enzymes such as bile. Bacteria and other pathogenic/opportunistic microbes can easily survive transit through the mouth and into the small intestine if the PH of the stomach is not low enough.

Hydrochloric acid is required to liberate vitamin B12 from food. There are also genetic variations and other contributing factors that can cause hydrochloric acid insufficiency. (1)

Proton Pump inhibitors(PPI’s) induce hydrochloric acid insufficiency. We can compare this to having hypochlorhydria(very low hydrochloric acid in the stomach). In a study done on 30 patients taking PPI’s 37% were found to have an overgrowth of bacteria in the small intestine. Patients with a PH less than 3.8 had no bacterial overgrowth.(2)

An infection with H.Pylori can also lead to low HCL, gastritis, and even stomach cancer. Over 50% of the global population is infected with H.Pylori, however it only causes symptoms in about 10% of people.(3) H-pylori is a deep rooted infection and can be very hard to eradicate.

Small Intestine Bacterial Overgrowth

As HCL and Bile release slow down SIBO(small intestinal bacteria overgrowth) will begin to occur.

Many of the symptoms of SIBO mirror those of CFS.

WebMD reports the symptoms of SIBO as:

Studies have also shown a definite correlation between an overgrowth of bacteria in the small intestine and FM/CFS. In two studies done it was found that 78% of patients with FM, and 77% of patients with CFS both had SIBO.(10) That is roughly 4/5 people, an alarmingly high number.

SIBO sets the stage for CFS, and becomes a cycle that can be hard to break. Certain microbes such as candida can irritate and poke tiny holes into the small intestine, resulting in leaky gut. Leaky gut leads to a whole slew of symptoms, some of which are brain fog and autoimmune conditions.(11)

SIBO can be the gateway for many of the symptoms people with CFS experience. SIBO can produce toxins such as D-lactic acid, Tyramine, Tartaric acid,  and Hydrogen sulfide. Bacterial cellular debris can stimulate the production of endogenous interleukin-1 and tumor necrosis factor. LPS can cause inflammation and mitochondrial impairment.(12)

How Is This Connected to CFS/FM/ME?

Anything that overloads your system will cause a deficit in ATP production. This can happen by multiple means- some common causes are a strong infection of any type, heavy metals, oxidative stress, and even overloading the digestive system with bad food and toxins.

As stated above, an overgrowth in the small intestine can block absorption of nutrients furthering depletion of ATP. As this cycle continues, the body will run low on energy and the immune system’s effectiveness declines. Substances that pass through the small intestine due to leaky gut are not recognized by the immune system. They are attacked and trapped in the lymph nodes, further depleting ATP and congesting the lymphatic system.(13)

It is important to supplement and correct other issues that can both cause, and be caused by low HCL. Without enough of certain vitamins as well as cellular ATP, HCL production will be diminished.(14)

As microbes overgrow in the small intestine the mitochondria becomes damaged, and the membrane becomes permeable. Viral infections can also induce membrane permeability.(15)

This becomes a vicious cycle: When you do not have enough HCL, bile is not released. When Bile is not released it will allow an overgrowth of bacteria. This overgrowth will compete for your nutrients and block the uptake of many medicines and supplements. Without bile being released regularly, stones can accumulate in the gallbladder and liver which further block the release of bile.(8) Toxins which need to be released sit in the liver, furthering damage to this vital organ.


Methylation and genetic mutations are also a key factor in the equation. As stated before, HCL deficiencies prevent absorption of B12.

A few functions of methylation include:


Certain genetic defects such as MTHFR, MTR, MTRR, and BHMT mess up the recycling/absorption of methylfolate and b12.(17) Methylation is too broad a topic to cover in this post, however is is vitally important to address. For more information check out the work of Ben Lynch, ND, and Rich Van Konynenburg, PhD.

Sources and More Info

1:http://www.hsph.harvard.edu/nutritionsource/b-12-deficiency/ “Vitamin B12 Deficiency: Causes and Symptoms.” The Nutrition Source. N.p., n.d. Web. 07 Apr. 2014.


3: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318258/ Sachs, George, and David R. Scott. “Abstract.” National Center for Biotechnology Information. U.S. National Library of Medicine, 02 Apr. 2012. Web. 07 Apr. 2014.

http://www.pnas.org/content/103/12/4333.full “How Bile Acids Confer Gut Mucosal Protection against Bacteria.” How Bile Acids Confer Gut Mucosal Protection against Bacteria. N.p., n.d. Web. 07 Apr. 2014.

5:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1786299/?page=2 Percy-Robb, I. W., and J. G. Collee. “Formats:.” National Center for Biotechnology Information. U.S. National Library of Medicine, 30 Sept. 1972. Web. 07 Apr. 2014.

6:http://metabolichealing.com/bile-deficiency-heartburn-poor-digestion-toxicity/“Bile Deficiency: Heartburn, Poor Digestion, Toxicity.” Metabolic Healing. N.p., n.d. Web. 07 Apr. 2014.

7:http://www.marchestau.com/EN/articles_full.php?id=72 “Marché Tau.”Marché Tau. N.p., n.d. Web. 07 Apr. 2014.

8:http://gastro.ucsd.edu/fellowship/materials/Documents/Gallstones/pathogenesis gallstones.pdf

9:http://www.webmd.boots.com/digestive-disorders/small-intestinal-bacteria-sibo “Digestive Health Centre.” Small Intestinal Bacterial Overgrowth (SIBO) Symptoms and Treatment. N.p., n.d. Web. 07 Apr. 2014.


11:http://www.ncbi.nlm.nih.gov/pubmed/22109896 “Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 07 Apr. 2014.

12:http://www.academia.edu/3862817/Nut…etal_Inflammation_and_Chronic_Health_Problems “Join Academia.edu & Share Your Research with the World.”Nutritional and Botanical Treatments Against “Silent Infections” and Gastrointestinal Dysbiosis, Commonly Overlooked Causes of Neuromusculoskeletal Inflammation and Chronic Health Problems. N.p., n.d. Web. 07 Apr. 2014.

13: http://www.wisegeek.org/why-do-lymph-nodes-become-swollen.htm “Why Do Lymph Nodes Become Swollen?” WiseGEEK. N.p., n.d. Web. 07 Apr. 2014.

14.http://www.aspirenaturalhealth.com/…e-puzzle-post-149-by-dr-tim-gerstmar-3262012/ “Sulfur, and Sulphate Reducing Bacteria – Another Piece in the Puzzle – Post 149 By: Dr. Tim Gerstmar – 3/26/2012 – Aspire Natural Health | Holistic Medicine RedmondAspire Natural Health | Holistic Medicine Redmond.” Aspire Natural Health Holistic Medicine Redmond RSS. N.p., n.d. Web. 07 Apr. 2014.

15: books.google.com/books?id=mQ4b_GMFgoIC

16: http://www.nleducation.co.uk/resour…osis-the-mitochondrial-and-immune-connection

17: http://www.drnibber.com/methylation-important/ “What Is Methylation and Why Is It Important? | Dr Nibber.” Dr Nibber. N.p., n.d. Web. 07 Apr. 2014.

18: http://www.heartfixer.com/AMRI-Outcomes-Non-CV-Autism-Methyl Cycle.htm

19: http://en.wikipedia.org/wiki/Sulfur “Sulfur.” Wikipedia. Wikimedia Foundation, 04 May 2014. Web. 07 Apr. 2014.

20: http://www.gilbertssyndrome.com/detoxification.php “The Body’s Detoxification System.” The Body’s Detoxification System. N.p., n.d. Web. 07 Apr. 2014.

21: http://www.ncbi.nlm.nih.gov/pubmed/11581495″Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 07 Apr. 2014.

22: http://textbookofbacteriology.net/innate_3.html “Immune Defense against Bacterial Pathogens: Innate Immunity.” Immune Defense against Bacterial Pathogens: Innate Immunity. N.p., n.d. Web. 07 Apr. 2014.

23: http://en.wikipedia.org/wiki/Extracellular_matrix“Extracellular Matrix.”Wikipedia. Wikimedia Foundation, 04 May 2014. Web. 07 Apr. 2014. 24:http://en.wikipedia.org/wiki/Coxsackievirus “Coxsackievirus.” Wikipedia. Wikimedia Foundation, 04 May 2014. Web. 07 Apr. 2014.

23.1:Chia, JKS, Chia, AY;(2008), “Chronic fatigue syndrome is associated with chronic enteroviral infection of the stomach,” Journal of Clinical Pathology 2008;61:43-48.

23.2 http://www.ncbi.nlm.nih.gov/pubmed/14556267

23.3 http://jvi.asm.org/content/85/13/6714.short

23.4 http://www.enterovirusfoundation.org/associations.shtml

25:http://forums.phoenixrising.me/index.php?threads/getting-worse-from-imunovir.8107/page-5“Getting Worse from Imunovir?” Phoenix Rising ME / CFS Forums. N.p., n.d. Web. 07 Apr. 2014.

26: www.ncbi.nlm.nih.gov/pubmed/2160136“Result Filters.” National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 07 Apr. 2014.

27: http://jb.asm.org/content/98/1/167.full.pdf

28 http://www.serotune.com/blogs/artic…e-symptoms-and-causes-of-serotonin-deficiency“What Are The Symptoms and Causes of Serotonin Deficiency.” Serotune. N.p., n.d. Web. 07 Apr. 2014.

29http://www.aspirenaturalhealth.com/…e-puzzle-post-149-by-dr-tim-gerstmar-3262012/“Sulfur, and Sulphate Reducing Bacteria – Another Piece in the Puzzle – Post 149 By: Dr. Tim Gerstmar – 3/26/2012 – Aspire Natural Health | Holistic Medicine RedmondAspire Natural Health | Holistic Medicine Redmond.” Aspire Natural Health Holistic Medicine Redmond RSS. N.p., n.d. Web. 07 Apr. 2014.

30http://treatautismnow.wordpress.com/2010/06/05/phenols-pst-and-sulphur-metabolism/ “Phenols , PST and Sulphur Metabolism | TreatAutismNow.” TreatAutismNow. N.p., n.d. Web. 07 Apr. 2014.