Chronic Fatigue Syndrome, Functional Mitochondriopathy, and Enterohepatic Dysfunction

Abstract

Chronic fatigue syndrome (CFS) has remained a medical enigma since it was first reported in the late 1980s by Paul Cheney, MD, PhD, who—along with his medical partner in Incline Village, Nevada—made the observation of a group of his patients all having serious and unremitting fatigue following a significant winter flu season. I was introduced to Dr Cheney by Scott Rigden, MD, an expert in the study of chronic fatigue syndrome and also a key advisor to me during the founding days of the Institute for Functional Medicine. From 1989 to 1991, Dr Cheney was an important contributor to the development of concepts underlying the Functional Medicine model.

Chronic fatigue syndrome (CFS) has remained a medical enigma since it was first reported in the late 1980s by Paul Cheney, MD, PhD, who—along with his medical partner in Incline Village, Nevada—made the observation of a group of his patients all having serious and unremitting fatigue following a significant winter flu season.¹ I was introduced to Dr Cheney by Scott Rigden, MD, an expert in the study of CFS and also a key advisor to me during the founding days of the Institute for Functional Medicine. From 1989 to 1991, Dr Cheney was an important contributor to the development of concepts underlying the functional medicine model.

During the 1990s, there was considerable discussion about the etiology of CFS, which is commonly referred to as myalgic encephalomyelitis (ME) in the United Kingdom. CFS/ME is now recognized to be a complex, chronic medical condition. It is characterized by a symptom cluster presenting as pathological fatigue and malaise that is worse after exertion, cognitive and immune dysfunctions, muscle pain, lymphadenopathy, and sleep disturbances. It is estimated that between 1 and 2.5 million people in the United States have this condition, resulting in an annual treatment cost of $17 to $24 billion dollars.² A2015 review³ published in the Annals of Internal Medicine examined 35 clinical trials involving chronic fatigue patients between 1988 and 2014. The range of interventions used in these studies included immune-activating drugs, anti-inflammatories, antivirals, antidepressants, graded exercise, and cognitive behavioral therapies. Modest improvement was demonstrated in some cases, but no therapy was found to be sufficient in eliminating the condition.³

The search for answers continues. In March 2016, National Institutes of Health (NIH) Director Francis Collins, MD, PhD, and Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, announced funding of an NIH intramural study on CFS/ME. Although patients will not receive treatment, a number of potential contributing causes to the etiology of the condition will be evaluated, including viral infection, Lyme disease, neuroendocrine and immune dysfunctions, and metabolic factors.⁴ This study began in the fall of 2016 and is expected to run for 3 to 5 years.

When considering the many therapies that have been studied during the last 3 decades, graded exercise in combination with cognitive behavioral therapy has demonstrated the greatest potential for improving function in patients with CFS/ME; this was documented in the results of a clinical trial published in Lancet in 2011.⁵ These findings were further confirmed in a 2017 Lancet publication describing a trial that examined the value of guided graded exercise plus personalized medical care versus medical care alone in the treatment of CFS/ME.⁶

Given that 3 of the dominant presenting symptoms associated with CFS/ME are fatigue, exercise intolerance, and muscle pain, what is the mechanism by which graded exercise is of therapeutic advantage in the treatment of CFS/ME? This question takes us back to my collaboration with Paul Cheney and clinical work that was taking place at the Functional Medicine Research Center in the early 1990s.

Mitochondrial Function and CFS

In 1989, in collaboration with Drs Cheney and Rigden, my research group recognized that the fatigue and muscle pain symptoms associated with CFS/ME correlated with the experiences of people who had moderate mitochondrial deficiencies termed functional mitochondriopathies. It is well known that mutations that influence mitochondrial function in mitochondrial or nuclear DNA can exist in homozygous or heterozygous genotypes. The type of genetic mutation and the degree of its expression in the phenotype as a mitochondrial metabolic disorder can result in a wide range of symptoms and severity, from mild to extreme. The cell types most affected by mitochondrial dysfunction are those with the highest mitochondrial activity, which include the heart, brain, immune system, and muscles.⁷ Notably, these organs and systems also often represent sites of disturbed function in patients with CFS/ME.

In patients with CFS/ME, mitochondriopathies can be associated with altered carbohydrate, protein, or fat metabolism, with the result being a shift toward anaerobic metabolism and lactate production. In turn, this state is clinically associated with fatigue, exercise intolerance, altered cognition, and muscle pain.⁸

My research team postulated that mitochondria in CFS/ME patients may have altered function due to a combination of genetic susceptibility and exposure to mitochondrial toxins. Today, we know that many drugs and chemicals are mitochondrial toxins, as well as secondary metabolites derived from the gut microbial metabolism.⁹ Although this fact was not as well understood in the late 1980s, my group—in collaboration with Dr Scott Rigden—designed and executed a small observational clinical trial focused on improving intestinal function and supporting hepatic detoxification in chronic fatigue patients to see if we could improve energy levels and reduce muscle pain. We used the term enterohepatic therapy to describe our approach, which involved using a tailored diet and a prebiotic medical food in the course of 16 weeks of intervention. Significant clinical improvement was noted in the patients we studied.¹⁰ Our research continued beyond this initial trial, and in 1998 I collaborated with several colleagues on an article about the potential of using this enterohepatic approach for the nutritional support of patients with AIDS wasting syndrome.¹¹

Proof-of-Principle Clinical Trial of Enterohepatic Therapy

Following the encouraging results we observed in our original trial, my team went on to design and execute a 10-week, proof-of-principle clinical study using a comparator control group and a controlled protocol to test the effectiveness of enterohepatic therapy in individuals with CFS. This trial involved 106 patients with CFS of varying degrees of severity. Eighty-four patients were randomized to the enterohepatic treatment group; they were prescribed a low allergy diet and the same medical food product used in our previous study, which was a formula that contained specific nutrients to support both a healthy microbiome and hepatic detoxification enzyme function. Twenty-two patients were assigned to the control group; these individuals received only counseling on implementing a healthy diet. The medical food product contained the following: fructooligosaccharides and inulin (both prebiotics); medium chain triglycerides to support mitochondrial bioenergetics; hypoallergenic rice protein concentrate with added lysine and threonine; high molecular weight rice dextrins as resistant starch; enhanced levels of specific nutrients such as N-acetylcysteine, L-glutamine, glycine, pantothenic acid, riboflavin, niacin, thiamine, folic acid, and cobalamine; and the minerals magnesium, molybdenum, and chromium to support hepatic detoxification processes.

The clinical endpoints of the study were evaluated using a patient-reported outcome survey we called the Medical Outcome Survey (MOS) and the lactulose/mannitol challenge test to evaluate gastrointestinal mucosal integrity. Oral caffeine clearance, a sodium benzoate challenge, and urinary sulfate-to-creatinine analysis were used as markers of hepatic detoxification function.

After 10 weeks, there was a statistically significant difference in MOS values between the 2 groups, with the treatment group having an average 52% reduction of their symptoms. The control group had an average 22% reduction in symptoms (P < .01). Beyond the clinical improvement in energy, pain, and quality of life indices, the treatment group had a statistically significant improvement in phase 2 glycine conjugation activity (P < .01), which demonstrated improved hepatic detoxification function. The urinary sulfate-to-creatinine excretion ratio, which is a surrogate marker for hepatic sulfation detoxification function, was significantly improved in the treatment group as well (P < .01). In patients with the most significant symptoms, the intervention resulted in a statistically significant reduction in urinary lactulose/mannitol ratio as compared with the control group (P < .02). This indicated improvement in gastrointestinal mucosal integrity and implied improvement in the intestinal microbiome and its effect on the enteric immune system.

My fellow investigators and I believed the results of this study confirmed our hypothesis that patients who presented with symptoms of chronic fatigue and were treated with an enterohepatic therapeutic program would have a more positive outcome than patients who were provided only with dietary advice. Improvement in gastrointestinal symptoms after intervention with the enterohepatic therapy program may have been the result of a favorable alteration in gastrointestinal flora, improvement in gastrointestinal mucosal and immune function, or both. What was observed, however, is that the alteration in gut mucosal integrity and gastrointestinal symptoms correlated with improvement in both hepatic detoxification function and gastrointestinal mucosa integrity.¹²

The results of this clinical trial suggested an important clinical association among gastrointestinal function, hepatic detoxification, fatigue, and muscle pain-related symptoms. Interestingly, the results of a companion study our research team collaborated on with investigators at the University of Oregon showed that specific dietary intervention and a regular walking program could improve mitochondrial bioenergetics in exercising muscle of women, as measured by phosphorus 31 (P31) nuclear magnetic resonance (NMR) signals of the inorganic phosphate-to-phosphocreatine ratio.¹³ P31 NMR technology is a noninvasive method for evaluating in vivo mitochondrial bioenergetic function. The positive results of the enterohepatic therapy trial clinical trial in patients with fatigue and muscle pain and the results of the study demonstrating the beneficial effect that a specific tailored diet had on mitochondrial bioenergetic function gave my fellow collaborators and me confidence that an important association had been made and additional studies were warranted.

Support for the Enterohepatic Therapy in the Treatment of Fatigue and Pain-related Syndromes

There is a very important clinical difference between a history of lifelong intolerance to exercise and muscle pain and the development of this condition after some sort of precipitating trigger such as a viral infection, exposure to a toxic chemical, or a traumatic life event. A lifelong history suggests the potential for an acute genetic inborn error in mitochondrial function, whereas an event associated with exposure to a trigger suggests an induced mitochondrial dysfunction.¹⁴ An example of the latter would be “sick building syndrome” (SBS), which is characterized by fatigue and exercise intolerance that follows an exposure to water damaged buildings and mold.¹⁵ Both SBS and CFS are related to alteration of immune system function that results from the exposure to specific triggering agents that create altered mitochondrial function and an increase in inflammation.

A 2016 study of the metabolic features of CFS demonstrated that patients with this condition have defects in 20 different metabolic pathways, with nearly 80% of those pathways related to aspects of mitochondrial metabolism. In this study, the investigators found that even though the triggering events leading to the production of symptoms of CFS were diverse, the cellular metabolic response in patients was statistically robust and chemically similar to the evolutionarily conserved persistent mitochondrial response to environmental stress.¹⁶

In 2017, Montoya et al¹⁷ reported that CFS was correlated with the elevation of a specific group of inflammatory mediators. This implies that CFS/ME is an immunological disorder that is triggered by exposure to specific substances. These exposures, in turn, activate the release of specific types of proinflammatory mediators, which then affect mitochondrial function by reducing bioenergetics in tissues with a high level of mitochondrial activity, such as the heart, immune cells, muscle, liver, and nervous system.

In 2000, I was introduced to Martin Pall, PhD. At that time, Dr Pall was a professor of biochemistry and basic medical sciences at Washington State University, and he was studying CFS/ME. Dr Pall had contracted the disease himself while at a medical meeting in Europe. It had come on suddenly and resulted in debilitating fatigue and muscle pain. He dedicated his work to the understanding of the etiology of CFS/ME and published a number of studies demonstrating the connection between activation of the immune system and the induction of mitochondrial dysfunction as the key hallmarks of the disease.^18,19,20

Dr Pall’s early work supported the recognition that CFS/ME resulted from an immune dysfunction associated with mitochondriopathy resulting in cellular oxidative stress and chronic tissue-specific inflammation. There is now strong evidence from numerous investigators that CFS/ME is related to functional mitochondriopathy and activation of the immune inflammatory response.^21-25 Among many interesting studies, one of particular note was the evaluation of CFS/ME in veterans of the Gulf War. The participants in this study were veterans with disabilities, many of whom were considered to be highly fit individuals performing at elite physical levels before their service in Kuwait and/or Iraq during the Gulf War conflict of 1990 to 1991. Their mitochondrial function was evaluated using the noninvasive technique of tissue specific P31 NMR spectroscopy evaluation. Data from this study were reported to be the first direct evidence supporting the hypothesis that disabling fatigue, muscle pain, cognitive dysfunction, and low cardiac performance among Gulf War veterans with disabilities may be related to deficiencies in mitochondrial function.²⁶

Nearly 2 decades have passed since my colleagues and I set out to explore the potential underlying causes of CFS/ME. Worldwide, advances in understanding have been made incrementally, but each new discovery signals forward progress. A theme that emerges from my recent review of the literature is that evidence in support of our early work on the association between the onset of CFS/ME and exposure to triggering agents that increase types of inflammatory immune response, reduced hepatic detoxification reserves, and inhibition of mitochondrial activity that results in tissue specific energy deficits has expanded and evolved in ways that may lead to groundbreaking discoveries about this debilitating condition.

The Microbiome Connection to CFS/ME

With the advent of more precise metabolomics, a detailed understanding of the metabolic disturbances associated with CFS/ME has become better understood. Overwhelming evidence suggests that the condition is related to the induction of inefficient mitochondrial energy production.²⁷ As research in this field advanced, it was noted that some of the metabolites associated with CFS/ME were connected to bacterial metabolism. These bacterial metabolites originate in the intestinal microbiome, and a number of them serve as immune inflammatory triggers or mitochondrial toxins. It has recently been reported that CFS/ME is associated with intestinal dysbiosis and distinct bacterial metabolic disturbances that may affect disease severity through their influence on the intestinal immune system, hepatic detoxification, and mitochondrial function.²⁸

Some areas of research are both controversial and yet also revolutionary. Borody et al²⁹ report that fecal microbial transplant has been found to be successful in a 70% reduction in the initial symptoms of CFS/ME and a 58% sustained response. They suggest that agents that cause dysbiosis, such as antibiotic therapy, poor quality diet, stress, lack of sleep, alcohol, and drugs, can all induce alterations in the intestinal immune system and have adverse influence on mitochondrial function.

It is now well established that the activity of the microbiome is connected to the individual’s mitochondrial function through the production of metabolites that are either “friendly” to mitochondria, such as short-chain fatty acids, or “unfriendly,” such as kynurenic acid and other amino acid metabolites.³⁰ This indicates that alterations in the intestinal microbiome can be another of the many triggers that adversely affect mitochondrial function and contribute to the etiology of CFS/ME.

It is gratifying to know that early work I was involved in has now gained considerable support through the independent findings of other researchers around the world. Most important—and the core motivation for many of us engaged in scientific research—is that this work offers new potential therapeutic approaches to CFS/ME. The contribution offered by my team, which is the demonstration that a combination of medical nutrition intervention focused on gastrointestinal restoration and support of hepatic detoxification can be used to alleviate the debilitating symptoms of CFS/ME, gives me deep satisfaction as both a scientist and an advocate for the reduction of the burden of chronic disease. Among the exciting research areas to follow both now and in the future, certainly the microbiome ranks high. To learn more, I highly recommend a report published in Cell this year titled “Microbiome and Longevity: Gut Microbes Send Signals to Host Mitochondria,” which provides an excellent summary of the progress that has been made over the past few decades in understanding the important role the microbiome has on host mitochondrial function and how this interaction potentially connects to health and aging.³¹

Biography

Jeffrey S. Bland, PhD, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.