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CREATING SYNTHESIS
Chronic Fatigue Syndrome, Functional
Mitochondriopathy, and Enterohepatic Dysfunction
Jeffrey S. Bland, PhD, FACN, FACB, Associate Editor
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
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.
C
hronic 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 A 2015
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,
18 Integrative Medicine • Vol. 16, No. 5 • October 2017
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.
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
Bland—Creating Synthesis
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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
Bland—Creating Synthesis
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
Integrative Medicine • Vol. 16, No. 5 • October 2017 19
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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
20 Integrative Medicine • Vol. 16, No. 5 • October 2017
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
Bland—Creating Synthesis
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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
Bland—Creating Synthesis
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