Dr. Shaw discusses
microbial metabolites in autism, developmental disorders, illness and
various conditions. This interview is reccomended reading for people
seeking information on bowel disorders, candida, and dybiosis (and links
to those subjects lead here).
How did you
get interested in the role of urinary metabolites of microorganisms and
their role in human conditions?
I became interested
in using gas chromatography-mass spectrometry (GC/MS) to detect abnormal
microbial metabolites when I worked at the Center for Disease Control
(CDC).
At CDC, GC/MS
was used to identify the species of pure cultures of isolated bacteria.
I wondered why you couldn’t directly test human body fluids directly for
products of microorganisms. Later, while working at Children’s Mercy Hospital,
the pediatric hospital for the University of Missouri at Kansas City Medical
School, I became interested in the role of abnormal urinary metabolites
while evaluating two brothers who had autism as well as occasional muscle
weakness (Clin Chem 41:1094-1104,1995).
Since some
inborn errors of metabolism are associated with muscle weakness, I was
really looking for metabolites characteristic of these conditions which
were all negative. Instead, I noticed that several unusual compounds were
consistently elevated. None were adequately described in the medical literature.
Colleagues in
the field of metabolic diseases said they were probably from gut flora
(microorganisms). Since several of these compounds were analogs (altered
forms) of normal Krebs cycle compounds, I thought these compounds might
be significant, perhaps as anti-metabolites. At the same time, I was testing
the culture media of a large number of different yeast and bacteria strains
from the human gastrointestinal tract in order to find out which compounds
in the human might be derived from the yeast and bacteria.
During the same time period,
I began a collaborative study of evaluating urine samples of patients
with schizophrenia obtained by Dr. Gattaz at the Central Mental Health
Institute of Germany in Mannheim.
These samples were very valuable
since they were obtained from patients who were drug-free. Thus, any biochemical
abnormalities would be due to their condition and not a drug effect.
A child with an acute psychotic
reaction had been tested when relatively well and then was tested again
during the psychotic reaction had a much higher level of a compound derived
from tyrosine during the psychosis than when he was well. A colleague
in the field suggested that this compound was derived from microorganisms
in the intestine.
The compound that was elevated
in this child during the psychotic episode was also found in a large percentage
of the adults with schizophrenia. Since tyrosine is the raw material used
by the body for the production of neurotransmitters, I suspected that
this product might be very important.
When
did you even begin to suspect the connection between human disease and
yeast abnormalities in Krebs cycle metabolism?
The compound
that led to the discovery was tartaric acid.
The brothers
with autism and severe muscle weakness had extremely high values of tartaric
acid in their urine. Another child with autism had a urine value of tartaric
acid 600 times than that of normal children.
The only source
of tartaric acid is yeast. This compound forms a sludge in the wine brewing
process and has to be removed. Wine is sugar fermented by yeast to alcohol
and other products. Humans do not produce this material.
When I pulled
the medical charts of several other children with autism, they had similar
abnormalities and immediately I entertained a possible causal connection.
The next step
seemed obvious. If these compounds were from yeast and were causing
some of the symptoms of autism, antifungal drugs which kill yeast should
reduce some of the symptoms of autism.
At that time
a two year old boy was currently being evaluated for autism at the hospital
where I worked and I had just done the organic acid test. The child had
been developing normally up to about 18 months of age and had a vocabulary
of 100 words. He was treated several times for ear infections with antibiotics
and developed thrush (a Candida or yeast infection of the mouth and tongue).
His behavior
deteriorated quickly after that. He lost all speech, became extremely
hyperactive, woke up all night long, lost eye contact with his parents
and was diagnosed with autism. His organic acids that I thought were due
to the yeast, including tartaric acid, were very elevated.
The neurologist
at the hospital would not prescribe the antifungal drug Nystatin for the
child so the parents and I convinced an outside pediatrician to prescribe
it. The child’s eye contact returned by the following day and the elevated
organic acids decreased markedly, although it took 60 days to return to
the normal values. Tartaric acid is a muscle toxin and as little as 12
grams have been fatal to a human. (One gram is about the weight of a cigarette.)
Tartaric
acid is also extremely elevated in many patients with fibromyalgia who
also have muscle and joint pain. A large percentage of patients with fibromyalgia
respond favorably to treatment with malic acid. Tartaric acid is an
analog (close chemical relative) of malic acid. Malic acid is a key intermediate
in the Krebs cycle, a process used for the extraction of most of the energy
from our food. Presumably tartaric acid is toxic because it inhibits the
biochemical function of the normal compound, malic acid. I presume that
supplements of malic acid are able to overcome the toxic effects of tartaric
acid by competition at the enzyme level.
In these two
brothers with autistic features, can you explain where these Krebs cycle
metabolites came from and how they might effect behavior?
Most of
the abnormal metabolites are almost surely from yeast and/or fungi
in the gastrointestinal tract since they decline following an antifungal
drug, Nystatin that is not absorbed into the bloodstream.
Many,
but not all, autistic children have a background of frequent infections
(especially otitis media) which are treated with broad spectrum
antibiotics. One parent reported that her child had 50 consecutive
ear infections before he was 5 years old.
Some
children, however, may have elevated metabolites after only a single
antibiotic exposure. Over 700 articles in the medical literature
document antibiotic stimulation of yeast growth.
Since
both early onset and high frequency of otitis media are associated
with greater severity of autism (J Autism and Dev Dis 17:585,1987
), a yeast connection seemed worthwhile to evaluate.
Many children
with autism have a history of developing normally and then regressing.
This regression is often associated with thrush (a yeast infection
of the mouth and tongue) and/or frequent antibiotic use.
Many
children who use antibiotics never develop autism. Doesn’t this disprove
your hypothesis?
Many
smokers never develop lung cancer and a small percentage of people who
develop lung cancer have never smoked. Nevertheless, there is little doubt
that smoking causes lung cancer. Who gets lung cancer and who survives
depends on other genetic and environmental factors.
I
have found that these metabolites are not specific for autism but may
also be associated with other neurological conditions such as attention
deficit hyperactivity, seizures, learning disabilities, or speech
disorders. In one set of identical twins, one of the twins was autistic
while the other was not autistic but had speech difficulty.
The
factors that influence which condition is present probably include which
metabolites are elevated, how high their concentrations are, how long
the exposure to these products lasts, the number of exposures, and differences
in the ability to detoxify these products.
Other
significant modulating factors in autism and other yeast-related illnesses
are immunodeficiencies which are very common
in autism and may be present in other disorders as well. Some individuals
may be so immunodeficient that even a single antibiotic exposure may alter
the gut flora significantly.
Sudhir
Gupta MD, a clinical immunologist in California estimates that a high
percentage of autistic children have a significant immune dysfunction
and may include myeloperoxidase deficiency, a genetic deficit that impairs
yeast killing by the white blood cells, IgA deficiency, complement C4b
deficiency, IgG deficiency, or IgG subclass deficiency.
In
one case, Gupta obtained complete remission of autism by infusions of
gamma globulin (a concentrate of human antibodies). I saw the before and
after videotapes of this child and the transformation is remarkable.
Environmental
toxins might also be important in weakening the immune system. The news
is full of incidents of marine life (seals, dolphins, and fish) with unusual
infections or tumors following exposure to PCB’s and other toxins.
My
doctor says everyone has yeast in their intestine and if yeast were the
cause of all these disorders then everyone would be adversely affected.
How do answer that assertion?
The
most important question is not whether yeast are present or not. The
critical factors are the quantity of yeast and the kinds and amounts of
toxic products they produce.
Everyone
in this society has carbon monoxide in their blood and can tolerate a
low value. When the amount of carbon monoxide increases, some individuals
feel depressed, some have headaches, some feel tightness in the chest
or angina, some experience nausea and vomiting, some become dizzy, some
develop dimming of vision. As values increase, symptoms may include convulsions,
coma, respiratory failure, and death. Individuals who recover from severe
carbon monoxide poisoning may suffer residual neurological damage.
Different people will respond with different symptoms to the same concentration
of carbon monoxide. Why is it surprising that exposure to a wide range
of toxic yeast products at different times and at different ages might
produce different symptoms?
If
I suggested that there were a carbon monoxide connection with all of the
diverse symptoms associated with carbon monoxide exposure, no one would
challenge me. The reason that the carbon monoxide connection is accepted
is because carbon monoxide can be easily measured in blood. The toxic
yeast products were just discovered, but as knowledge of them increases,
acceptance of the yeast-related illnesses will increase.
The
philosopher Schopenhauer said, "All truth goes through three stages. First,
it is ridiculed. Then, it is violently opposed. Finally, it is accepted
as self-evident." Within five years, people who ignore the importance
of yeast-related illness will be in the same camp with those in the Flat-Earth
Society.
What
conditions in adults are associated with abnormal products of yeast and
bacteria from the gastrointestinal tract?
Adult
conditions include fibromyalgia, chronic fatigue syndrome, schizophrenia,
adult attention deficit disorder, systemic lupus erythematosus, inflammatory
bowel disease, colitis, interstitial cystitis, depression (both unipolar
and bipolar), multiple sclerosis, and HIV infection. I don’t claim
all of these disorders are caused by abnormal gastrointestinal microorganisms
but some of the symptoms are probably exacerbated by this problem in many
of these conditions and may indeed be causative in a portion of these
disorders.
What
is the role of yeast metabolism with respect to these urinary metabolites
and their effects on the body’s metabolism?
It
is possible that several of the yeast metabolites inhibit the Krebs Cycle
and thus general cell energy production. The high concentration of the
unusual yeast sugar arabinose and/or high tartaric acid may inhibit gluconeogenesis,
the process that the body uses to restore blood sugar when it gets too
low.
Indeed,
an autistic child with the highest arabinose (40 times the normal limit)
was severely hypoglycemic (blood glucose 20-50 mg %; normal is 100 mg
%) almost all of the time.
Many
patients with fibromyalgia have significant hypoglycemia. Severe hypoglycemia
can markedly impair neurological function.
In
addition the arabinose may have other unknown toxic roles. I have tested
infants who lost eye contact with the mother, an early symptom of autism,
after antibiotic administration. Nystatin restored normal eye contact.
I
think the yeast and their biochemical products are causally related to
the autism and many other disorders but it may take a decade or more to
prove it conclusively. I do not think we can afford to have all the data
before we take action.
Could
frequent antibiotic therapy set the stage for the increased production
of these urinary metabolites?
Definitely. The
pharmaceutical industry knew about the yeast overgrowth problem in the
1950’s when oral antibiotics were introduced. A number of antibiotics
combined with the antifungal drug Nystatin were produced in the 1950’s
but the use of these combination products was killed by the FDA which
took the position that these products shouldn’t be used for prophylactic
use.
How
can one reduce, either by medication, diet and/or natural substances,
these urinary metabolites that are associated with these yeast caused
illnesses?
Any antifungal
drug may be effective, but Nystatin is one of the most popular. Virtually
every antifungal drug is being used by knowledgeable physicians to treat
autism including fluconazole (Diflucan), ketoconazole (Nizoral), and Sporonox,
Lamisil, and Amphotericin B.
A large number
of health food store products are antifungal including garlic, grapefruit
seed extract, and caprylic acid. Lactobacillus acidophilus and related
bacteria also appear to be useful.
William Crook,
the author of The Yeast Connection, has talked about the restriction
of dietary sugar being important in reducing the yeast overgrowth. In
a study conducted at a school for autistic children in Montreal, some
improvements in symptoms were found with diet restrictions only.
So,
in reality we are saying that inappropriate gut flora or dysbiosis may
effect neuropsychiatric disorders such as schizophrenia and ADD?
Yes,
that appears to be the case. The last half of this century could be termed
the era of antibiotics. The next century will be involved in developing
new antimicrobial treatments (probiotics or beneficial bacteria) or other
therapies that have less potential for harming the normal flora. Pasteur
and others found that lethal strains of bacteria causing Anthrax could
be rendered harmless if animals were given other benign bacteria simultaneously.
Does
this discovery give some credence to the popularized yeast syndrome and
the benefit of Nystatin therapy in reducing a wide parameter of symptoms,
some of which include behavior or psychiatric problems?
Definitely. I
have done testing on patients with virtually every disorder mentioned
in The
Yeast Connectionand found evidence of abnormal microbial metabolites
in all of them.
In
your opinion, could the overuse of antibiotics be a significant factor
in yeast-related problems?
Definitely.
Bernard Rimland’s data indicates a marked increase in new cases of autism.
It is during this same period that the use of antibiotics has skyrocketed.
Numerous
studies have linked frequent otitis media
with attention deficit hyperactivity. A number of these studies assumed
that normal development was disturbed by the temporary hearing loss, but
I think the role of dysbiosis really needs to be examined and will ultimately
prove to be very significant.
Could
nonfungi but also other pathogens cause similar metabolites that may effect
the health of the individual?
Yes,
it appears that certain members of the Clostridia family produce abnormal
tyrosine derivatives that may influence behavior. Other unusual species
of bacteria such as the Propionobacteria may be important in other disorders
such as Tourette’s syndrome and obsessive compulsive disorder.
We
discovered that certain metabolites that were not reduced by antifungal
drugs were completely eliminated by metronidazole (Flagyl) or vacomycin.
Some of the individuals with these metabolites are positive by immunoassay
for Clostridium difficile, an organism that frequently proliferates with
frequent antibiotics and is not killed by common broad spectrum antibiotics
like penicillin and tetracycline.
The
clinical symptoms in patients with extremely high levels of these bacterial
metabolites are sometimes very unusual. One woman with very high levels
had a seizure following each meal for a period of several months following
antibiotic therapy. About 50% of schizophrenics have very high levels.
One patient with schizophrenia had both yeast and bacteria metabolites
in her urine that were fifty times the upper limit of normal. It has been
known for years that many patients with schizophrenia had high levels
of an enzyme called CPK-MM in their blood during an acute psychotic reaction.
CPK-MM is an enzyme derived from muscle tissue; large amounts of the enzyme
spill out from damaged muscle I suspect that these cases may be caused
by the high levels of muscle-toxic tartaric acid.
A psychiatrist in Dallas, Texas, Richard Jaeckle MD, has found that he
could treat some cases of acute psychosis with antifungal drugs and/or
desensitization injections to molds. Dr. Jaeckle suggests that an elevated
uric acid, CPK, and white blood cell count in psychosis are indicative
of a yeast etiology. When we’ve done longitudinal tests, worsening of
clinical symptoms is paralleled by increased metabolite excretion. High
doses of L. acidophilus may be equally effective as metronidazole in reducing
these abnormal tyrosine products.
Metronidazole
has a lot of side effects and I do not recommend it unless other safer
therapies have failed. In addition, metronidazole can upset the ecological
balance in the gastrointestinal tract and lead to a yeast overgrowth.
There is no need to eradicate an organism completely; the real need is
to restore balance and the beneficial bacteria work well although very
high doses may be needed for short periods of time for more severe microbial
dysbiosis.
What
type of investigations would you like to see to further clarify the role
of antibiotics, dysbiosis or abnormal fungal growth and its relationship
to neuropsychological disorders in children?
I
would like to see a large epidemiological study done by the Center for
Disease Control (CDC) in which these microbial metabolites were tested
in a large population of infants, say 20,000 and then rechecked monthly
for five years. I suspect that the incidence of significant developmental
and neurological disorders such as seizures, ADD, and autism would be
much higher in the group with more antibiotic usage and that children
who develop neurological and developmental problems will have been exposed
to much higher levels of metabolites.
Why
does antifungal drug therapy need to be continued so long in so many people
with yeast disorders?
No
one knows for sure. Most physicians who have been using antifungal drugs
to treat autism usually prescribe for six months or longer and similar
duration of treatment may be used in other yeast-related disorders.
Several
factors are important including drug resistance, toxic environmental exposures,
virus weakening of the immune system, deficiencies of the immune system,
the high sugar diet of the average American, and toxins from the yeast
that suppress the immune system.
People
with HIV infection frequently have problems with candidiasis and patients
on chemotherapy have frequent yeast and fungal infections due to their
weakened immune system. Many strains of Candida produce gliotoxins, compounds
which fragment the DNA of the white blood cells, leading to a depression
of the immune system. Inborn (genetic) deficiencies of the immune system
are also very important in determining which individuals are most susceptible
to yeast-related illnesses. Mercury toxicity can also cause recurrent
Candida problems.
I
don’t understand why yeast would have anything to do with autoimmune diseases
like systemic lupus erythematosus. Can you offer an explanation?
Rheumatic
fever is an autoimmune disease involving inflammation of the heart, joints,
and other tissues. This disease often follows strep throat. Certain of
the streptococcal antigens are similar to heart tissue. When, the immune
system reacts against the strep, the antibodies also react against the
heart.
The
situation with Candida is very similar. The Candida possesses proteins
on its surface that are similar to many types of human tissue. When the
body mounts an immune response against the Candida, some of the antibodies
may react against placenta, ovary, adrenal, thymus, liver, pancreas, spleen,
brain, and liver.
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"Yeast-related mental
disturbances, Psychiatric symptoms elicited through biological mechanisms."
An interview with Richard G. Jaeckle MD Mastering Food Allergies 10:
1-4, 1995.
