: Nystatin, Tartaric Acid levels lowered ( which is good)

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Gastrointestinal Bacteria Facts

a.. There are 500 or more different species

b.. 30-40 different species predominate

c.. There are approximately 1-10 X 1013 or 10-100 trillion bacteria

cells in colon

d.. Comparable to the 100 trillion cells in human body

e.. Anaerobic bacteria predominate

f.. 90% of species may be unidentified

g.. Bacteria constitute about 50% of the content of feces

h.. There are about a million times more bacteria in the colon than in

the stomach

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Detecting GI Microbial Overgrowth (Dysbiosis)

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 detected by GC/MS while

evaluating two brothers who had autism as well as occasional severe muscle

weakness.

Since some inborn errors of metabolism are associated with muscle

weakness, I was really looking for metabolites characteristic of genetic

diseases which were all negative. Instead, I noticed that several unusual

compounds were consistently elevated in urine samples. None were adequately

described in the medical literature. Colleagues in the field of metabolic

diseases said they were probably from gut flora (microorganisms) and were

therefore unimportant. Since several of these compounds were analogs (or altered

forms) of normal Krebs cycle compounds, I thought these compounds might be

significant, perhaps as anti-metabolites.

During the same time period, 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 in the gastrointestinal tract.

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Yeast Metabolites in the Urine of Children with Autism

The compound that led to the discovery of yeast as the source of many of

these compounds in the urine of autistic children 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 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-water fermented by

yeast (Saccharomyces cerevisiae) to alcohol and other yeast products. Humans do

not produce this chemical.

When I pulled the medical charts of several other children with autism,

they had similar abnormalities and immediately I wondered about 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. However, the two

brothers did not receive antifungal therapy until nearly a year later.

At nearly the same time, a two-year-old boy was currently being evaluated

for autism in the neurology department at the children's hospital where I worked

and I had just done the urine organic acid test. The child had been developing

normally up to about 18 months of age and had a vocabulary of about 200 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.

This pattern of normal development and regression associated with

antibiotics is extremely common in autism and is especially common in males with

autism (about a 20/1 male/female ratio). His organic acids were very elevated,

which I thought was due to the yeast, including tartaric acid. The neurologist

at the hospital would not prescribe the antifungal drug Nystatin for the child

so the parents and I convinced their family physician to prescribe it.

The child's eye contact returned by the following day and the elevated

organic acids decreased markedly, although it took over 60 days for the urine

tartaric acid to return to the normal range (Figure 1).

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Figure 1 - Child with high tartaric acid was started on the antifungal

drug, Nystatin, and tested. Even after 68 days, tartaric increased when the dose

was reduced in half and then decreased again when the full dose was restored.

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At day zero (Figure 1), the day that the child had the organic acid test

done, the tartaric acid value in urine was over 300 mmol/mol creatinine, a very

high value--about twenty times the normal value. (Most chemicals measured in

urine are divided by the urine creatinine concentration to compensate for

different amounts of fluid intake in different individuals.) Following the

treatment with the Nystatin, the level of the tartaric acid decreased

considerably and continued to decrease as the Nystatin was continued.

Within a couple of days of starting the antifungal drug Nystatin, the

child--who had lost most of normal development--began to improve and eye contact

came back. His extreme hyperactivity began to go away and he began to have a

greater amount of focus. The sleep pattern improved as well. Nystatin is an

antifungal drug which indicated to me that a yeast or fungus (these terms are

somewhat interchangeable in that they are very closely related biologically) was

causing the secretion of this compound in the intestinal tract.

After 68 days the child's mother started running out of Nystatin and began

giving only half doses so that she didn't run out of it. During that time the

tartaric acid starting increasing. When she got the Nystatin prescription

refilled and restored the full dose of Nystatin, the tartaric acid decreased.

What this indicated to me was that the Nystatin was causing a marked

reduction in this urine tartaric acid. The other significant finding was that

even after two months of Nystatin, the biochemical abnormality would reappear

within a short time of stopping the antifungal drug.

I have now detected this same phenomenon in hundreds of other cases. Even

after six months of antifungal treatment, there is often a biochemical " rebound "

and loss of improvements after discontinuing antifungal therapy. This rebound

also occurs after other antifungal drugs as well.

Several explanations are possible for this phenomenon:

a.. Because of one or more defects in the immune system such as IgA

deficiency, IgG deficiency, or severe combined immunodeficiency disease (SCID)

which are found in most children with autism, the yeast, which are everywhere in

our environment including the food we eat, repopulate the intestinal tract very

rapidly.

b.. The yeast are very resistant and have not been completely eliminated

even after six months of antifungal therapy

c.. The yeast have genetically transformed some of the human cells that

line the intestinal tract so that some of the human cells now contain yeast DNA.

These genetically transformed human cells produce both yeast and human products

and are somewhat sensitive to antifungal drugs but are not killed by them and

produce yeast products whenever antifungal drugs are absent.

d.. Some of the yeast are hidden in recesses of the intestinal tract or

in the deeper layers of the mucosa that lines the intestine where they are

relatively safe from the drug. Although their numbers are small, they readily

repopulate the intestine after antifungals are stopped.

e.. In addition to the immune system taking inventory of its own cells,

it seems increasingly likely that the immune system also takes an inventory of

bacteria and yeast cells present in the intestinal tract soon after birth. This

inventory is performed by a group of cells called the CD5+ B-cells, which are

among the very first immunological cells to appear in the developing embryo and

appear to play a role in tolerance to intestinal microorganisms in postnatal

life. These cells may play a role in regulating the secretion of IgA, the

antibody class that is secreted into the intestinal tract and which may select

which microorganisms are tolerated in the intestinal tract. Furthermore, the

eradication of normal flora especially when antibiotics are administered

repetitively during infancy may cause the CD5+ cells to reject these normal

organisms at a later age. Any cells that are on this early inventory may be

awarded immune tolerance and will not be attacked later on by the immune system.

Either antibiotic use in infancy or yeast infection of the mother during

pregnancy may result in later immune tolerance to yeast.

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Response of Children with Autism to Antifungal Therapy

Improvements commonly cited by parents of autistic children treated with

antifungal therapy include: decreased hyperactivity, more eye contact, increased

vocalization (more words and more usage), better sleep patterns, better

concentration, increased imaginative play, reduced stereotypical behaviors (such

as spinning objects), and better academic performance. Two children with autism

treated with a combination of antifungal therapy, EPD treatment for food

allergies, and gluten and casein free diet have completely recovered from

autism.

More than 1000 children with autism have been treated with a wide variety

of antifungal agents such as Nystatin, Lamisil, Sporanox, Nizoral, Diflucan,

caprylic acid, grapefruit seed extract, and garlic extract with good clinical

response in perhaps 80-90%. A survey of parents of autistic children by Rimland

reports that antifungal therapy is ranked the most effective (by a wide margin)

of all drug therapies used for the reduction of autistic symptoms.

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Molecular Basis of Tartaric Acid Toxicity

The abnormal metabolites derived from yeast were first discovered in two

brothers with autism. In addition to their autism, these brothers had a muscle

weakness that was so severe that sometimes they could not even stand up. A

neurologist colleague, Enrique Chaves, MD, told me that virtually all the

autistic children he examined had hypotonia.

Both of these brothers excreted high amounts of tartaric acid in the

urine. Biopsy of the muscle and examination by electron microscopy revealed

normal structural features except for an unexplained " granularity. "

Electromyography, EEG's, brain scans, and nerve conduction velocities were all

normal.

A toxicology manual indicates that tartaric acid is a highly toxic

substance. As little as 12 gm has caused human fatality with death occurring

from 12 hours to 9 days after ingestion. Gastrointestinal symptoms were marked

(violent vomiting and diarrhea, abdominal pain, thirst) and followed by

cardiovascular collapse and/or acute renal failure. A gram is approximately the

weight of a cigarette.

This compound especially damages the muscles and the kidney and may even

cause fatal human nephropathy (kidney damage) which was of interest to me, since

the two brothers with autism had the extreme muscle weakness as well as evidence

of impaired renal function.

A young Korean child with autism had a value of 6000 mmol/mol creatinine,

a value that is about 600 times the median normal value. Assuming that the yeast

in the intestine of the child were producing tartaric acid at a constant rate,

this child would be exposed to 4.5 grams per day of tartaric acid, over

one-third of the reported lethal dose of tartaric acid! (The child's value

returned to normal after a few weeks of antifungal treatment.)

Tartaric acid is an analog (a close chemical relative) of malic acid

(Figure 2). Malic acid is a key intermediate in the Krebs cycle, a biochemical

process used for the extraction of most of the energy from our food. Presumably

tartaric acid is toxic because it inhibits the biochemical production of the

normal compound, malic acid (Figure 3). Tartaric acid is a known inhibitor of

the Krebs cycle enzyme fumarase which produces malic acid from fumaric acid.

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Figure 2 - Composition of Malic & Tartaric Acids

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Yeast Byproducts, Malic Acid Supplementation, & Fibromyalgia

Interestingly, I have found that tartaric acid and/or other yeast

byproducts are also elevated in urine samples of adults with the disorder

fibromyalgia, a debilitating disease associated with muscle and joint pain,

depression, foggy thinking, and chronic fatigue. (Dr. Kevorkian has assisted in

the suicide of two people with this disorder, which is tragic since a simple

antiyeast treatment may help relieve the symptoms of this disorder.)

A large percentage of patients with fibromyalgia respond favorably to

treatment with malic acid which is present in health food supplements such as

Fibrocare and Supermalic. I presume that supplements of malic acid are able to

overcome the toxic effects of tartaric acid by supplying deficient malic acid.

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Figure 3 - The Krebs Cycle demonstrates the conversions of raw materials

into Glucose, the main fuel for the brain.

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Treatment with the antifungal drug Nystatin kills the yeast and values for

tartaric acid steadily diminish with antifungal treatment. Fifty percent of

patients with fibromyalgia often suffer from hypoglycemia even though their diet

may have adequate or even excessive sugar.

One of the reasons for the hypoglycemia may be due to the inhibition of

the Krebs cycle by tartaric acid. The Krebs cycle is the main provider of raw

materials such as malic acid that can be converted to blood sugar (Figure 3) by

the process called gluconeogenesis when the body uses up its glucose supply.

If sufficient malic acid cannot be produced, the body cannot produce the

sugar glucose, which is the main fuel for the brain. The person with

hypoglycemia feels weak and their thinking is foggy because there is

insufficient fuel for their brain. Of course, consumption of sugar may provide

short-term relief but which also stimulates yeast overgrowth and within a short

time symptoms are even worse.

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Arabinose, Yeast, Autism, Alzheimer's Disease & Schizophrenia

Arabinose is a five carbon sugar with an aldehyde function called an

aldose, which is frequently elevated in autism.

In some children with autism, arabinose concentrations may exceed 50 times

the upper limit of normal. A scattergram of urine arabinose values comparing

normal and autistic children in the same age range is given below (Figure 4).

Figure 4 - Normal levels of Arabinose & Levels in Individuals with Autism

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The exact biochemical role of arabinose is unknown, but a closely related

yeast alcohol arabitol has been used as a biochemical indicator of invasive

candidiasis. We have never found elevated arabitol in any of the urine samples

tested and we have not found arabinose in the culture media of multiple isolates

of Candida albicans isolated from stool samples of autistic children

(unpublished data).

We suspect that arabitol produced by yeast in the intestinal tract is

absorbed into the portal circulation and then converted to arabinose by the

liver. Hypoglycemia occurs in inborn errors of fructose metabolism in which

fructose inhibits gluconeogenesis and it is possible that children with autism

might be deficient in one or more enzymes involved in the metabolism of

pentoses. Elevated protein-bound arabinose has been found in the serum

glycoproteins of schizophrenics and in children with conduct disorders and

alteration of protein function by arabinose is another mechanism by which

arabinose might effect biochemical processes.

Women with vulvovaginitis due to Candida were found to have elevated

arabinose in the urine; restriction of dietary sugar brought about a dramatic

reduction in the incidence and severity of the vulvovaginitis. Thus, one of the

mechanisms of action of antifungal drug therapy for autism might be to reduce

the concentration of an abnormal carbohydrate produced by the yeast that can not

be tolerated by the child with defective pentose metabolism. Arabinose tolerance

tests should be able to rapidly determine if such biochemical defects are

present in children with autism. (Go to page 2.)

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