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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 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?

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 Connection and 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.

References

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Autism/PDD

Questions & Answers With Dr. Shaw