INTERVIEW WITH DR. WILLIAM SHAW ABOUT MICROBIAL METABOLITES IN AUTISM AND OTHER DEVELOPMENTAL DISORDERS

How did you get interested in the role of abnormal metabolites and autism?

While at CDC, I found that microbiologists used to identify the species of bacteria from pure cultures.  I wondered if it were possible to test human body fluids directly for microbial products.  (Microbial products also called metabolites are compounds given off by bacteria and yeast, similar to a person breathing.)   Later, while working at a hospital, I became interested in the role of abnormal urinary metabolites while evaluating two brothers.  They had autism as well as occasional muscle weakness.

Since some errors of metabolism are associated with muscle weakness, I was looking for those metabolites.  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 (bacteria in the intestinal tract).  Since several of these compounds were altered forms of normal compounds, I thought they might be significant, perhaps as antimetabolites.

When did you begin to suspect the connection between autism and these abnormalities?

When I pulled the medical charts of several other children with autism.   They had similar abnormalities and immediately I entertained a possible connection.   Through researching literature on these abnormal compounds, I found they were common in yeast.

The next step seemed obvious.  If these compounds were from yeasts and were causing some of the symptoms of autism, antifungal drugs, which kill yeast, should reduce some of the symptoms of autism.
At the time a two year old boy was currently being evaluated for autism at the hospital where I worked.  I had just done the organic acid test.  His organic acids that I thought were due to the yeasts were very elevated.  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 (Candida or yeast infection of the tongue).  His behavior deteriorated quickly after that.  he lost all speech, became extremely hyperactive, woke up all night long, lost eye contact with parents and was diagnosed with autism.

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 next day, the child's eye contact returned and, after a week the elevated organic acids decreased markedly.

In these two brothers with autistic features, can you explain where these abnormal microbial products came from and how they might effect behavior?

Most of the abnormal microbial products are almost surely from yeast and/or fungi in the gastrointestinal tract, since they decline following the use of an antifungal drug, Nystatin.

Many, but not all, autistic children have a background of frequent infections (especially ear infection), which are treated with broad spectrum antibiotics.   One parent reported that her child had 50 consecutive ear infections before he was five years old.  Some children, however, may had elevated metabolites after only a singular antibiotic exposure.

Over 700 articles in the medical literature document antibiotic stimulation of yeast growth.  Since both early onset and high frequency of ear infection are associated with greater severity of autism, 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 and/or frequent antibiotic use.

Using our testing, we have also biochemically documented the "yeast die off" or Herxheimer reaction which follows the initial use of antifungal drugs.   During the first three days of antifungal use, values for these microbial metabolites increase dramatically and begin to normalize near day four.

The big question is why do many kids use antibiotics and not develop autism?  

I have found that these metabolites are not specific for autism, but may also be associated with other neurological conditions.  Some of these are attention deficit hyperactivity, seizures, learning disabilities, or speech disorders.  In one set of identical twins, one of the twins was autistic while the other had speech difficulty, but was not autistic.
Other contributing factors in autism include immunodeficiencies (which are very common in autism), and probably differences in the ability to detoxify certain compounds.  Some individuals may be so immunodeficient that even a single antibiotic exposure may alter the gut flora significantly.

Sudhi Gupta MD, a clinical immunologist at the University of California at Irvine estimates that a high percentage of autistic children have a significant immune dysfunction.  This 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 was 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.

What is the role of yeast metabolism with respect to these metabolites and the onset of autism?

It is possible that several of the yeast metabolites inhibit the Koreas Cycle (the Koreas Cycle is the process most cells use to obtain energy) and thus general cell energy production.  The high concentration of the unusual yeast sugar arabinose may inhibit the manufacture of glucose.  Indeed, an autistic child with the highest arabinose (40 times the normal limit) was severely hypoglycemic (blood glucose 20-50mg %: normal is 100 mg %) almost all of the time.  This child was completely normal until being treated for Strep throat at nine months of age.  Severe hypoglycemia impairs neurological function - low glucose, low brain function.

In addition, the arabinose produced by the yeast may have other unknown toxic roles.  I had tested infants who lost eye contact with the mother (an early symptom of autism), after antibiotic administration.  Nystatin resorted normal eye contact.  I think the yeast and their biochemical products may be related to the autism and other disorders.  However, it may take a decade or more to prove it conclusively.  I don't think we can afford to have all the data before we take action, since there is marked improvement after getting rid of yeast, and side effects are minimal.

Could frequent antibiotic therapy set the stage for the increased production of these yeast metabolites?

Definitely.  The pharmaceutical industry knew about the yeast overgrowth problem in the 1950s when oral antibiotics were introduced.  A number of antibiotics combined with the antifungal drug Nystatin were produced in the 1950s, but the use of these combination products was killed by the FDA.  It took the position that these products should be used for prophylactic use.

How can one reduce these abnormal metabolites that are associated with these autistic features?

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), Sproronox.

A large number of health food store products are antifungal including garlic, grapefruit seed extract, and caprylic seed extract, and caprylic acid.   Lactobacillus acidophilus and related bacteria also a 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.  This is most likely because yeast are stimulated by sugar to grow and divide.

So, in reality we are saying that inappropriate gut flora or dysbiosis may affect a neurologic syndrome such as autism?
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 (probioitcs or beneficial bacteria) or other therapies that has less potential for harming young children.  Pasteur and other found that lethal strains of bacteria 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 and 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.  The abnormalities that we have found are not specific to autism.  Similar metabolites from yeast or certain bacteria are found in seizures, adult depression, fibromyalgia, chronic fatigue syndrome, child psychosis, schizophrenia, and severe hyperactivity.

In your opinion, could the overuse of antibiotics be a significant factor in behavior problems?

Definitely.  Dr. Bernard Rimland's data indicates a marked increase in new cases of autism.  It is during this time period that the use of antibiotics has skyrocketed.  Numerous studies have linked frequent ear infection 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.

What other pathogens could cause similar metabolites and affect the health of the individual?

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).   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 penicillins 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 after each meal for a period of several months following antibiotic therapy.   In addition, about 50% of schizophrenics have very high levels.  A high dose of L. acidophilus may be equally effective as metronidzole in reducing 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.  The L. acidophilus work well although very high dose may be need for a short periods of time for more severe microbial dysbiosis.

What type of investigations would you like to see further clarify the role of antibiotics, dysbiosis or abnormal fungal growth and their relationship to neurolpsychological disorders?

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 10,000 and then rechecked monthly for a couple of years.   I suspect that the incidence of developmental and neurological disorders would be much higher in the group with more antibiotic usage.  I think we will find children who develop neurological and developmental problems will have been exposed to much higher levels of metabolites.

How long does antifungal drug therapy need to be continued?

No one knows for sure.  Most physicians who have been using antifungal drugs to treat autism usually prescribe it for six months or longer.  I know of some children who have been treated for three years.  The antifungal therapy is probably not a cure, since the metabolites become elevated and the behavior regresses when the drug is discontinued.  This may because of the impaired immune system.

Dr William Shaw received a Ph.D. in biochemistry and human physiology from the Medical University of South Carolina.  He is board certified in the fields of Clinical Chemistry and Toxicology by the American Board of Clinical Chemistry.  He has supervised large endocrinology, nutritional biochemistry, toxicology, and immunology departments in positions at the center for Disease Control and Smith Kline Clinical Laboratories in Atlanta.  He was Director of Clinical Chemistry, Endocrinology and Toxicology at Children's Mercy Hospital, the teaching hospital of the University of Missouri at Kansas City School of Medicine.  He is now the Director of the Great Plains Laboratory for Health, Metabolism, and Nutrition, in Overland Park Kansas, specializing in urine organic acid testing.   For more information call (913) 341-8949 or visit their website at http://www.greatplainslaboratory.com/