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Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia

By William Shaw, Ph.D.


Introduction

The role of Clostridia difficile in the etiology of pseudomembranous colitis has been well-documented. My work indicates that overgrowth of the gastrointestinal tract by multiple Clostridia species may be as important as yeast/fungal overgrowth in the etiology of a wide range of disorders. Sidney Finegold, MD, the chief of the Anaerobic Bacteria Laboratory at UCLA, estimates that there may be over a 100 species of Clostridia in the GI tract.

Several years ago, I began a collaborative study of evaluating urine samples of patients with schizophrenia obtained by Dr. Walter Gattaz, a research psychiatrist 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 disease and not a drug effect. Five of the twelve samples from the patients with schizophrenia contained a very high concentration of a compound identified by GC/MS as a tyrosine derivative, which I have now identified as 3-(3-hydroxy-phenyl)-3-hydroxypropionic acid. (Shaw, William. "Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia" Nutritional Neuroscience. 13. (2010): 135-43. Print.)

During the same period of time, I performed urine organic acid testing on a child being evaluated for a conduct disorder at an outpatient psychiatric clinic. The concentration of HPHPA in the urine was elevated compared to urine samples in normal children. Several weeks later this child had an acute psychotic reaction and was admitted to the children's hospital. The concentration of HPHPA in the urine was much higher during the acute psychotic episode than in the previous sample and remained extremely elevated until the acute psychosis resolved. A colleague in the field of metabolic diseases suggested that this compound might be derived from microorganisms in the intestine. Since the amino acid tyrosine is the raw material used by the body for the production of neurotransmitters, I suspected that this product might be very important in altering key biochemical pathways for neurotransmitters in the brain.



Treatment of Patients with Elevated HPHPA

Patients with values of HPHPA greater than 500 mmol/mol creatinine in the urine almost always have severe neurological, psychiatric, or gastrointestinal disorders such as autism, severe depression, psychotic behavior or schizophrenia, muscle paralysis, or colitis or sometimes a combination of these disorders. Treatment of a severely autistic child with six weeks of oral Vancomycin therapy resulted in an estimated six months in developmental progress as assessed by a developmental psychologist. Psychotic individuals with high HPHPA have been successfully treated using Vancomycin instead of antipsychotic medication. However, even individuals in the high normal range may benefit from therapeutic intervention. One patient with acute schizophrenia had a value that was 150 times the median normal value in addition to elevated yeast metabolites as well. Several of the patients with high urine concentrations of HPHPA had positive stool immunoassay tests for Clostridium difficile, leading me to suspect that Clostridia species were responsible for the production of this compound. Treatment of a wide variety of patients with elevations of this compound with drugs that kill Clostridia such as Vancomycin and Flagyl resulted in nearly complete elimination of this compound in urine samples.


Effects of Flagyl Therapy

Diagnosis & Sex

Age

Length of time (Days) from start of Flagyl Therapy

Urinary 3-(3-hydroxy-phenyl)-3-hydroxypropionic
acid*

Autism, male

4

0

435

 

 

6

184

 

 

16

1

 

 

21 (stopped Flagyl)

5

 

 

24

2

 

 

43

236

 

 

93

274

Previous C. difficile infection and uncontrolled diarrhea, female

54

0

396

 

 

13

1

Autism, male

3

0

549

 

 

19

1

 

 

30

3

Autism male

4

0

1362

 

 

11

28

 

 

15

3

*Measured in mmol/mol creatinine.

Note that in the first patient in the table the values for HPHPA began to increase back to their previous values after discontinuation of Flagyl.

I suspect that the reason for this "rebound" is that the Clostridia, the producers of this particular compound, are spore formers. The spores are completely resistant to the drug, which in this case is Flagyl. When the administration of Flagyl is stopped, these spores re-colonize the gastrointestinal tract. One of the ways to prevent this re-colonization is to re-seed the intestine with L acidophilus.

The marked decrease in 3-(3-hydroxy-phenyl)-3-hydroxypropionic acid followed treatment with metronidazole and Vancomycin, the antibacterial agents most commonly recommended for C. difficile and other Clostridia infections. Phenylpropionic acid and monohydroxyphenylpropionic acid which are very closely related biochemically to this compound are produced by several species of Clostridia.

Clostridia were the only organisms that produced phenylpropionic acid after they evaluated 67 different isolates of microbes from nine different genera of bacteria and Candida albicans. Furthermore, they found that metronidazole, clindamycin, and combined therapy of ticarcillin, clavulanate, and oxacillin abolished gut flora producing phenylpropionic acid; these drug therapies generally kill Clostridia. Cefalzolin, cefuroxime, ampicillin, chloramphenicol, and gentamicin did not abolish phenylpropionic production. This latter group of drugs are generally ineffective against Clostridia species.

Richard Jaeckle, MD, a psychiatrist and allergist in Austin, Texas has treated a number of psychotic individuals using antifungal therapy and finds that psychotic patients with elevated CPK, uric acid and white cell counts may respond favorably to antifungal treatment. Patients with psychotic behavior may have gastrointestinal overgrowth of both yeast and Clostridia.

We were very interested in a possible role in the mechanism for autism for HPHPA because it is related structurally to the neurotransmitters dopamine and norepinephrine, because similar compounds are inhibitors of dopamine decarboxylase, the enzyme responsible for the conversion of dihydroxyphenylalanine (DOPA) to dopamine, and because of the possibility of the formation of false neurotransmitters from abnormal microbial products of phenylalanine such as 3-hydroxyphenylalanine and 2-hydroxyphenylalanine. Both of these products are isomers of tyrosine that would form false neurotransmitters when transported into the neurons.

High DHPPA (3,4 dihydroxyphenylpropionic acid), a unique but similar compound, indicates excessive intake of chlorogenic acid, a common substance found in beverages and in many fruits and vegetables, including apples, pears, tea, coffee, sunflower seeds, carrots, blueberries, cherries, potatoes, tomatoes, eggplant, sweet potatoes, and peaches. Harmless or beneficial bacteria such as Lactobacilli, Bifidobacteria, and E. coli mediate the breakdown of chlorogenic acid to 3,4-dihydroxyphenylpropionic acid (DHPPA), and high values may indicate increased amounts of these species in the GI tract. In addition, one Clostridia species, C. orbiscindens, can convert the flavanoids luteolin and eriodictyol, occurring only in a relatively small food group that includes parsley, thyme, celery, and sweet red pepper to 3,4-dihydroxyphenylpropionic acid. The quantity of Clostridia orbiscindens in the GI tract is negligible (approximately 0.1% of the total bacteria) compared to the predominant flora of Lactobacilli, Bifidobacteria, and E. coli. Consequently, this marker is essentially useless as a general Clostridia marker but may be a good indicator of the presence of beneficial flora.

High HPHPA is associated with behavioral, gastrointestinal, and/or neuropsychiatric effects. Gastrointestinal symptoms may include diarrhea or constipation. Neuropsychiatric effects are more common when values exceed 500 mmol/mol creatinine. HPHPA is an abnormal phenylalanine metabolite produced by gastrointestinal bacteria of Clostridia species, including, C. sporogenes, C. botulinum, C. caloritolerans, C. mangenoti, C. ghoni, C. bifermentans, C. difficile, and C. sordelli. In most cases, Clostridia overgrowth can be controlled by supplementation, with 30 billion cells per day of Lactobacillus rhamnosus GG (Culturelle) and/or 2-6 billion cfu's of Saccharomyces boulardii.

Dr. Shaw's article on HPHPA published in the peer-reviewed journal, Nutritional Neuroscience.


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