Arabinose, a sugar aldehyde or aldose, reacts with the epsilon amino group of lysine in a wide variety of proteins and may then form cross-links with arginine residues in an adjoining protein, thereby cross-linking the proteins and altering both biological structures and functions of a wide variety of proteins.

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Figure 5 - Crosslinked Proteins

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Figure 6 - Pentosidine Levels by Age

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This adduct of arabinose, lysine, and arginine is called a pentosidine (Figure 5). The tissue concentration of this adduct is almost linearly related to age (Figure 6). The epsilon amino group of lysine is a critical functional group of many enzymes to which pyridoxal (vitamin B-6), biotin, and lipoic acid are covalently bonded during coenzymatic reactions; the blockage of these active lysine sites by pentosidine formation may cause functional vitamin deficiencies even when nutritional intake is adequate. In addition, this epsilon amino group of lysine may also be important in the active catalytic site of many enzymes.

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Figure 7 - Proteins Modified as a Result of Pentosidine Formation

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Pentosidines, Autism, Alzheimer’s & Neurofibrillary Tangles in the Brain

Protein modification caused by pentosidine formation is associated with crosslink formation (Figure 7), decreased protein solubility, and increased protease resistance. The characteristic pathological structures associated with Alzheimer disease contain modifications typical of pentosidine formation. Specifically, antibodies against pentosidine immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease.

In contrast, little or no staining with anti-pentosidine antibodies is observed in apparently healthy neurons of the same brain. The modification of protein structure and function caused by arabinose could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.

Since the process of pentosidine formation is an oxidative one, the use of antioxidants as well as antifungal therapy appears to be a promising therapy for Alzheimer’s disease. Glutathione has been reported to inhibit pentosidine formation. Supplementation with the vitamins biotin, pyridoxal (B-6), and lipoic acid (whose function at protein epsilon amino groups may be blocked by pentosidines derived from arabinose) might also be beneficial because of functional deficiencies due to pentosidine formation (Figure 8).

Not surprisingly, neurofibrillary tangles similar to those found in the brains of Alzheimer’s victims have also been reported in the brain of an autistic person at autopsy. It has been reported that frequent urinary tract infections and high amounts of circulating immune complexes are associated with more severe Alzheimer disease. The use of antibiotics to treat urinary tract infections would of course lead to yeast overgrowth of the gastrointestinal tract.

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Figure 8 - Role of Arabinose in Proteins & Vitamin Connections

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Clostridia, Dihydroxyphenylpropionic & Psychosis

Knowledge about Clostridia species is much more limited. 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 their 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 is very similar to but is not identical to 3,4-dihydroxyphenylpropionic acid. I have termed this compound dihydroxyphenylpropionic acid-like compound (DHPPA-like compound). This compound is an isomer of dihydroxyphenylpropionic acid, but I have not yet identified the exact isomer. (Some other laboratories that report this compound are not reporting the isomer that is clinically significant.)

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 DHPPA-like compound 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 DHPPA-like compound 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.

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Treatment of Patients with Elevated DHPPA-like Compound

Patients with values of DHPPA-like compound 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 DHPPA 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 DHPPA-like compound 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.

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Effects of Flagyl Therapy

Table 1 - Effects of Flagyl Therapy on Urinary Excretion of Dihydroxyphenylpropionic-like Compound

Diagnosis & Sex	Age	Length of time (Days) from start of Flagyl Therapy	Urinary dihydroxyphenylpropionic 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.

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Note that in the first patient in the table the values for DHPPA-like compound 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 dihydroxyphenylpropionic acid-like compound follow 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 this compound 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.

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Summary

Products of gastrointestinal microorganisms that have been largely ignored in the past appear to play major roles in human metabolism, development, aging, and disease. Abnormal bacterial products of the amino acid tyrosine are elevated in psychosis, depression, autism, seizures, as well as gastrointestinal disorders like colitis. Treatment of this overgrowth of bacteria that appear to be largely of the Clostridia species has resulted in significant clinical improvement or complete remission of symptoms in a number of cases.

Elevation of yeast metabolites such as tartaric acid and arabinose are found in many of the same disorders and are even more common in autism, SLE, Alzheimer’s disease, fibromyalgia, attention deficit hyperactivity, and chronic fatigue syndrome. The arabinose may interfere with gluconeogenesis and also may through pentosidine formation significantly alter protein structure, transport, solubility, and enzymatic activity as well as triggering autoimmune reactions to the modified proteins.

The finding of pentosidine in the neurofibrillary tangles of Alzheimer’s brains and its absence from normal areas of the brain may indicate a direct role of a yeast byproduct in accelerating the normal aging process. Tartaric acid from yeast overgrowth has a direct toxic effect on muscles and is an inhibitor of a key Krebs cycle enzyme that supplies raw materials for gluconeogenesis and offers an explanation for many of the symptoms of fibromyalgia. (Return to page 1.)

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