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Clostridia metabolites inhibit human dopamine-beta-hydroxylase, increasing toxic dopamine metabolites and severe oxidative stress in autism. William Shaw PhD The Great Plains Laboratory,Inc www.gpl4u.com. Dialogues Clin Neurosci . 2011;13:55-62. Autism Insights 2010:2 1–11. William Shaw.
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Clostridia metabolites inhibit human dopamine-beta-hydroxylase, increasing toxic dopamine metabolites and severe oxidative stress in autism William Shaw PhD The Great Plains Laboratory,Inc www.gpl4u.com
William Shaw Nutritional Neuroscience 2010 Vol 13 No 3: 1-10
Structure of 3-(3-hydroxyphenyl)-3-hydroxypropionic acid 5 6 3 2 1 CHOHCH2COOH 1 4 Hydroxyl group 2 3 Propionic acid group HO Phenyl group
“It was observed that mentally ill patients, in general, seem to excrete much larger amounts of HPHPA than do most normal people.” • Most patients with mental retardation excrete very low amounts of HPHPA. Journal of Biological Chemistry 225:269-278,1957
Increased Urinary Excretion of Analogs of Krebs Cycle Metabolites and Arabinose in Two Brothers with Autistic Features. W Shaw. ClinChem 41:1094-1104, 1995. HPHPA
Child psychosis during hospitalization (simulated from memory) HPHPA HPHPA
Clostridia species that produce HPHPA precursors • C. difficile-pseudomembranous colitis • C. sporogenes • C. botulinum-food poisoning • C. mangenoti • C. ghoni • C. bifermentans • C. caloritolerans
Figure 2. Distribution of values for HPHPA Clostridia metabolite in urine samples of male infants, control boys, and boys with autism. 3-(3-hydroxyphenyl)-3-hydroxypropionic acid HPHPA -mmol/mol creatinine Control boys 2-13 years Control infants Autistic Boys 2-13 years
Main brain neurotransmitters Norepinephrine and dopamine
Catecholamine Synthesis Mainly adrenal gland
Catabolism of Dopamine Organic acid test
Norepinephrine Catabolism Organic acid test
Endoscopy of colon of patient with mild Clostridium difficile overgrowth
Endoscopy of colon of patient with severe Clostridium difficile overgrowth- pseudomembranous colitis
Formation of p-cresol from tyrosine by Clostridia bacteria PST tyrosine 4-hydroxy- phenylpyruvic 4-hydroxy- phenylacetic p-cresol p-cresol sulfate 14728–14733 PNAS August 25, 2009 vol. 106 no. 34
NH2 CH2CHCOOH CH2CH2COOH NH2 NH2 CH2COCOOH CH3 CH2CHCOOH CH2CHCOOH HO HO HO CH2CH2COOH NH2 NH2 HO CHOHCH2COOH CH2CHCOOH HO NH2 phenylalanine phenylalanine hydroxylase phenylpropionic acid microbial tyrosine microbial 3-hydroxyphenyl- propionic acid microbial tyrosine analog HO tyrosine hydroxylase human beta-oxidation 4-hydroxyphenyl- pyruvic acid 3-(3-hydroxyphenyl) -3-hydroxypropionic acid (HPHPA) HO HO 3,4-dihydroxyphenyl Alanine (DOPA) human beta oxidation enzymes dopamine COOH 4-cresol glycine HVA HO 3-hydroxy- benzoylglycine (3-hydroxyhippuric) VMA norepinephrine 3-hydroxybenzoic acid epinephrine
Critical effect of intestinal bacteria on brain neurotransmitters Organic acid test Organic acid test Organic acid test
Brain Intestine ** * ** ** * **** **** **** **** ** * * * ****** * * * * ** * ***** Blood vessels ***** * * ***** ******* * * * * * B * * ***** * * ***** * B* * Body * ***** * * * * * * * * *** * * Kidney * * * =Clostridia bacteria **** * * * * ** * *= products 0f Clostridia Urine cup * * * * * * * * B= bacteria (beneficial) ** **** *** ***** *****
Effect of HPHPA on brain neurotransmitters (Dopamine) Clostridia HPHPA Mmol per Mol creatinine HVA Mmol per Mol creatinine Date
Effect of HPHPA on brain neurotransmitters Dopamine metabolite HVA Mmol per Mol creatinine Norepinephrine Metabolite VMA Mmol per mol creatinine HVA (dopamine) Date
Effect of HPHPA on brain neurotransmitters HVA/VMA Indicator of Dopamine to Norepinephrine ratio HPHPA Mmol per Mol creatinine Date
Linan Chen, et al(2008) Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. J. Neurosci. 28, 425–433 • Dopamine is a very reactive molecule compared with other neurotransmitters, and dopamine degradation naturally produces oxidative species. • More than 90% of dopamine in dopamine neurons is stored in abundant terminal vesicles and is protected from degradation. • However, a small fraction of dopamine is cytosolic, and it is the major source of dopamine metabolism and presumed toxicity. • Cytosolic dopamine undergoes degradation to form 3,4-dihydroxyphenylacetic acid (DOPAC) and HVA as well as hydrogen peroxide via the monoamine oxidase pathway.
Figure 1. Toxicity of excess dopamine Homovanillic acid (HVA) Dihydroxyphenylacetic (DOPAC)
Linan Chen, et al(2008) Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. J. Neurosci. 28, 425–433 • Alternatively, dopamine undergoes oxidation to form superoxide, hydrogen peroxide, and o-quinone or reacts with cysteine residues on glutathione or proteins to form cysteinyl-dopamine and cysteinyl-DOPAC conjugates. • These biochemical abnormalities caused by excess dopamine may cause severe neurodegeneration of neural pathways that utilize dopamine as a neurotransmitter.
Prevalence of Clostridium difficile in the gastrointestinal tract of hospitalized children under two years of age. Med DoswMikrobiol; 2010;62(1):77-84 (Poland) • 178 fecal samples of children aged 2 months to 2 years,hospitalized in 2003-2006 were examined for the presence of toxin A/B of C. difficile. • Toxigenicity of strains was confirmed using PCR. • Susceptibility to antimicrobials was determined. • The percentage of children infected with C. difficile was 68.6%. • All strains were susceptible to Vancomycin and metronidazole(Flagyl)
Summary • Clostridia metabolites HPHPA, 4-cresol, and 4-hydroxyphenylacetic are toxic because they inhibit key enzyme that converts dopamine to norepinephrine • Toxic dopamine metabolites use up glutathione and person is much more susceptible to other toxic chemicals like mercury, pesticides, antibacterial soaps
Actapsychiatrbelg 80:249-265,1980 Main dopamine metabolite HVA mmol/mol creatinine p<0.01
B. Garreau et al. Disturbances in dopamine metabolism in autistic children: results of clinical tests and urinary dosages of homovanillic acid (HVA). Actapsychiatrbelg 80:249-265,1980. • Dopamine metabolite (homovanillic acid or HVA) in urine was more elevated in children with autism than in PDD and the severity of symptoms was related to the concentration of HVA • High dopamine production in brain is associated with repetitive, stereotypical, obsessive, compulsive behaviors • The effects of norepinephrine are alertness and arousal, and influences on the reward system. Norepinephrine is important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback.
Before Treatment HVA/VMA= 2.58 (Excess dopamine)
After Treatment HVA/VMA= 1.38
Factors involved in autism, Clostridia toxicity measured in urine organic acid test • HVA-(homovanillic acid)-Major metabolite of dopamine, a major brain neurotransmitter associated with abnormal autistic behavior when it is elevated • VMA-(vanillylmandelicacid)- Major metabolite of norepinephrine- important for the exploratory behavior essential for learning relations between sensory input, decision processing, motor output, and behavioral feedback.
Factors involved in autism, Clostridia toxicity measured in urine organic acid test • 4-hydroxyphenylacetic- Clostridia metabolite that is a phenol that is detoxified by phenol sulfo-transferase (PST), leading to increased susceptibility to acetaminophen toxicity. 4-Cresol and HPHPA are also PST inhibitors. • HVA /VMA ratio –indicates whether there is a healthy balance in the brain between norepinephrine and dopamine
Factors involved in autism, Clostridia toxicity measured in urine organic acid test • Pyroglutamic acid- high values indicate deficiency of glutathione, a major cause of dopamine toxicity and increased susceptibility to most environmental chemicals • 4-Cresol- Major metabolite of Clostridium difficile- blocks dopamine beta hydroxylase leading to excess dopamine and abnormal behavior • HPHPA-Major metabolite of multiple Clostridia species- blocks dopamine beta hydroxylase leading to excess dopamine and abnormal behavior
Clinical usefulness of Clostridia treatments • Schizophrenia • Psychosis • Depression • Chronic fatigue • Tics, Tourette’s • Autism • ADD, ADHD • Obsessive compulsive disorder (OCD) • Seizure disorders • Gastrointestinal disorders, diarrhea, constipation,Crohn’sdisease,colitis
Effects of 3-hydroxyphenylalanine in rats • Headweaving • Predominantly backward walking • Wet dog shakes • Hyperactivity • Hyper-reactivity Dyck LE, Kazakoff CW, Dourish CT. The role of catecholamines, 5-hydroxytryptamine and m-tyramine in The behavioural effects of m-tyrosine in the rat. European Journal of Pharmacology 1982; 84(3-4): 139-149
Two months of nystatin and Lactobacillus acidophilus GG therapy in a child with autism
Effect of anti-Clostridia therapy on urine excretion of HPHPA* in woman with depression and chronic fatigue
Treatments for Clostridia bacteria • Vancomycin-oral-not intravenous-5-10 mg/Kg/day div into 3 doses • Flagyl (metronidazole)-30 mg/Kg/day div into 3 doses-10 days • Lactobacillus acidophilus GG-10 -100 billion per day • Alternate name Lactobacillus rhamnosus • (Only bacteria probioticpatented for use in control of Clostridia)-Culturelle-VSL #3 • Saccharomycesboulardi (yeast) • Micellized or IV glutathione or n-acetylcysteine to increase brain glutathione and reduce neurotoxic dopamine metabolites • High protein diet (phenylalanine, tyrosine) may increase production of toxic Clostridia metabolites
Summary of Clostridia dopamine abnormalities in autism • Elevated HPHPA and similar phenolic compounds from multiple species of Clostridia are elevated in more than two-thirds of children with autism. • Elevated HPHPA and cresol inhibit the conversion of dopamine to norepinephrine, resulting in marked increase in dopamine. • Dopamine metabolites deplete brain glutathione and also produce marked excess of oxygen superoxide free radicals, 2500 molecules for each dopamine metabolite • Brain and sympathetic nervous systems normally using norepinephrine switch to dopamine, drastically altering brain and sympathetic nervous system function
Summary of Clostridia dopamine abnormalities in autism • Presence of this abnormality is determined with HPHPA, cresol, and other phenolic compounds in the Great Plains organic acid test • Stool testing not useful since HPHPA producing and Non-HPHPA species are not differentiated • Glutathione depletion by excess dopamine determined by pyroglutamic acid marker in organic acid test. • Clostridia treated for 10-14 days with vancomycin or flagyl,followed by several months high dose probiotics-culturelle or VSL-3 • Repeat testing every 3 months to prevent recurrence