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COUPLED DYSBIOSIS & METABOLIC DYSFUNCTIONS IN AUTISM –POSSIBLE REMEDIES

COUPLED DYSBIOSIS & METABOLIC DYSFUNCTIONS IN AUTISM –POSSIBLE REMEDIES. Jon B. Pangborn, Ph.D., F.A.I.C., C.C.N. TODAY’S ASSIGNMENT:.

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COUPLED DYSBIOSIS & METABOLIC DYSFUNCTIONS IN AUTISM –POSSIBLE REMEDIES

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  1. COUPLED DYSBIOSIS & METABOLIC DYSFUNCTIONS IN AUTISM –POSSIBLE REMEDIES Jon B. Pangborn, Ph.D., F.A.I.C., C.C.N.

  2. TODAY’S ASSIGNMENT: To explore how impaired methionine-to-taurine metabolism and reduced methylation, together with infection, impact autism. We will consider possible natural and nutritional remedies.

  3. DISCLOSURES • Father of formerly autistic child – now adult • Left chemical engineering 29 years ago to investigate biochemistry and autism • Past President, Doctor’s Data Laboratory • Klaire Labs Consultant 1981-1999 • Great Smokies Diagnostic Lab (Genova) 1995-2005 • Cofounder: Defeat Autism Now! 1995 • Coauthor: Autism: Effective Biomedical Treatments • Consultant: Kirkman Labs since 2000 • Senior Scientific Consultant, ARI

  4. IN PERSPECTIVE • There are many different autisms: Primarily Genetic Mostly acquired Inherited faults toxic/infectious stressors • Considering ASD people as a group, there are cell-wide and extracellular anomalies. • Don’t get hung up on one enzyme/protein, one cell compartment, one gene, one epigenetic process, one cytokine, one toxicant or infectious agent or any single theory or model.

  5. TODAY’S FOCUS • Deficient methylation of lipids adjacent to neuronal receptors can cause loss of neuronal and network synchrony. See: Deth, Molecular Origins of Human Attention Kluwer Acad Pub, 2003. • Methionine metabolism can be disordered in multiple ways such that methylation is deficient, oxidant stress occurs, and an inflammation becomes a persistent, maladaptive condition. • Mitochondrial dysfunction is probable when vitamin B12 (as AdoCobalamin) and carnitine are deficient and maybe when Clostridia dysbiosis occurs.

  6. TODAY’S FOCUS2 • Xenobiotic (e.g. organophosphate) and elemental (e.g. mercury) toxicants can be contributory. • Many infectious agents and foreign substances can lead to oxidant stress when taurine is deficient. • There are nutritional aids for: methylation, reducing inflammation, mitochondrial support and alleviating dysbiosis.

  7. Methionine Transsulfuration to Cysteine and Glutathione Methionine Methylation Potential (SAM/SAH) THF SAM MTase 2 1 5,10-CH2THF Cell Methylation MS SAH B12 MTHFR 5-CH3THF SAHH Adenosine Homocysteine 1 Folate Cycle Methionine Cycle Transsulfuration Pathway SJJ CBS B6 Cystathionine 2 Antioxidant Redox Potential (GSH/GSSG) B6 3 Cysteine 3 GSH GSSG

  8. CYSTEINE TO TAURINE (main route) From cystathionine GSH cysteine Dietary cystine cysteine sulfinic a GSH GSCys dioxygenase decarboxylase P5P Stable OCl- Chloroamine taurine hypotaurine phagocyteoxygenase

  9. CELL MEMBRANE TRANSCOBALAMIN OHCblCYTOSOL MeH4folatemethionine GSH Lysosome OHCbl GSCbl Cbl MeCbl reductase MS H4folate homocysteine reductase ATP PROPIONATE MMA AdoCbl SUCCINATE CARNITINE mutase C-P COMPLEX C.A. cycle MITOCHONDRION

  10. CARNITINE FORMATION 3 SAM L-lysine trimethyl-L-Lysine 3 methylations CYTOSOL MITO MEMBRANE MITO 4 biochemical transformations L-carnitine requiring P5P, NAD, O2, ascorbate and α-ketoglutarate x 2

  11. CARNITINE CH3 CH3―+N― CH2―CH―CH2―COOH CH3 OH

  12. ACTIONS OF CARNITINE • Using a translocase transporter, CARNITINE escorts fatty acids (as fatty-acyl carnitine) through the inner mitochondrial membrane. • Combines with excesses of organic acids (propionic, isovaleric, 3-methylglutaric, valproic, others) to accomplish a detoxication function.

  13. REVIEW: FOUR INTERRELATED PARTS OF BIOCHEMISTRY 1. Methionine → SAM, methylation →→ cysteine with some homocysteine recycle using methyls provided by folate to Cbl on MS. 2.Cysteine →→ taurine or cysteine →→ GSH Taurine scavenges OCl- GSH neutralizes H2O2 and during cellular immune and detoxifies and makes B12 defense activities. work. 3. B12 →→GSCbl: cytosolic homocysteine → methionine and mitochondrial cleanup of propionate via MMA 4. Carnitine, needs methylation for formation, also cleans up propionate and other excess organic acids.

  14. WHAT’S GOING WRONG?SO MUCH THAT WE HAVE TO STUDY IT PIECEWISE METHIONINE → SAM → S-ADENOSYLHOMOCYSTEINE methylation Reduced methylation causes varying deficiencies of – melatonin choline/TMG/DMG creatine methylated catecholamines carnitine methylated CG pairs on DNA methylated fatty acids Remedies: supplements of melatonin, creatine, L-carnitine, TMG, DMG. See ARI Publication 34.

  15. CAN A VIRUS IMPAIR METHYLATION IN NEURONS? Note: Documentation in rat brain cells of reduced neuronal receptor phospholipid methylation during paramyxovirus infection (measles, mumps) – Münzel and Koschel, Proc. Natl. Acad. Sci. (USA) 79 (1982) 3692-6. Β-adrenergic receptors affected – loss of catecholamine-stimulated methylation

  16. SAH HOMOCYSTEINE (Hcy) METHIONINE ADENOSINE CYSTATHIONINE CYSTEINE • Adenosine accumulates, SAH accumulates, SAH/SAM ratio increases, methylation slows. Adenosine elevated in ASD, 20% per plasma, 33% per RBCs. • Adenosine Deaminase (ADA) Binding Protein = DPP4 or CD26 is inhibited by: mercury, antimony, lead, orga-nophosphates, streptokinase, casomorphin peptides. See Püschel et al. Eur J Biochem 126 (1982) 359-65 Vojdani et al., Int.J.Immunopath Pharmacol 16 3 (2003) 189-99

  17. SAH HOMOCYSTEINE (Hcy) METHIONINE ADENOSINE CYSTATHIONINE CYSTEINE 3. Genetic variants for ADA, methionine synthase, formation of cystathionine and methylated folate = risk factors for ASD. 4. Hcy → Methionine hindered by oxidation of reduced cobalamin (Co+1) 5. Some Hcy tied up as Hcy thiolactone if PON (paraoxonase, Hcy thiolactonase) weak – organophos-phate toxicity; 40-fold activity variance in humans 6. Functional P5P coenzyme inadequacy

  18. SAH HOMOCYSTEINE (Hcy) METHIONINE ADENOSINE CYSTATHIONINE CYSTEINE REMEDIES FOR POSSIBLE PROBLEMS • Methylcobalamin and folinic acid • B6/P5P, Zinc, Magnesium, Melatonin • Trimethylglycine, Dimethylglycine • Diet and detoxification (helps ADA Binding Protein – DPP4) • Antioxidant nutrients, digestive enzymes • Not recommended: Methionine, SAM, Cysteine, NAC

  19. CYSTEINE TAURINE • Cysteine dioxygenase downregulated in autism (inflammation); see studies by Waring. • Functional P5P coenzyme inadequacy • Urinary loss of taurine due to beta-aminoaciduria, mostly elevated beta-alanine – Bacterial dysbiosis Anserine and carnosine Pyrimidine disorder, PDD, see studies by Page

  20. CYSTEINE TAURINE REMEDIES FOR POSSIBLE PROBLEMS • Antiinflammatory meds, digestive aids • B6/P5P, zinc, magnesium, melatonin • Antioxidant nutrients • Taurine, 100-250 mg/day with breakfast

  21. RELEASE OF OXIDANTS BY PHAGOCYTIC NEUTROPHILS (PMN LEUKOCYTES) WHEN TAURINE IS INADEQUATE Phagocyte – a cell that ingests microorganisms, foreign particles, other cells, and kills, digests or decomposes them. Oxidant killing is a normal, body-defense mechanism: Respiratory Burst O2-, H2O2, OCl- Taurine limits collateral damage by scavenging OCl- See Dinauer et al., Chapt 189 in Scriver et al., Eds., TheMetabolic and Molecular Bases of Inherited Disease, 8th Ed.

  22. SEE: DISTURBANCES OF AMINO ACID METABOLISM: CLINICAL CHEMISTRY AND DIAGNOSIS, Hans J. Bremer, et al., Urban & Schwarzenburg, 1981 p225 Table B24. Free amino acids in human polymorphonuclear leukocytes (Houpert et al. 1976) Amino Acidnmoles/million cells Taurine 15.47 Aspartic acid 1.52 Alanine 1.51 Lysine 1.36 Glutamic acid 1.29 Astrocytes: Taurine also the most abundant AA. See Urenjak et al. J.Neurosci 13, 3 (1993) 981-89

  23. WHAT PROVOKES PHAGOCYTIC ACTIVITY AND OXIDATIVE PROCESSES? • Bacteria (staph, strep, Salmonella, Enterobacter, Proteus, Klebsiella, Microbacteria, others) • Yeasts (Candida, Aspergillus) • Wheat germ agglutinin, substances that “clump” cells • Fine particles, organic & inorganic, engine & powerplant exhausts • Fluorides • Some viruses (naked virus w/o lipid envelopes – rhino, papilloma, rotoviruses)

  24. CLOSTRIDIA OVERGROWTH • Anaerobic organism; can’t assay by standard culture, often identified by chemical markers: propionic acid, phenyl & hydroxyphenyl propionates, indole propionate, phenol, para-cresol, acetic acid, acetates, phenyllactate. - See Elsden et al. Arch.Microbiol 107,3 (1976) 283-8 • Many types: C.difficile, propionicum, tetani (credit to Ellen Bolte, 1996), sporogenes, botulin, and many more. • Propionic acid and propionates induce autistic behavior in rats – See work of Derrick MacFabe.

  25. CLOSTRIDIUM DIFFICILE: ANTIBIOTIC RESISTANT STRAIN • First public notice: Warrey & Pipin - Lancet 2005; Cloud & Kelly – Curr Opinion Gastroenterol 23,1 (207) 4-9; Baines & O’Connor – J.Microb.Chemother 62,5 (2003) 1078-85; Spigaglia et al. PMID 18480338; Saxon et al. PMID 18710908 • Vancomycin sends it to spore form; later it comes back with a vengeance • Ciprofloxacin, Levofloxacin and 20 more antibiotics (esp. fluoroquinolones) have no lasting effect. “What almost kills it, makes it stronger.”

  26. NATURAL ANTIBIOTIC FUNCTION IS A TWO-PRONGED ATTACK • Toxic killing agents, plus • Agent that disables organisms’ defenses See: Proc.Natl.Acad.Sci (USA) 97 (2000) 1433 Drs. Lewis (Tufts) and Stermitz (Col. State U) Studied Barberry: berberine + 5’methoxyhydnocarpin

  27. WHAT HERBALS HAVE NATURAL ANTIBIOTIC ACTION AGAINST CLOSTRIDIA? • Thyme, oregano, cumin (at low levels). See Dorman & Dean, J. Appl.Microbiol. 88 (2000) 308-16 • Curcumin (turmeric) provides antioxidant protection, lowers cytokines (inc. TNF-α), regulates COX-2 and downregulates NF-Kappa B. • See – Chainani-Wu J.Alt.Complement Med 9 (1) 2003 161-8 Bundy, Walker et al. Prac Nutr Soc 63 2004 126A Guo, Kuo et al. Biochem Pharmacol 680 2004 51-61 Menon & Sudheer Adv Exp Med Biol 575 2007 105-25

  28. WHAT PROBIOTICS REDUCE OR HELP TO KILL C. DIFFICILE? Saccharomyces boulardii is effective for C. difficile disease. S. boulardii and Lactobacilus rhamnosis both reduce antibiotic-associated diarrhea. See: McFarland LV “Meta-analysis of probiotics for the prevention of antibiotic-associated diarrhea and the teatment of Clostridium difficile disease” Am J Gastroenterol. 2006 Apr: 101 (4) 812-22 Segarra-Newnham M “Probiotics for C-difficile-associated diarrhea: focus on L. rhamnosis GG and S. boulardii” Ann.Pharmacother 2007 Jul; 41 (7): 1284-7

  29. WHAT PROBIOTICS REDUCE OR HELP TO KILL C. DIFFICILE? Lactobacillus plantarum administration to antibiotic-treated patients reduces colonization of C. difficile. See – Plummer S, Weaver MA et al. “C. difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhea” Int Microbiol. 2004 Mar; 7 (1): 59-62 Klarin B, Wulft M et al. “L. plantarum 299v reduces colonization of C. difficile in critically ill patients treated with antibiotics” Acta Anaesthesiol Scand. 2008 Sep; 52 (8): 1096-102

  30. SHORT HISTORY OF MEDICINE Problem: I have an earache…. 2000 B.C. Here, eat this root. 1000 A.D. That root is heathen. Here, say this prayer. 1850 A.D. That prayer is superstition. Here, drink this potion. 1940 A.D. That potion is snake oil. Here, swallow this pill. 1985 A.D. That pill is ineffective. Here, take this antibiotic. 1997 A.D. That antibiotic ruins your own immunity. Here, eat this root.

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