Part Two: How do we identify and address this?

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• Converts dopa to melanin • Can also serve as a back up route to dopamine.
Tyrosine may give rise to dopa via two distinct enzymatic means: tyrosinase or tyrosine hydroxylase.
High levels of DHPPA due to bacterial infection may deplete tyrosinase for the backup route.
Salicylates and phenols may also deplete/impair tyrosinase and back up route.
Melanin is related to hair color
Melanin is related to hair color This pathway may also relate to methionine levels so it ties back to nutrigenomics
Relationship between oxidative stress, aging, methionine levels, thioreductase, previous PPT on role of SAMe, also melatonin
Other considerations of chronic bacterial infection: Strep example
H2O2 (neutrophils, monocytes, strep) glutatione peroxidase glutathione tyrosine dopamine T3T4
NAD tryptophan serotonin calcium dysregulation
glutathione glutamate
normal flora
Vit K
antibodies brain stem
neuraminidase viral spread streptokinase CD26 GAGs glutathione leaky gut TNF TNF OCD, Tourettes, stims
Streptococcal infection Macrophages Neutrophils
H2O2 H2O2 H2O2
Induction of neutrophils leads to decreased BH4 levels as neopterin is made preferentially instead of tetrahydrobiopterin
Lithium is concentrated in the thyroid and can inhibit iodine uptake. This is why it is important to monitor both the levels of iodine as well as lithium on essential mineral tests and supplement lithium only as needed for low values that may occur as a result of detoxification and excretion of mercury. Iodine is no longer included on the standard essential element test, and needs to be ordered as a separate test. As an alternative, a topical iodine test can be performed.
IUBMB Enzyme Nomenclature EC Common name: iodide peroxidase
Reaction: iodide + H2O2 = iodine + 2 H2O
Other name(s): iodotyrosine deiodase; iodinase; iodoperoxidase (heme type); thyroid peroxidase; iodide peroxidase-tyrosine iodinase; iodotyrosine deiodinase; monoiodotyrosine deiodinase; thyroperoxidase; tyrosine iodinase Systematic name: iodide:hydrogen-peroxide oxidoreductase
Decreased tyrosine leads to decreased dopamine
Chronic Streptococcal Infection
Streptococcal infection TNF alpha
TNF alpha is associated with…
• • • •
• • •
Tourettes syndrome OCD behavior “stims” PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) perserverative speech rheumatoid arthritis leaky gut
Connectivity map of TNF
Nature Cell Biology, Feb. 2004, Vol. 6, No. 2
Tryptophan breakdown pathway is triggered by bacterial infection as well as interferon gamma
Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is
observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophandepletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.
Curr Med Chem. 2003 Aug;10(16):1581-91 Wirleitner B, Neurauter G, Schrocksnadel K, Frick B, Fuchs D.
Journal of Neurochemistry Volume 93 Page 611 - May 2005 doi:10.1111/j.1471-4159.2005.03070.xVolume 93 Issue 3 Tryptophan metabolism and oxidative stress in patients with Huntington's diseaseN. Stoy*, G. M. Mackay†, C. M. Forrest†, J. Christofides‡, M. Egerton‡, T. W. Stone† and L. G. Darlington§
Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction.
Implication of microbial infection in Huntington’s Disease as well as glutamate
Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway
Yuhong Danga, William E. Dalea and Olen R. Brown
Indoleamine 2,3-dioxygenase (IDO) reacts with either oxygen or superoxide and tryptophan (trp) or other indoleamines while tryptophan 2,3-dioxygenase (TDO) reacts with oxygen and is specific for trp. These enzymes catalyze the rate-limiting step in the kynurenine (KYN) pathway from trp to quinolinic acid (QA) with TDO in kidney and liver and IDO in many tissues, including brain where it is low but inducible. QA, which does not cross the blood-brain barrier, is an excitotoxin found in the CNS during various pathologies and is associated with convulsions. We proposed that HBO-induced convulsions result
from increased flux through the KYN pathway via oxygen stimulation of IDO. To test this, TDO and IDO of liver and brain, respectively, of Sprague Dawley rats were assayed with
oxygen from 0 to 6.2 atm HBO. TDO activity was appreciable at even 30 μM oxygen and rose steeply to a maximum at 40 μM. Conversely, IDO had almost no detectable activity at or below 100 μM oxygen and maximum activity was not reached until about 1150 μM. (Plasma contains about 215 μM oxygen and capillaries about 20 μM oxygen when rats breathe air.) KYN was 60% higher in brains of HBO-convulsed rats compared to rats breathing air. While the oxygen concentration inside cells of rats breathing air or HBO is not known precisely, it is clear that the rate-limiting, IDO-catalyzed step in the brain
KYN pathway (but not liver TDO) can be greatly accelerated in rats breathing HBO.
Abbreviations: AIDS, acquired immuno deficiency syndrome; CNS, central nervous system; HBO, hyperbaric oxygen; HPLC, high-pressure (or performance) liquid chromatography; IDO, indoleamine 2,3-dioxygenase [EC]; KA, kynurenic acid; KYN, kynurenine; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NMDA, N-methyl -aspartate; QA, quinolinic acid; TDO, tryptophan 2,3-dioxygenase [EC]; trp, tryptophan
• Antibiotic effects • Deficiency of niacinamide will drive the breakdown of tryptophan • Bacteria can breakdown tryptophan • May inhibit proviral integration • Helpful in reversing the arrest of T cell proliferation that is linked to tryptophan depletion
Vitamin B3
• Niacin • Nicotinic acid • Nicotinamide • Niacinamide • NAD+ Glutathione recycling • NADH • NADP+ BH2 and BH4 • NADPH
Dopamine Serotonin
Benfotiamine Riboflavin CoQ10/idebenone NADH/niacinamide Pantothenic acid ATP Carnitine
Breakdown Niacinamide
1/3 NAD+ NADH 2/3
Breakdown Tryptophan
A deficiency in niacinamide will drive breakdown of tryptophan. Reduced levels of tryptophan will result in decreased levels of serotonin.
Cognitive Inflexibility After Prefrontal Serotonin Depletion
H.F. Clarke, et al.
Science, May 7, 2004
Selective depletion of serotonin produced perseverative behavior.
serotonin perseverative behavior
Consequences of Streptococcal Infection
Glutamate Glutathione TNF alpha Streptokinase NADase NAD tryptophan glutathione recycling serotonin & melatonin TNF & IL6 CD26 TNF detoxification
Consequences of Streptococcal Infection
inflammatory mediators leaky gut T cells and B cells due to chronic infection Glutathione peroxidase H2O2 tyrosine T3/T4
(2GSH +H2O2  GSSG + 2H2O)
Neuraminidase (aids in viral infection)
Multifaceted approaches to address bacterial issues
Effect of combination of use of lactobacillus and agents to solubilize cell wall
So, if we can use EDTA to increase the hydrophobicity it should help with gram positive bacteria.
Importance of knowing which organisms you are dealing with and choosing your combination approach wisely
Concept of using multiple approaches simultaneously is not a new one. Used in food preservation as well as antibiotic resistance
FIGLU + kynurenic or quinolinic or DHPPA
Run CSA “clean”
Not clean
Run DNA stool Address specific microbes Environment Nutrigenomics
Address specific microbes Environment Nutrigenomics
iron or SHMT +
Run CSA “clean”
Not clean
Run DNA stool Address specific microbes Environment Nutrigenomics
Address specific microbes Environment Nutrigenomics
Run CSA “clean”
Not clean
Run DNA stool Address specific microbes Environment Nutrigenomics
Address specific microbes Environment Nutrigenomics
The compound - dodecenal - was isolated from the fresh leaves of cilantro, or coriander,
Herbs to Consider
Haemophilus Pseudomonas Shigella Staphylococcus Streptococcus Klebsiella Escherichia Salmonella garlic,goldenseal,sage,GSE,thyme,oregano, mycoceutics juniper, garlic,GSE,thyme oregano,uva ursi, goldenseal, cranberry, mycoceutics goldenseal, garlic, GSE,sage, mycoceutics garlic, goldenseal,wormwood,juniper,GSE,thyme, oregano, mycoceutics garlic,echinachea,roemary,sage,barberry, goldenseal, oregon grape GSE, mycoceutics juniper,uvaursi,,goldenseal,sage, GSE, wormwood,thyme, oregano, echinachea,mycoceutics goldenseal, garlic,juniper,sage, GSE, mycoceutics cilantro, corriander,juniper, wormwood,goldenseal, sage, GSE, mycoceutics
7 Herbs Basic Mix
Neem Myrrh Oregon Grape Barberry Goldenseal Cranberry Uva ursi Rotate/modify herb choices based on sensitivity testing
Additional Supports to Consider
Pseudomonas Staphylococcus Streptococcus Klebsiella Escherichia Salmonella
PSX RNA, EDTA, chitosan*, malic acid, lactoferrin STAX RNA, IMF 5, chitosan*, EDTA at a separate time from chitosan, lactoferrin STRX RNA, IMF 5, chitosan*, EDTA at a separate time from chitosan, lactoferrin KLX RNA, EDTA, chitosan*, malic acid, lactoferrin IMF 5, ECX EDTA, chitosan*, malic acid, lactoferrin SALX RNA, EDTA, chitosan*, malic acid, lactoferrin
* As long as NO shellfish allergies
Home oxygen HBOT (check CSA before and after, keep gut herbs in place) Oxydrene Penta water Aerobic O7 (depending on sodium levels) Potassium Aerobic O7 (depending on potassium levels) Paradex (source of wormwood, garlic) Bay leaf Mycoceutics C.Language RNA CLX RNA Antioxidant Compounded Supplement
threonine iron
FIGLU + kynurenic or quinolinic
Run CSA “clean”
Not clean
Run DNA stool Address specific microbes Environment Nutrigenomics
Address specific microbes Environment Nutrigenomics
Specific microbes
•Address specific microbes •Run CSA and DNA stool test so you know what organisms you need to address specifically. Choice of herbs, supplements, RNA, antibiotics. Look at combination approaches, work with your doctor. •Environment •We are talking about the “gut environment”. Work on gut pH (stomach pH, low dose CCK, buffers) •B12 support •Bowel Formula and other supplements to help with inflammatory pathways •Normal flora, general gut herbs •Nutrigenomics •SHMT support list •ACAT support list (BHMT 1,2,4) •MTHFR A1298C support list
Example 1 DHPPA + FIGLU suspect anaerobes
Picture 4
Picture 3