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Nutritional Dumping (Part 1 of 3): Transulfuration Pathway, Sulfur Sensitivities, Ammonia, & Hydrogen Sulfide

Updated: Feb 6

This article is not medical or healthcare advice. Before you start on any health related regimen you should seek the care of your Primary Care Provider or an M.D.


This article is not related to mal absorption due to poor bile flow, enzymatic insufficiency, compromised genetic transporters for specific nutrients across the intestinal lining, or mal absorption due to high levels of oxalates. This article touches on several common situations that i see where the body dumps specific nutrients based on various factors , one being genetics.


Part 1 : Transulfation Pathway UpRegulation - "Sulfur Issues"

There are several key genes in this pathway (SUOX, CBS, CTH CDO, PAPSS1, PAPSS2, SULT1A1, SULT2A1) , that if compromised, in particular, CBS upregulations, can lead to 'dumping' of several B vitamins: B2, B3, B6; eventually depletion of Cysteine after B6 is exhausted, and excess taurine. The most well studied CBS Gene mutations are C699T and A360A. MTHFR 1298C and COMT mutations can also contribute to additional issues here.


When the CBS gene becomes upregulated, sulfur intake will be drawn down this pathway in an accelerated manner, along with homocysteine, consuming B2, B3, and more so B6. Initially homocysteine will be low, below 6 typically, and if its below 5, its going quite fast, and depleting various nutrients and creating toxic byproducts in the process. There will be little conversion of cysteine to glutathione, but rather to taurine. This leads to 'over-methylation', so methyl folate will likely cause reactions, and to a lesser extent Methyl B12. Various symptoms become present: anxiety, aggression, anger, and reactivity. Serine, will get depleted as one of the cofactors for the CBS genes. Literature suggests Flax Seeds and Red Korean Gensing can slow down an upregulated CBS gene, along with reduced sulfur in the diet for some period of time. [16]


Digestion issues are also often present, including gss that smells like rotten eggs, from excess hydrogen sulfide produced by an over growth of hydrogen sulfide producing bacteria. Stools can appear soft, light and or orange/clay like in color.


The transsulfuration pathway, leads to either taurine or glutathione production. When the pathway is upregulated, often homocysteine and cystathionine convert too quickly to taurine, leaving not enough glutathione for the body. Low glutathione can compromise immune function, and lead to high levels of toxicity and oxidative stress and excess oxidized glutathione (which inhibits the SULT1A1 and SULT2A1 genes) - leading to sulfur reactions. This can also lead to recurrent bacterial, viral, parasitic, and fungal infections, cancers, and toxic metal sensitivities.


Elevated levels of TNF-A can also stimulate the CBS gene, so in parallel, both an intersection of TNF-A genetics and functional levels can be helpful. TNF-A can be upregulated for a variety of reasons, one of them being gut inflammation. [15]


During a CBS upregulation, homocysteine along with other amino acids, vitamins, and minerals quickly escape along with toxins, and wastes, both depleting the body and taxing the system. Kidney and liver stress often result, and low back pain is one signal of kidney stress. Getting a Comprehensive Metabolic Panel and checking Urea/BUN levels for kidney functional along with EGFR can be informative.


This process may also raise glutamate levels causing excitotoxicity - over activation of the NMDA Receptors (GRIN genes). Glutamate excitotoxicity is the pathological process implicated in several neuro degenerative diseases, and neuro cognitive challenges are often present in these clients. The increase in glutamate, ammonia and urinary sulfates in the system can be damaging to the liver and kidneys and brain.


Ammonia is removed by the Urea Cycle, and one of the key genes in that pathway, ARG1, is inhibited by phenols. Be careful here - lots of high phenols in the diet can restrict your ability to clear ammonia (coffee, teas, berries, herbs and spices). On the flip side, ARG1 is stimulated by retonic acid, and ALA, EPA, and DHA. [18,19, 20]

CBS upregulations may lead to blood sugar fluctuations, and can stress the fight-or-flight response, constantly stimulating the adrenal glands, leading to adrenal fatigue. Look for low levels of Potassium and Sodium on your hair mineral test. If calcium and or magnesium are also low (3 low or 4 low pattern) adrenals are even more compromised. Finally, monitoring testosterone levels is important for males here if you are a carrier of the CBS upregulation mutations, as well as maintaining levels of minerals such as copper, zinc, molybdenum, and manganese which can affect hormones.


BH4

This is a compound that is a cofactor along with iron and B6 used to make serotonin, dopamine, thyroid hormones, and melanin, in addition to detoxifying ammonia from the body. BH4 can also become depleted with the CBS mutation. BH4 also helps contain a very serious process called Ferroptosis - implicated in LH and CFS. MTHFR 1298c gene mutations, chronic bacterial infections, and aluminum, can also lead to low BH4 levels. Low levels of BH4 were seen in all CFS patients in a study by Pall, and these low levels can also lead to mast cell degranulation or mast cell activation disorder - driven mostly by the uncoupling of NOS2 and NOS3 during BH4 depletion. CBS upregulation can upset the urea cycle, lead to higher ammonia (BUN) and then deplete BH4. Glutathione also becomes depleted by high levels of ammonia.


A Slow CBS Gene.....

Many different mutations on the CBS gene may cuase it work slower than normal, leading to high homocysteine, and also potentially high methionine. High homocysteine is directly linked to increases in all cause mortality, particularly CVD, and oxidative damage in the endothelial wall of blood vessels and contributes to vascular plaque formation.


Considerations For CBS Mutations (Genetic Testing, Nutritional Testing, Diet, Supplements)


Genetic Testing

  1. Have your M.D. or primary care physician look for upregulations on the CBS or CTH genes first.

  2. Have your M.D. or primary care physician look for mutations on the key genes (SUOX, PAPSS1, PAPSS2, SULT1A1, SULT2A1), and then MTHFR1298c and COMT next if adrenal fatigue is part of the equation.

  3. Have your M.D. or primary care physician look for mutations on the key genes involved as cofactors for these primary genes: Molbdenum absorption and transport, Iodine absorption and transport, Selenium absorption and transportB2 absorption and transport, B6 absorption and transport, and Glutathione production (GCL, GCLC) and recycling (GSR).

Nutritional / MicroNutrient Testing

  1. Consider a good micro nutrient panel - the 3 most popular well known ones are: SpectraCell, Vibrant America, and Genova's Nutreval. All have pros and cons. This should help you assess B1, B2, B6, Serine, Glutathione, and molybdenum.

  2. A hair mineral test can be a supplemental panel - levels of potassiu, sodium, magnesium, calcium are good indicators of adrenal function. Also levels of ioduine, selenium, and molydenum are all precursors to make B2 functional:).

  3. Consider a good amino acid urine profile (Doctors data, Moasic) to assess Glycine, Serine, Taurine, Methionine, Threonine, and Cysteine levels.

  4. Consider a methylation blood panel to check SAMe, SAH, Methionine, and homocysteine levels.

  5. A good stool test to see what sulfur producing bacteria may be over abundant and driving too much production of hydrogen sulfide - which can over stimulate the NMDA receptors leading to neuro and cognitive over whelm. The main culprits: Desulfovibrio, Wadsworth Bilophila Wadsworthia, E Coli, Klebsiella, H Pylori, Clostridria, Staph, Strep, Citrobacter, Ruminicoccus, Enterrobacter, Prevotella, Camplyobacter, Shigella, Salmonella.

  6. CMP - Comprehensive Metabolic Panel to assess ammonia/urea/BUN levels.

  7. A hydrogen sulfide SIBO breath test can be informative too - but my experience is if the above issues are known and in play - it almost always is in play too.

Diet Considerations

  1. Move to a lower sulfur, lower phenol, lower oxalate diet for some short period of time 1-3 weeks and see what difference you notice while providing the cofactors needed to make the pathways more functional.

  2. Move to a lower phenol, oxalate, and salicylate diet as well as the same pathways are used as well.

Supplements

  1. Consider things to slow down the pathway if testing reveals up regulations are present and active. Flax Seeds, and Red Korean Gensing are two favorites.

  2. Supplement the needed cofactors in the pathway based on testing results and guidance of your primary care physician.

  3. Supplement in ways to slow down the over-methylation if confirmed to be present, and also avoid direct stimulation of methylation (methyl folate and methyl b12, and lots of other methyl donors).

  4. Consider supports to lower the ammonia and excess sulfur in your system if needed - charcoal, spirulina, acetyl l carnitine, and bizmuth (not pepto).

  5. Things like B1, Zn, B6, and Butyrate that help improve gut wall integrity while also calming down IL-17 (rosemary, cats claw, thyme) which, if high, can compromise gut wall integrity.

  6. Supplement as needed to support glutathione production and recycling, as well as BH4 recycling, production, and if needed exogenous BH4 (royal jelly).

  7. Selecting the appropriate anti microbial herbs to take care of the hydrogen sulfide producing bacteria that are over grown.

  8. Hydroxy B12, Benfothiamine - a form of B1, B2, and Molybdenum can help lower Hydrogen Sulfide, and sulfur in general.

Adrenal Fatigue and Sulfur Sensitivities

Symptoms of adrenal fatigue include tiredness, depression, brain fog, lowered immunity, sleep disturbances, difficulty losing weight, fertility issues, PMS, anxiety, heart palpitations, sensitivities to certain foods and medications, and mild depression, to name a few. A family history of heart disease, deep vein thrombosis, peripheral neuropathy, chronic fatigue, fibromyalgia, stillbirths, and miscarriages is often present.


In addition to the CBS and transulfation pathway issues noted above, The COMT gene which degrades hormones and neuro transmitters if compromised (slowed) can let these compounds accumulate in the nervous system. This can cause anxiety, insomnia, migraines, and irritability.


H2S - SIBO, Colon Health, and Parkinson's

Hydrogen sulfide is implicated in a variety of gastro intestinal issues, aside from the more famous Hydrogen Sulfide SIBO. From colitis, to colon health, its often in play. [6,8] It also has a role to play in Parkinsons ( i see this in neuro degenerative cases) - too much hydrogen sulfide over activates the NMDA receptors - neuronal death. [17]


I encourage you to explore the list of references below for additional details.


References:

  1. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Csaba Szabo 1Céline Ransy, etal.  Br J Pharmacol.

  2. Human Sulfide:Quinone Oxidoreductase Catalyzes the First Step in Hydrogen Sulfide Metabolism and Produces a Sulfane Sulfur Metabolite. Michael R. Jackson,

  3. Sulfate's Critical Role for Maintaining Exclusion Zone Water: Dietary Factors Leading to Deficiencies. Senef, Nigh, et al. December 2019. Water 11:22-42. DOI:10.14294/WATER.2019.5

  4. Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Matthew Whiteman 1Sophie Le TrionnaireMohit Chopra, et al. Clin Sci (Lond). 2011 Dec;121(11):459-88. doi: 10.1042/CS20110267. PMID: 21843150

  5. NMDA receptor function, memory, and brain aging. John W. Newcomer, MD; Nuri B. Farber, MD, et al. Dialogues Clin Neurosci. 2000 Sep; 2(3): 219–232. doi: 10.31887/DCNS.2000.2.3/jnewcomer. . PMCID: PMC3181613. PMID: 22034391

  6. Enhanced Synthesis and Diminished Degradation of Hydrogen Sulfide in Experimental Colitis: A Site-Specific, Pro-Resolution Mechanism. Kyle L. Flannigan, 1 Jose G. P. Ferraz, 2 Rui Wang, 3 and John L. Wallace 1 , 2 , *PLoS One. 2013; 8(8): e71962.

  7. The endogenous hydrogen sulfide producing enzyme cystathionine-β synthase contributes to visceral hypersensitivity in a rat model of irritable bowel syndrome

  8. Emerging role of hydrogen sulfide in colonic physiology and pathophysiology

  9. Hydrogen sulfide: advances in understanding human toxicity. Tee L Guidotti. Int J Toxicol

  10. Medical Management Guidelines for Hydrogen Sulfide. Agents for Toxic Substances and Disease Registry. (H2S). CAS# 7783-060-4UN# 1053

  11. Adverse reactions to the sulphite additives. Hassan Vally1,2 and Neil LA Misso3Gastroenterol Hepatol Bed Bench. 2012 Winter; 5(1): 16–23. PMCID: PMC4017440

  12. Case Report: A Fatal Case of Acute Hydrogen Sulfide Poisoning Caused by Hydrogen Sulfide: Hydroxocobalamin Therapy for Acute Hydrogen Sulfide Poisoning Yuji Fujita1,2, *, Yasuhisa Fujino, et al. Journal of Analytical Toxicology, Vol. 35, March 2011

  13. Effectiveness of Personalized Low Salicylate Diet in the Management of Salicylates Hypersensitive Patients: Interventional Study. Paulina K. Kęszycka,* Ewa Lange, and Danuta Gajewska. Grazyna Czaja-Bulsa, Academic EditorNutrients. 2021 Mar; 13(3): 991.

  14. Porphoria, The Ultimate Cause of Common, Chronic, and Envirnomental Illness. Steven Rochlitz. PhD.

  15. Feel Good About Your SNPs, Your Roadmap To Health, Dr. Amy Yasko

  16. The Devil In The Garlic, Greg Nigh, ND, LAc.

  17. Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson's Disease. Kari Erik Murros. Cells . 2022 Mar 12;11(6):978. doi: 10.3390/cells11060978. PMID: 35326429. PMCID: PMC8946538. DOI: 10.3390/cells11060978

  18. Retinoic acid promotes the development of Arg1-expressing dendritic cells for the regulation of T-cell differentiation. Jinsam Chang 1Shankar Thangamani et al. 2013 Apr;43(4):967-78.

  19. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40

  20. Phenolic Compounds as Arginase Inhibitors: New Insights Regarding Endothelial Dysfunction Treatment. Bruno Rodrigo Minozzo 1Daniel Fernandes 2Flávio Luís Beltrame 1Planta Med. . 2018 Mar;84(5):277-295. doi: 10.1055/s-0044-100398. Epub 2018 Jan 17. PMID: 29342480. DOI: 10.1055/s-0044-100398





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