Ammonia/Kidney Damage From Mercury Theory Of Autism

[Elephanto]

Starting points

Functional GABA Deficiency May Be Cause Of Autism

Glutamine :

Glutamine supplementation increases GABA :
Oral L-glutamine increases GABA levels in striatal tissue and extracellular fluid. - PubMed - NCBI

Increased glutamate and decreased glutamine in Autism :
Increased Glutamate and Homocysteine and Decreased Glutamine Levels in Autism: A Review and Strategies for Future Studies of Amino Acids in Autism
Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder. - PubMed - NCBI

Children with ASD exhibited a significant elevation of plasma GABA and glutamate/glutamine ratio, as well as significantly lower levels of plasma glutamine and glutamate/GABA ratios compared to controls.

( high GABA is the only that doesn't fit, perhaps the GABA concentrations aren't sufficient to undo the damage of increased glutamate in absence of conversion to glutamine and increased Ammonia)

Glutamine decreases intestinal permeability
Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions

Increased intestinal permeability in autism :
Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. - PubMed - NCBI

High percentage of abnormal IPT values were found among patients with autism (36.7%) and their relatives (21.2%) compared with normal subjects (4.8%). Patients with autism on a reported gluten-casein-free diet had significantly lower IPT values compared with those who were on an unrestricted diet and controls.

Increased opioid peptides (from Milk & Gluten) uptake due to increased intestinal permeability in Autism and also increase intestinal permeability :
Peptides’ role in autism with emphasis on exorphins

Considerable intestinal problems are found in autistic spectrum disorders (36–38) which would result in increased uptake. Casein and gluten can also release inflammatory cytokines in autism (39) and such cytokines increase permeability of endothelial barriers (40). In autism increased gut permeability has been established (41, 42) and, therefore, the prerequisite conditions for the postulated mechanism are present.

Glutamine acts as a neuroprotectant :
Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

Glutamine detoxifies Ammonia :
Pivotal role of glutamine synthetase in ammonia detoxification. - PubMed - NCBI

Ammonia :

Increased Ammonia concentrations in autism :
Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. - PubMed - NCBI

The concentration of fecal ammonia was also significantly greater in ASD participants than controls (42.7 ± 3.3 vs. 32.3 ± 1.9 mmol/kg).

Ammonia decreases glutamine synthetase (conversion of glutamate to glutamine) and stimulates glutamate :
Glutamine synthetase in brain: effect of ammonia. - PubMed - NCBI

The induction of GS expression in these specific areas would balance the increased ammonia and glutamate uptake and protect against neuronal degeneration, whereas, decrease of GS expression in non-glutamatergic areas could disrupt the neuron-glial metabolic interactions as a consequence of hyperammonemia

The over-stimulation of glutamate receptors may also favour nitric oxide (NO) formation by activation of NO synthase (NOS), and NO has been implicated in the pathogenesis of several CNS diseases. Hyperammonemia could induce the formation of inducible NOS in astroglial cells [...]

Breath ammonia as tool for detection of advanced kidney impairment :
Measurement of breath ammonia for detection of patients with chronic kidney disease. - PubMed - NCBI

Breath ammonia levels (3.32 ± 2.19 ppm vs. 0.49 ± 0.08 ppm; p = 0.003) and measured electric current (4.33 ± 0.25 mA vs. 4.01 ± 0.01 mA; p = 0.003) were significantly higher in the CKD group.

Mercury causes kidney damage :
Molecular interactions with mercury in the kidney. - PubMed - NCBI

All forms of mercury have toxic effects in a number of organs, especially in the kidneys.

Mercury in High Fructose Corn Syrup :
Study Finds High-Fructose Corn Syrup Contains Mercury

Almost half of tested samples of commercial high-fructose corn syrup (HFCS) contained mercury, which was also found in nearly a third of 55 popular brand-name food and beverage products where HFCS is the first- or second-highest labeled ingredient, according to two new U.S. studies.

High Fructose intake causes kidney damage :
Dietary fructose causes tubulointerstitial injury in the normal rat kidney. - PubMed - NCBI
Fructose, but not dextrose, accelerates the progression of chronic kidney disease. - PubMed - NCBI
(feel free to disregard this one, I'm sure a combination of many of the actions/supps I listed are going to be enough for kidney/Ammonia protection; I wouldn't mind a counter-argument but just don't think I'm trying to say that you have to drop sugar to achieve positive results)

Zinc supplementation decreases Ammonia :
Zinc supplementation reduces blood ammonia and increases liver ornithine transcarbamylase activity in experimental cirrhosis. - PubMed - NCBI
Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. - PubMed - NCBI

The serum zinc levels were inversely correlated with blood ammonia in the fasting state.

Lower serum Zinc levels in Autism :
The Relationship between Zinc Levels and Autism: A Systematic Review and Meta-analysis

There was significant statistical difference between plasma Zn concentration and autistic patients besides healthy controls: -0.253 (95% CI: 0.498 to -0.007).

Chronic liver disease is linked with High Ammonia and Vitamin D deficency :
Serum 25-hydroxyvitamin D deficiency and hepatic encephalopathy in chronic liver disease

Importantly, OHE rarely occurred with normal Vitamin D levels [...] This is a similar relationship to the association of elevated serum ammonia with the development of OHE[

Activation of Vitamin D into 1,25 dihydroxy Vitamin D requires kidney function :

The second activation process to 1,25 dihydroxy vitamin D occurs predominantly in the kidney

Lower Vitamin D (25-OHD levels) in Autism :
Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. - PubMed - NCBI

The mean 25-OHD levels in patients with severe autism were significantly lower than those in patients with mild/moderate autism. Serum 25-OHD levels had significant negative correlations with Childhood Autism Rating Scale (CARS) scores.

Collectively, 80.72% (67/83) of subjects who received vitamin D3 treatment (300 IU/kg/day not to exceed 5000 IU/day) had significantly improved outcome

High Ammonia in Alzheimer's :
Hyperammonemia in Alzheimer's disease. - PubMed - NCBI

Ammonia levels positively associated with Glutamate, negatively associated with Glutamine and Glycine in Schizophrenic patients :
Association between the blood concentrations of ammonia and carnitine/amino acid of schizophrenic patients treated with valproic acid. - PubMed - NCBI

The blood ammonia level was positively correlated with the serum glutamate concentration (r = 0.44, p < 0.01) but negatively correlated with glutamine (r = -0.41, p = 0.01), citrulline (r = -0.42, p = 0.01), and glycine concentrations (r = -0.54, p < 0.01).

In the case of Autism, while Glycine should be beneficial the serum levels were found to be unchanged compared to controls :
Body fluid levels of neuroactive amino acids in autism spectrum disorders: a review of the literature

Compared with HCs, GLY levels in plasma (Tirouvanziam et al. 2011) and serum (Shinohe et al. 2006) of ASD subjects have been reported to be unchanged

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There is low glutamine and high glutamate in autism. Glutamine supplementation increases GABA. Perhaps from a deficiency of the enzyme that converts glutamate into glutamine (glutamine synthetase), which is downregulated by Ammonia, and glutamine synthetase itself participates to Ammonia detoxification. High Ammonia concentrations are found in Autism. As Ammonia concentrations decrease, the need for glutamine synthetase decreases. Glutamine protects intestinal layers and has been shown to reduce intestinal permeability. There is increased intestinal permeability in autism. Reduced absorption of nutrients from the intestinal permeability could explain an average of 25% lower serum Zinc levels.

Ammonia also affects cognition negatively. Serum zinc levels are inversely correlated with blood Ammonia in the fasting state. Poor kidney functions lead to high Ammonia. I'm thinking the way vaccines affect certain babies could start them with high Ammonia and damaged kidney functions, leading to reduced synthesis of Glutamine and the start of a looping cascade. Mercury has toxic effects in a number of organs, especially in the kidneys. Overt Hepatic Encephalotaphy is linked with high Ammonia and it has a strong relationship with Vitamin D deficiency. Serum 25-OHD is lower in Autism and activation of Vitamin D requires kidney function. Fun fact for the hair crowd : "Prolactin levels increased along with reduced kidney function".

The abnormal intestinal permeability in children with autism is hypothesized to increase the uptake of opioid-triggering peptides found in Milk and Gluten. "The syndrome of autism was similar in psychological terms to that seen in children who had received morphine was put forward by Panksepp in 1978" And since most of Serotonin is produced in the gut, chronic intestinal permeability leads to elevated Serotonin levels, as such this also accounts for elevated Serotonin in autism. "In case of IBS patients with predominant diarrhea subtype, there is increased serotonin production leading to increase in secretions."

So I know some of these studies have so far only been proven in specific states like chronic liver disease and Schizophrenics using valproic acid, but I'm trying to add as many hints to depict a larger picture. I'll edit the thread if I can find proof of the same mechanisms happening in other conditions.

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I propose then that optimizing kidney function, removing Ammonia, avoiding Mercury sources and perhaps using Taurine to increase the excretion of heavy metals should be the starting points to solve the looping cascade leading to disturbed cognition and lowered Glutamine in Autism.

Things that reduce Ammonia / ameliorate kidney function :
Thiamine (300mg), Niacinamide, Zinc, Cinnamon, Biotin, Potassium, Adequate hydratation, Bicarbonate, Calcium + Low phosphate intake, Vitamin D, Progesterone, Thyroid, Magnesium and decalcifying agents, avoiding marathon running / excessive exercise, avoiding high fructose intake, avoiding NSAID except Aspirin, avoiding Aspartame, avoiding Mercury sources.

Sources of mercury : High Fructose Corn Syrup, seafood, vaccines, dental amalgams, some artificial food colorings, pesticides.

 

[Elephanto]

@haidut If you have time to read this, I would like your perspective on it.

I know that you have posted studies about Glutamine's involvement in cancer, which is why I wouldn't advice supplemental Glutamine but it appears that 1) it is significantly lower in Autism and 2) poor kidney function / high Ammonia will result in lower Glutamine levels from a reduced conversion of Glutamate to Glutamine by glutamine synthetase. Both Ammonia and the resulting glutamine synthetase downregulation seem to affect all the parameters involved in autism (GABA, high glutamate, increased intestinal permeability and so increased Serotonin + decreased Zinc absorption + increased effect from dietary opioid peptides, lower bioactive Vitamin D and other cognitive defects from Ammonia alone)

If Glutamine deficiency is an ideal, then reducing Ammonia and optimizing kidney function would be pro-cancer from the resulting increased Glutamine by this logic. I'd think that the overall net effects of having an increased conversion of Glutamate to Glutamine simply by optimizing the removal of Ammonia leads to better health and cognition than trying to minimize Glutamine in all possible ways. One could add Arginine restriction/depletion and using other anti-cancer strategies to mitigate any potential cancer-promoting effect from Glutamine.

 

[haidut]

@haidut If you have time to read this, I would like your perspective on it.

I know that you have posted studies about Glutamine's involvement in cancer, which is why I wouldn't advice supplemental Glutamine but it appears that 1) it is significantly lower in Autism and 2) poor kidney function / high Ammonia will result in lower Glutamine levels from a reduced conversion of Glutamate to Glutamine by glutamine synthetase. Both Ammonia and the resulting glutamine synthetase downregulation seem to affect all the parameters involved in autism (GABA, high glutamate, increased intestinal permeability and so increased Serotonin + decreased Zinc absorption + increased effect from dietary opioid peptides, lower bioactive Vitamin D and other cognitive defects from Ammonia alone)

If Glutamine deficiency is an ideal, then reducing Ammonia and optimizing kidney function would be pro-cancer from the resulting increased Glutamine by this logic. I'd think that the overall net effects of having an increased conversion of Glutamate to Glutamine simply by optimizing the removal of Ammonia leads to better health and cognition than trying to minimize Glutamine in all possible ways. One could add Arginine restriction/depletion and using other anti-cancer strategies to mitigate any potential cancer-promoting effect from Glutamine.

The problem is that cancer cells preferentially use glutamine to synthesize glucose and then convert that to fat and then oxidize the fat. So, a steady supply of glutamine and/or fat ensures tumor growth. The ammonia is simply a byproduct of the glutamine de-amination and while removing it will provide some relief it won't inhibit tumor growth. The role of glutamine in intestinal health is known but I think it is overrated, with magnesium and glycine playing a much more important role in preventing/reversing intestinal permeability.
Just my 2c.

 

[Elephanto]

@haidut
Thanks. From what I understand, glutamine synthetase levels adjust according to the concentrations of Ammonia, as in that if there is not much Ammonia available to convert to Glutamate by Glutamate dehydrogenase (GDH) (inter-converting enzyme), there is less Glutamate needed to be converted to Glutamine by glutamine synthetase. As such the strategy of optimizing kidney function and lowering Ammonia doesn't result in a high level of Glutamine but corrects deficiency from Hyperammonia and decreases neurotoxic Glutamate levels.

 

[haidut]

@haidut
Thanks. From what I understand, glutamine synthetase levels adjust according to the concentrations of Ammonia, as in that if there is not much Ammonia available to convert to Glutamate by Glutamate dehydrogenase (GDH) (inter-converting enzyme), there is less Glutamate needed to be converted to Glutamine by glutamine synthetase. As such the strategy of optmizing kidney function and lowering Ammonia doesn't result in a high level of Glutamine but corrects deficiency from Hyperammonia and decreases neurotoxic Glutamate levels.

Right, I do not disagree with that. What I am saying is that in a case of cancer, simply addressing the hyperammonemia will probably not help much and somehow restricting glutamine supply is probably also needed. The cancer field has already recognized this feature of cancer cells and has developed some drugs to effectively deprive cancer cells of glutamine.
Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model

 

[Elephanto]

@haidut Not denying that cancer cells use glutamine as fuel but what do you think of those :

we found that low-glutamine-induced histone hypermethylation resulted in cancer cell dedifferentiation and resistance to BRAF inhibitor treatment

Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. - PubMed - NCBI

Tumor dedifferentiation: an important step in tumor invasion. - PubMed - NCBI

You wrote that hypoxia causes hypermethylation and cancer progression, but it also promotes dedifferentiation.
"Conversely, estrogen, cortisol, aldosterone, prolactin, serotonin, NO, etc are "growth" and de-differentiating agents. Stress, toxins, chronic infections and perceived inability to escape from restrictive environments is what activates the second group."

So couldn't starving a cancer cell of energy (glucose, oxygen, fat or glutamine) cause this effect, and establish a state where the appearance of new cancer mutations is favorable ?

 

[haidut]

@haidut Not denying that cancer cells use glutamine as fuel but what do you think of those :


Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. - PubMed - NCBI

Tumor dedifferentiation: an important step in tumor invasion. - PubMed - NCBI

You wrote that hypoxia causes hypermethylation and cancer progression, but it also promotes dedifferentiation.
"Conversely, estrogen, cortisol, aldosterone, prolactin, serotonin, NO, etc are "growth" and de-differentiating agents. Stress, toxins, chronic infections and perceived inability to escape from restrictive environments is what activates the second group."

So couldn't starving a cancer cell of energy (glucose, oxygen, fat or glutamine) cause this effect, and establish a state where the appearance of new cancer mutations is favorable ?

Given that fat oxidation and amino acid oxidation are stress signals, restricting them (e.g. what I meant by "starvation" in that quote) would be healthful as it helps re-establish the cell quorum "10-4" - i.e. everything is OK.

 

[somuch4food]

Some points I would add that comes from Nathan Hatch's book on reducing ammonia:

• Melatonin increases proliferation of ammonia producing bacteria in the gut
• Ammonia bacteria love to feast on proteins
• Melatonin increases at night, so low protein in the evening can help reduce proliferation
• Melatonin is reduced by sunlight and GABA
• B1, B7 and Lithium are efficient at reducing ammonia
• A short protein fast is helpful against ammonia bacteria (2 meals overnight)

 

[Elephanto]

@somuch4food
Thanks, useful to know.

About Melatonin, seems to be mitigated.

Melatonin in autism spectrum disorders. - PubMed - NCBI

Twenty clinical studies have reported improvements in sleep parameters with exogenous melatonin supplementation in ASD, including longer sleep duration, less nighttime awakenings and quicker sleep onset. A recent meta-analysis of five randomized, double-blind, placebo-controlled crossover trials examining exogenous melatonin supplementation in ASD reported significant improvements with large effect sizes in total sleep duration and sleep onset latency compared to both baseline and placebo. Six studies reported that the nighttime administration of exogenous melatonin was associated with better daytime behaviors.

Peat mentioned once that Melatonin can have a restricting effect on Serotonin, but he dislikes it in general.

Chronically high Glutamate levels in autism should predict lowered Melatonin production.
Modulation of Pineal Melatonin Synthesis by Glutamate Involves Paracrine Interactions between Pinealocytes and Astrocytes through NF-κB Activation

 

[somuch4food]

About Melatonin, seems to be mitigated.

I was strictly addressing the relationship of melatonin with ammonia producing gut bacteria. So, reducing melatonin can reduce the ammonia load on the body.