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Vitamin D Is Endotoxin (LPS / TLR4) Antagonist, May Treat LPS-linked Conditions

Discussion in 'Scientific Studies' started by haidut, Aug 3, 2016.

  1. haidut

    haidut Member

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    The activation of TLR by various substances like endotoxin, ethanol / alcohol, opioids, SSRI, etc is involved in the pathogenesis of many conditions, especially IBD, colon cancer, periodontal disease, etc. There are very few effective endotoxin antagonists in clinical use, which is unfortunate since they have the potential to treat a variety of serious systemic conditions. I posted about niacinamide and potentially riboflavin antagonizing the effects of endotoxin but as far as I know these vitamins are not true TLR "receptor" antagonist. Thus, while I was searching for such direct antagonists I stumbled upon a number of studies showing that vitamin D3 and its "activated" form calcitriol are both potent TLR4 antagonists, with proven clinical effects. Some of the studies below are human, and as you can see as little as 2,000 IU D3 daily prevented eclampsia in many women at risk for the condition. Higher doses in the range of 20,000 IU - 25,000 IU have the potential to treat even more serious conditions like colon cancer. What is amazing is that some of the studies identified profound TLR4 antagonism even from very small doses of about 500 IU vitamin D3 daily, especially when combined with pregnenolone / progesterone. One of the studies went as far as suggesting that vitamin D would be viable treatment for sepsis given how effective it is an antagonizing the effects of even large amounts of endotoxin.
    Finally, even high doses vitamin D3 used in some of these studies did not cause hypercalcemia, so the most feared side effect of vitamin D is apparently not that common.

    "...Consistent with these findings, our results showed that high-dose 1,25(OH)2D3 administration could significantly protect against liver inflammation and fibrosis in diabetic rats. However, some larger, randomized, placebo-controlled trials are required to detect the effects of vitamin D supplementation for the treatment of NAFLD and to determine the optimal levels of vitamin D. Furthermore, we found that the expression of TLR4, NF-κB, and TNF-α was downregulated by 1,25(OH)2D3 in a dose-dependent manner. We also observed differences in CD68 staining among groups, indicating changes in Kupffer cell/macrophage numbers. Many of the changes observed in the liver were secondary to the changes in Kupffer cell numbers, and these alterations may mediate the anti-inflammatory effects of high-dose 1,25(OH)2D3 in the liver of diabetic rats. Because high-dose 1,25(OH)2D3 may lead to problems such as hypercalcemia, we also tested serum calcium and phosphate levels. Our results showed that the levels of serum calcium and phosphate in rats treated with 1,25(OH)2D3 were not significantly different compared with those in normal rats."

    Animal studies:
    Vitamin D [1,25(OH)2D3] Differentially Regulates Human Innate Cytokine Responses to Bacterial versus Viral Pattern Recognition Receptor Stimuli. - PubMed - NCBI
    Vitamin D inhibits lipopolysaccharide-induced inflammatory response potentially through the Toll-like receptor 4 signalling pathway in the intestin... - PubMed - NCBI
    Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury. - PubMed - NCBI
    1,25(OH)2D3 downregulates the Toll-like receptor 4-mediated inflammatory pathway and ameliorates liver injury in diabetic rats. - PubMed - NCBI
    [Effect of 1,25-(OH)2D3 on expression of HMGB1 and TLR4 in the lungs of asthmatic mice]. - PubMed - NCBI
    1,25(OH)2D3-mediated amelioration of aortic injury in streptozotocin-induced diabetic rats. - PubMed - NCBI
    25-Hydroxyvitamin D3 attenuates experimental periodontitis through downregulation of TLR4 and JAK1/STAT3 signaling in diabetic mice. - PubMed - NCBI
    Vitamin D3 ameliorates herpes simplex virus-induced Behçet's disease-like inflammation in a mouse model through down-regulation of Toll-like recept... - PubMed - NCBI
    Influence of 1,25-dihydroxy vitamin D3 on TLR4-induced activation of antigen presenting cells is dependent on the order of receptor engagement. - PubMed - NCBI
    http://www.ncbi.nlm.nih.gov/pubmed/20214986
    http://www.ncbi.nlm.nih.gov/pubmed/16367934

    Human studies:
    http://www.ncbi.nlm.nih.gov/pubmed/26770399
    http://www.ncbi.nlm.nih.gov/pubmed/24373795
    http://www.ncbi.nlm.nih.gov/pubmed/16402404
     
  2. ecstatichamster

    ecstatichamster Member

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    those darn toll like receptors...thanks so much for all this @haidut

    do you know if aspirin or caffeine affect TLRs?
     
  3. OP
    haidut

    haidut Member

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    I don't think aspirin affect TLR4 directly. Caffeine does have some antagonistic effects but it mostly through downregulation of TNFa and not direct antagonism like vitamin D does.
     
  4. milk_lover

    milk_lover Member

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    Why especially when combined with pregnenolone/progesterone? Do they also antagonize TLR4?
     
  5. OP
    haidut

    haidut Member

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    Not that I know of, but they antagonize serotonin and that plays a big role in endotoxin toxicity.
     
  6. thyrulian

    thyrulian Member

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    I was found vitamin D-deficient a while back.

    Should plenty of sun be enough?

    I've supplemented before (Estroban & others), but the results were iffy.
     
  7. milk_lover

    milk_lover Member

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    That makes perfect sense from personal experience. I ate the same meal in two days in a row at the same restaurant (large portion of white rice fried in a lot of oil, I think PUFA). The first meal was ok and I didn't feel irritated or stomach pain. The second meal was a totally different experience; felt irritated and anxious after the meal. I forgot my pregnenolone capsule in the second day :mask

    I think Peat said a large area of the body should be exposed to the sun for an extended period of time to obtain enough vitamin D from the sun. With the amount of PUFA in our bodies these days, I would think it's risky to expose our bodies to the sun unless you put some kind of natural sun blocker on your face like coconut oil or some coffee and aspirin. Vitamin D supplementation seems to be very effective in raising vitamin D levels from the studies I've seen. I am speculating here.
     
  8. Jayfish

    Jayfish Member

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  9. Toni

    Toni Member

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    Is there a type or brand of D3 that you recommend?
     
  10. dbh25

    dbh25 Member

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    "Supplementing with Vitamin D may be dangerous. Yeah I said it. Those effects can be desirable or undesirable depending on how much and who’s taking it."
    You could say this about any supplement.
     
  11. Jayfish

    Jayfish Member

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    He elaborates...
     
  12. achillea

    achillea Member

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    A neurologist who is having fantastic results with Hormone D for migraines and helping with sleep disorders, She has a lot of first hand experience, She says the range in the blood is very small like 60-80ng/ml in the fall and as low as 50 in the spring. Listen to her videos as it is quite informative. Too much can be as bad if not worse than too little.
    http://drgominak.com/videos.html
    Vitamin D Hormone | Sleep, Chronic Pain, and Headaches
     
  13. dbh25

    dbh25 Member

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    He talks about instead of taking Vitamin D, you should raise your levels from hours in direct sunlight. (Yes, but not realistic for everyone, like obtaining all your nutrients from food). He also tells a story about people that decide to go on a forever plan of taking 5000 IU a day indefinitely b/c it's "healthy", don't get tested for Vitamin D level and don't consider the balance between vitamin D-magnesium-calcium. Which is silly, of course you should get your blood levels tested and adjust. Haidut's post describes high Vitamin D doses to treat problems like colon cancer.
     
  14. nikotrope

    nikotrope Member

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    I like Garrett Smith's work. A lot of his patients and also people in the paleo sphere had problems with vitamin D. But I think it's mainly because many supplements are not good quality and large doses without other fat-soluble vitamins are probably not a good thing.
     
  15. raypeatclips

    raypeatclips Member

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    @haidut Could this be read as a vitamin D deficiency causes issues with endotoxin and the people in the studies that benefit from d3 are deficient and simply correcting that deficiency? Do you think someone that has raised their blood levels to optimal ranges through vitamin D supplementation have a continuous protection against endotoxin is what I am trying to say?
     
  16. OP
    haidut

    haidut Member

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    Yes, deficient people would be more prone to endotoxin damage but the study was specifically on giving supplemental vitamin D to non-deficient organisms and it had a dose-dependent lowering effect on TLR4. So, healthy people experiencing endotoxin overload should benefit too even if their vitamin D levels are OK.
     
  17. raypeatclips

    raypeatclips Member

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    Fascinating, thank you for the reply.
     
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