Endotoxin Antagonists Part II (Article)
 
In the previous podcast on endotoxin antagonists I looked at things like citrus flavonoids and cocoa. In this article and then take a look at the effect of the fat soluble vitamins on endotoxin related inflammation.

Endotoxin Antagonists Part I

Some terms:

Endotoxin - Product of some bacteria structure known to cause inflammation. Also known as lipopolysaccharide and abbreviated to LPS. Part of gram negative bacteria cell wall.

CD14 - A protein involved detection of endotoxin.
TLR4 -  A protein involved detection of endotoxin.
TLR2 -  A protein involved detection of endotoxin.
MyD88 - A protein involved detection of endotoxin.
NFKB    Protein involved in genetic transcription changes in response to "stress", increasing cytokines.

LPS->LBP>CD14>TLR4>NFKB>TNFa >IL-

TNF/TNFa   Inflammatory cytokine
IL-1b               Inflammatory cytokine linked to pain
IL-6                 An inflammatory cytokine and an anti-inflammatory myokine.
Il-8                 Inflammatory cytokine

Epithelial cells -   Cells that form a semi-barrier between tissues
Intestinal epithelial cells - Form the lining of the small and large intestine


Vitamin D

Vitamin D can lower the immune activation in endothelial cells, limiting the activation of NFKB, which is one of the links in the chain of the major links from endotoxin detection to inflammation. It also limits the activation of interleukin-6 and interleukin-8, which would be expected by inhibiting NFKB. Endothelial cells line the interior of the blood vessels and so they might be particularly relevant to the capacity to restrain the spread of inflammation throughout the organism.

1,25-Dihydroxyvitamin D inhibits lipopolysaccharide-induced immune activation in human endothelial cells.

Another paper shows the effect on the endotoxin sensing protein TLR4 from vitamin D. Pre-treatment of the live animal tissues with vitamin D protected from an increase in the inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-8 and downregulated TLR4, Myd88 and NF-κB.

Vitamin D inhibits lipopolysaccharide-induced inflammatory response potentially through the Toll-like receptor 4 signalling pathway in the intestine and enterocytes of juvenile Jian carp

A study looked at vitamin D and its role in intestinal inflammation and epithelial barrier dysfunction. Vitamin D prevented an increase in permeability of the epithelial barrier. Vitamin D deficient rodents had altered composition of the gut microbiome.

Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation.

In a model investigating vitamin D deficiency’s role in pre-eclampsia, supplementation of 2000 IU of vitamin D3 over the course of 12 weeks had anti-inflammatory effects. In pre-eclampsia increased levels of inflammatory cytokines TNF-α, interleukin (IL)-6, and IL-1 are typically up-regulated. This paper showed lower levels of both TLR4, and the previously mentioned inflammatory cytokines in the vitamin D supplemented group.

Vitamin D3 alters Toll-like receptor 4 signaling in monocytes of pregnant women at risk for preeclampsia.

Various forms of vitamin D are being investigated for their role in inflammatory bowel disease and colorectal cancer, many of these pathways are thought to be regulated through TLR4.

Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer.

Vitamin D3 and progesterone show efficacy in reducing inflammation from traumatic brain injury in rodent models. TLR4 and NFKB were significantly reduced by the intervention.

Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury.

D3 reduces TLR4, lung inflammation and “lung remodelling” in rodents. Endotoxin is an known cause of some asthmas, probably by it's effect on increasing serotonin.

[Effect of 1,25-(OH)2D3 on expression of HMGB1 and TLR4 in the lungs of asthmatic mice].

D3 increases CD14, which is involved in endotoxin detection, but decreases TLR4,  the overall effect is of lowered TNFa(inflammation).

Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.

Vitamin A

Vitamin A sufficiency is necessary for proper epithelial barrier function. Supplementation of vitamin A shows improvements in gut integrity as measured by standard sugar tests. In one study a weekly dose of 5 mg (15,000 IU approx) of retinol for eight weeks was used. In another study large single dose of 60 mg (60,000IU approx) retinyl palmitate was used.

The effect of vitamin A on epithelial integrity.

Retinol and Retinol-Binding Protein: Gut Integrity and Circulating Immunoglobulins

Association of vitamin A and zinc status with altered intestinal permeability: analyses of cohort data from northeastern Brazil.


Vitamin A limits the effect of endotoxin on inflammation by suppressing toll  like receptors, including TLR4, and by down regulating inflammatory gene expression.

Retinol suppresses the activation of Toll-like receptors in MyD88- and STAT1-independent manners.


Vitamin A, as retinol palmitate counteracts the oxidative injury caused by septic shock in rodents models.
Retinol palmitate counteracts oxidative injury during experimental septic shock.


Vitamin E

Vitamin E, as free alpha-tocopherol, alpha-tocopherol succinate or alpha-tocopherol acetate, significantly inhibits the endotoxin induced production of tumour necrosis factor (TNF) in rodent models. The degree of inhibition of tumour necrosis factor was directly correlated to the blood levels of the alpha-tocopherol. This paper concludes that Vitamin E treatment may be effective for systemic inflammatory response syndrome and sepsis. The dose range was 100 mg per kilogram, though that would have to be altered to get human equivalent due to differences in metabolism.

Enteral vitamin E supplementation inhibits the cytokine response to endotoxin.

Another study suggests that vitamin E, as alpha-tocopherol acetate, can play a role in reducing endotoxin triggered increases in inflammatory cytokines and nitric oxide.

Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages

In rodent models vitamin E can protect against increases in plasma corticosterone and brain levels of the excitatory neurotransmitter glutamate. This might explain some of the mechanisms by which vitamin E, as alpha-tocopherol acetate, protects against the neurotoxicity of endotoxin.

Vitamin E protects against bacterial endotoxin-induced increase of plasma corticosterone and brain glutamate in the rat.

In vitamin E deficient rodents exposed to endotoxin an increase in the inflammatory cytokine interleukin-6 was seen over vitamin E sufficient controls. The relative increase in inflammation attributed to vitamin E deficiency was reversed by a polyphenol extract of black tea in another part of this experiment.

Endotoxin induced production of interleukin-6 is enhanced by vitamin E deficiency and reduced by black tea extract

In cell models vitamin E can attenuate the increase in the inflammatory cytokine tumour necrosis factor alpha.

Vitamin E inhibits endotoxin-mediated transport of phosphatases to lipid rafts.

Vitamin K2


Mice given oral vitamin K2 had lower expression of TLR4 and TLR2, the positive effects on (lowering) calcification of the aortic artery may be due to effects on TLR4 and TLR2, which were mainly found in the aortic plaques. While some atherosclerotic plaques were found in K2 treated mice, K2 prevented calcification.

Effects of Vitamin K2 on Calcification and Expression of Toll-like Receptor 2 as well as Toll-like Receptor 4 in Aortic Artery of Apo E-/-Mice

Prostaglandin E2 (PGE2) is an arachidonic acid derived ecosanoid involved in many inflammatory processes. When endotoxin increases Cyclooxyrgenase (COX) the systhesis of PGE2 is increased. Vitamin K2 inhibits the release of PGE2.

Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity.