Endotoxin Antagonists - Part III (Article)
 
This is part III on Endotoxin Antagonists. Here I will look at some B-Vitamins and their effects on endotoxin related processes.

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.
LBP    - Lipopolysaccharide binding protein. Binds endotoxin after detection.

The sequence of detection to inflammation is (partially)
LPS->LBP>CD14>TLR4>NFKB>TNFa >IL-(x)>COX(x)

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

iNOS > An enzyme catalysing the production of nitric oxide, induced by cytokines.
COX > Cyclooxygenase, a family of enzymes involved in the formation of prostaglandins.

So let’s take a look at some B vitamins.

B1 Thiamine (or Benfotiamine)

Benfotiamine is a fat-soluble analogue of and B1. Uveitis is degeneration of the eye, which can be caused by endotoxin. In rodents subjected to an injection of endotoxin which would induce uveitis, dosing with benfotiamine significantly ameliorated the damage. Measures were taken of inflammatory cytokines, and the increase induced by endotoxin was minimised by dosing with benfotiamine. Benfotiamine also buffered the increase in iNOS ( inducible nitric oxide synthase) and COX-2, as well as the activation of NFKB, which increases inflammatory cytokines. The authors suggest that the inhibition of activation of NFKB leading to a decrease in oxidative stress induced inflammatory markers may be a main factor in the prevention of uveitis.

Prevention of Endotoxin-Induced Uveitis in Rats by Benfotiamine, a Lipophilic Analogue of Vitamin B1

Benfotiamine inhibits NFKB, the transcription factor that increases inflammatory cytokines.

Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.

Thiamine deficiency results in increase in TNFa and likely increase in NFKB.

Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes.

Vitamin B2 - Riboflavin

Vitamin B2 prevents endotoxin induced increases in TLR4 and TNFa in cell models.

Immunomodulatory effect of riboflavin deficiency and enrichment - reversible pathological response versus silencing of inflammatory activation.

Supplementation of riboflavin and a probiotic including befitting bacteria seem to ameliorate the transport of bacteria and endotoxin in rodent models.

[The protective effect of supplementation of probiotics combined with riboflavin on the intestinal barrier of the rats after scald injury].

In endotoxin treated rodents riboflavin lowers pro-inflammatory cytokines including TNFa, Il-6 and IL-1, while decreasing nitric oxide levels. Some of the experiment in this paper show that riboflavin can increase survival rates from endotoxin induced sepsis in a dose-dependent manner. In one experiment runs were first dosed with E. coli bacteria, which is Gram-negative endotoxin producing bacteria, then dosed with vitamin B2 one hour later. Six hours later all of the 30 rodents in the control group died. Rodents dosed with 5, 10, 20, and 40 mg per kilogram showed survival rates of 20%, 30%, 55%, and 70% respectively, versus zero for the control group.

Highly Purified Vitamin B2 Presents a Promising Therapeutic Strategy for Sepsis and Septic Shock

Riboflavin also shows multiple mechanisms of action against bacterial infection in mice.

Enhancement of resistance to bacterial infection in mice by vitamin B2

Riboflavin has a prebiotic effect which feeds some bacteria and alters the balance of gut microbiota when using high doses. It increases a number of different commensal bacteria including F. prausnitzii. This is one of the most abundant bacteria found in the human digestive system, it is known to have multiple anti-inflammatory properties, to bolster gut barrier function and it is known to be low in inflammatory bowel disease, particularly Crohn’s disease. An inverse relationship is seen with this bacteria and the E. coli bacteria associated with Crohn’s.

The prebiotic concept and human health: a changing landscape with riboflavin as a novel prebiotic candidate?

Riboflavin significantly increases survival rates from endotoxin. A combination of riboflavin and the amino acid with valine increased survival rates further indicating a possible line of treatment for sepsis.

Potentiation by amino acid of the therapeutic effect of highly purified vitamin B2 in mice with lipopolysaccharide-induced shock.

 Vitamin B3 - Nicotinamide/Niacinamide - Nicotinamide Riboside

Niacinamide inhibits the clotting response seen in sepsis from endotoxin. It can normalise the increase in interleukin-6.
Nicotinamide inhibits endotoxin-induced monocyte tissue factor expression

Niacinamide inhibits the increase in the pro-inflammatory cytokines IL-1β, IL-6, IL-8 and TNFα in a dose-dependent manner in human blood samples. This paper suggests the findings demonstrate niacinamide may have great potential for treating inflammatory diseases.
Nicotinamide is a potent inhibitor of proinflammatory cytokines

Niacinamide limits the damage done to organs, including acute lung injury caused by endotoxin, by decreasing nitric oxide, iNos,  free radicals, pro-inflammatory cytokines, and restoring levels of ATP.
Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin.

Nicotinamide riboside (NR) is classed as vitamin B3, though it is a different substance to nicotinamide/niacinamide. Experiments show that it is protective for Alzheimer’s, high-fat diet induced obesity and hearing loss. The inflammatory cytokines TNFa and IL-6 are decreased by NR in the liver.
Nicotinamide riboside affects toll-like receptor 4-NF-κB pathway via sirtuin-dependent and –independent ways in AML12 hepatocytes


The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity.

Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models.


Vitamin B12 - Cobalamin

The hydroxy cobalamin form of vitamin B12 reduces the hypotension and toxicity associated with administration of endotoxin in rodents. Endotoxin administration results in increased nitric oxide and hydroxy cobalamin is a nitric oxide scavenger.
Hydroxocobalamin (vitamin B12a) prevents and reverses endotoxin-induced hypotension and mortality in rodents: role of nitric oxide.


INHIBITION OF NITRIC OXIDE SYNTHASE BY COBALAMINS AND COBINAMIDES*