Endotoxin (LPS) Is The Cause Of Venous Malformations In The Brain (CNS)

haidut

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As a former athlete I am keenly aware of the several conditions that are known to have much higher incidence in (even very young) athletes. Aside from cardiac arrest and kidney damage, other conditions with higher incidence in athletes include aneurysms and various other vascular disorders in the brain. Knowing the role of estrogen in varicose veins and weakening the vessel walls, I always suspected that estrogen is somehow involved but there was not much evidence I could find. Now, this recent study found that endotoxin and any other substance that acts through TLR4 is one cause of venous malformations in the brain known as cerebral cavernous malformation (CCM). The CCM conditions is closely related to aneurysms and in some countries it is even classified as a type of brain aneurysm. Endotoxin levels in the blood rise sharply when under stress, which of course includes all kinds of intense physical activity. So, the next time you go for a run or feel like you have endured a really stressful day, a little bit of TLR4 antagonist may go a long way towards protecting your brain and its vessels. I posted a few studies on TLR4 antagonists on the forum for those interested but the list includes commonly available substances like vitamin B2, vitamin D, vitamin A, Benadryl, cyproheptadine, progesterone, etc. Antibiotics also worked as the study mentioned, but killing the entire microbiome may not be practical goal for most people. Perhaps even more importantly, the study authors think that TLR antagonists (or antibiotics) may actually treat established CCM, so people with this condition or other types of aneurysms may want to discuss this with their doctor.

https://www.sciencedaily.com/releases/2017/05/170510132009.htm

"...Bacteria in the gut microbiome drive the formation of cerebral cavernous malformations (CCMs), clusters of dilated, thin-walled blood vessels in the brain that can cause stroke and seizures, according to new research published this week in Nature by researchers from the Perelman School of Medicine at the University of Pennsylvania."

"...Led by Mark Kahn, MD, a professor of Cardiovascular Medicine, the team's research suggests that altering the microbiome in CCM patients may be an effective therapy for this cerebrovascular disease. CCM disease, which occurs in about one in 100 to 200 people, can present in two forms. One is sporadic, accounting for 80 percent of cases, and is most frequent in older individuals. The remaining 20 percent are familial, inherited cases. In 2016, the Kahn lab discovered the molecular mechanism in endothelial cells that underlies the formation of CCMs. In the current Nature study, the team discovered that this molecular pathway is activated by TLR4, a receptor for the bacterial molecule lipopolysaccharide (LPS). Activation of TLR4 on brain endothelial cells by LPS vastly accelerated CCM formation. Conversely, if TLR4 was removed from endothelial cells genetically, or if the mice were treated with drugs that block TLR4 function, CCM formation is prevented."

"...Since TLR4 primarily responds to LPS from Gram-negative bacteria, Alan Tang, an MD-PhD student in the Kahn lab, proposed that bacteria from the animal's gut microbiome may drive CCM formation. To test this theory, he examined CCM formation in mice that were housed under germ-free conditions (in collaboration with the Children's Hospital of Philadelphia through the PennCHOP Microbiome Program Core Facility) or treated with antibiotics to reduce the number of bacteria living in the gut. In both cases, CCM formation was dramatically reduced, demonstrating a key role for bacteria in the pathology of CCM disease."

"...Working with the team from UNM and UCSF, they discovered that genetic variations that raise the amount of TLR4 that is produced are associated with higher numbers of CCM lesions, suggesting that the key role for LPS-TLR4 signaling identified in mice is also present in humans. These studies identify an unexpected, direct link between the microbiome and a common cerebrovascular disease. "This suggests that treatments designed to block TLR4 signaling or alter the microbiome may be used to treat this disease," Kahn said."
 

Regina

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As a former athlete I am keenly aware of the several conditions that are known to have much higher incidence in (even very young) athletes. Aside from cardiac arrest and kidney damage, other conditions with higher incidence in athletes include aneurysms and various other vascular disorders in the brain. Knowing the role of estrogen in varicose veins and weakening the vessel walls, I always suspected that estrogen is somehow involved but there was not much evidence I could find. Now, this recent study found that endotoxin and any other substance that acts through TLR4 is one cause of venous malformations in the brain known as cerebral cavernous malformation (CCM). The CCM conditions is closely related to aneurysms and in some countries it is even classified as a type of brain aneurysm. Endotoxin levels in the blood rise sharply when under stress, which of course includes all kinds of intense physical activity. So, the next time you go for a run or feel like you have endured a really stressful day, a little bit of TLR4 antagonist may go a long way towards protecting your brain and its vessels. I posted a few studies on TLR4 antagonists on the forum for those interested but the list includes commonly available substances like vitamin B2, vitamin D, vitamin A, Benadryl, cyproheptadine, progesterone, etc. Antibiotics also worked as the study mentioned, but killing the entire microbiome may not be practical goal for most people. Perhaps even more importantly, the study authors think that TLR antagonists (or antibiotics) may actually treat established CCM, so people with this condition or other types of aneurysms may want to discuss this with their doctor.

https://www.sciencedaily.com/releases/2017/05/170510132009.htm

"...Bacteria in the gut microbiome drive the formation of cerebral cavernous malformations (CCMs), clusters of dilated, thin-walled blood vessels in the brain that can cause stroke and seizures, according to new research published this week in Nature by researchers from the Perelman School of Medicine at the University of Pennsylvania."

"...Led by Mark Kahn, MD, a professor of Cardiovascular Medicine, the team's research suggests that altering the microbiome in CCM patients may be an effective therapy for this cerebrovascular disease. CCM disease, which occurs in about one in 100 to 200 people, can present in two forms. One is sporadic, accounting for 80 percent of cases, and is most frequent in older individuals. The remaining 20 percent are familial, inherited cases. In 2016, the Kahn lab discovered the molecular mechanism in endothelial cells that underlies the formation of CCMs. In the current Nature study, the team discovered that this molecular pathway is activated by TLR4, a receptor for the bacterial molecule lipopolysaccharide (LPS). Activation of TLR4 on brain endothelial cells by LPS vastly accelerated CCM formation. Conversely, if TLR4 was removed from endothelial cells genetically, or if the mice were treated with drugs that block TLR4 function, CCM formation is prevented."

"...Since TLR4 primarily responds to LPS from Gram-negative bacteria, Alan Tang, an MD-PhD student in the Kahn lab, proposed that bacteria from the animal's gut microbiome may drive CCM formation. To test this theory, he examined CCM formation in mice that were housed under germ-free conditions (in collaboration with the Children's Hospital of Philadelphia through the PennCHOP Microbiome Program Core Facility) or treated with antibiotics to reduce the number of bacteria living in the gut. In both cases, CCM formation was dramatically reduced, demonstrating a key role for bacteria in the pathology of CCM disease."

"...Working with the team from UNM and UCSF, they discovered that genetic variations that raise the amount of TLR4 that is produced are associated with higher numbers of CCM lesions, suggesting that the key role for LPS-TLR4 signaling identified in mice is also present in humans. These studies identify an unexpected, direct link between the microbiome and a common cerebrovascular disease. "This suggests that treatments designed to block TLR4 signaling or alter the microbiome may be used to treat this disease," Kahn said."
Great. It's good to know that all those common substances dear to us here double as TLR4 antagonists. You did not mention emodin/cascara. Maybe that's an etc.
I had a 3 hour seminar today. Haven't done one of those in many years. I came prepared with "sports drink" of OJ, gerolsteiner, inosine, sugar and salt), a tall red bull and another orange soda drink, cheese sticks and candy. Went fine. Of course, when we went to the bar afterwards, our group ordered beers. No food. No sugar. Oh well.
 

Regina

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Great. It's good to know that all those common substances dear to us here double as TLR4 antagonists. You did not mention emodin/cascara. Maybe that's an etc.
I had a 3 hour seminar today. Haven't done one of those in many years. I came prepared with "sports drink" of OJ, gerolsteiner, inosine, sugar and salt), a tall red bull and another orange soda drink, cheese sticks and candy. Went fine. Of course, when we went to the bar afterwards, our group ordered beers. No food. No sugar. Oh well.
and I don't think these measures I took are enough to prevent damage (TLR4 and collagen synthesis) of 3 hour intense exercise. Whenever I wasn't too keen on my partner, I could play the old lady card and sit off to the side. I played the elder statesman today. Also, it was so crowded we were like naked molerats.
I don't feel smug to have the info I've learned here. I wish my training community did it too. :-(
 

haidut

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@haidut what you suggest to lower endotoxin? like top 3 ways :)

Charcoal and antibiotics are the only things that would lower actual levels. But any TLR4 antagonist should reduce damage and there a number of substances like that I posted about on the forum, including pharma drugs like cyproheptadine, Benadryl or ketotifen.
 

Fractality

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the study authors think that TLR antagonists (or antibiotics) may actually treat established CCM

When they say "treat" established CCM, do you think they mean that the weakened vessel will be able to revert back to normal, or that it will be less likely to burst when TLR is antagonized? From a purely mechanistic worldview the vessel cannot revert back to normal and it must be "clipped" via intervention.
 

tankasnowgod

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Jan 25, 2014
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Charcoal and antibiotics are the only things that would lower actual levels. But any TLR4 antagonist should reduce damage and there a number of substances like that I posted about on the forum, including pharma drugs like cyproheptadine, Benadryl or ketotifen.

Vitamin C might be added to that list. Or, at least prevent translocation of endotoxin from the gut to circulation-

https://pdfs.semanticscholar.org/955b/7699974417c55ea3e6020754413793e71350.pdf

"Intense or endurance exercise produces a concentration of endotoxin in the blood similar to that found in patients with sepsis. Oral ascorbate pretreatment of as little as 1 gram has been demonstrated to completely block the increase in circulating endotoxin and nitrite typically found during and after intense exercise."

"Stress (including exercise) in general causes a mild ischaemia to the gut and LPS translocation increases dramatically. We know from exercise studies that oral ascorbate decreases or completely blocks LPS translocation from the gut. The most likely explanation here is that ascorbate attenuates the mild inflammatory response in the gut epithelium which is a response to decreased perfusion. Preventing mild inflammation prevents the increased vascular leaking associated with it."

Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon r... - PubMed - NCBI
 

CLASH

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@tankasnowgod
I have been using it as well, with some success with a chronic infection. I’m not so sure the contamination thing is as great of a threat as its made out to be with vit c. What I think is more likely is someone who reacts poorly to it actually has some type of infection and the vit C ramps up the immune system enhancing macrophage oxidative bursts. The pro-oxidant and anti-oxidant functions of the vitamin I think are both neccesary.

As a side note combining taurine and vit c together creates a pretty potent anti-anxiety.

Thanks for your response man.
 

Fractality

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Joined
Jan 23, 2016
Messages
772
When they say "treat" established CCM, do you think they mean that the weakened vessel will be able to revert back to normal, or that it will be less likely to burst when TLR is antagonized? From a purely mechanistic worldview the vessel cannot revert back to normal and it must be "clipped" via intervention.

I'm still curious about this...
 
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