Niacinamide fully reverses endotoxemia and leaky gut (from ethanol)

haidut

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The study below is a true gem due to both its broadness of impact, as well as the ease and low-cost of the therapeutic intervention it studied. Chronic endotoxemia, a cause and a result of increased gut permeability (aka "leaky gut") is now known to be a major cause of virtually all chronic degenerative conditions, and many of the acute ones as well (including seemingly unrelated issues such as viral/bacterial infections). Thus, one of the main goals of the pro-metabolic approach is to heal the gut and reduce both the production and systemic absorption of endotoxin (LPS). While tools such as charcoal, insoluble fiber, antibiotics, etc have their use in achieving this goal, the mechanism through which leaky gut develops had so far been largely unknown. As the study below demonstrated, leaky gut is nothing but energetic deficiency in disguise. Namely, since apparently intestinal epithelial cells (forming the bulk of the gut barrier) consume at least 20% of the ATP we synthesize daily, any sizable drop in ATP levels results in massive dysfunction in both the structure and function of these cells. On a related note, something similar has already been demonstrated to happen in the brain (a similarly highly-energetically-sensitive organ) - i.e. a mere 20% drop in brain ATP levels leads to violent, homicidal aggression in the organism experiencing this energetic drop. Endotoxin (LPS), produced by the gram-negative members of out microbiome, is known to deplete ATP levels in the epithelial cells. The study used another known ATP depleting agent - ethanol - to cause the energetic deficiency in the epithelial cells and, unsurprisingly, found that endotoxin levels in the blood massively increased. However, the study found that administering niacinamide at a human-equivalent dose (HED) of 30mg/kg daily, for 10 days, fully prevented the endotoxemia caused by ethanol, and reversed all the energetic (ATP, NAD, Krebs cycle function) deficits as well, thereby restoring the gut barrier function. In fact, niacinamide supplementation reversed the energetic deficits to a level surpassing the healthy control group! As I mentioned above, the study is relevant even for people who do not drink alcohol since endotoxin naturally formed in our intestines in response to feeding can also cause similar energetic depletion in the intestinal cells and thus cause the same state of "leaky gut" as ethanol. While 30mg/kg of niacinamide daily is not a small dose, it is below the daily dose even mainstream medicine considers toxic, and the duration of usage was just 10 days. Furthermore, the treatment lasted 10 days since ethanol was also administered for 10 days. If a person is not drinking daily, then the niacinamide treatment would also likely not be needed daily. In the absence of daily drinking, I think a reasonable protocol would be to take 30mg/kg on weekends (2 days), maybe twice a month, as a general prophylactic and/or gut-repair regimen. A daily dose of 200mg-300mg would probably have similar beneficial effects as the larger doses taken sporadically. Several human studies already demonstrated that a daily dose of 300mg niacinamide raises NAD levels to the same degree as 1,000mg daily.

NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function
NAD+ Supplement Protects Intestines from Alcohol in Mice

"...The permeability of the epithelial intestinal barrier is known to increase with age. The resulting condition, also known as “leaky gut,” can be exacerbated by dietary, lifestyle, and environmental factors, such as alcohol consumption [2]. While not lethal, like cancer or cardiovascular diseases, leaky gut is not a trifling matter. Recent studies have shown that intestinal contents, such as the bacterial byproduct lipopolysaccharide, become potent immune system triggers in the bloodstream. This is how a leaky gut causes inflammaging: the persistent systemic inflammation that drives multiple diseases of aging [3]."

"...In this new study, the researchers investigated the deleterious effects of ethanol on gut permeability in mice and whether they can be alleviated by NR. Over the course of the experiment, mice fed an ethanol-rich diet experienced intestinal barrier deterioration. However, in mice who also received NR, this effect, as measured by lipopolysaccharide (LPS) concentration in serum, was largely abolished."

"...Recent studies show that energy homeostasis is important for tight junction formation between intestinal epithelial cells [6]. The researchers confirmed that NAD+ levels were greatly depleted in those cells by ethanol, but elevated by NR supplementation – amazingly, above those of healthy controls. Levels of ATP, the molecule considered cellular “energy currency”, showed a similar dynamic."

"...Since most of the energy production in cells occurs in mitochondria, the researchers also analyzed mitochondrial health. As expected, levels of succinate dehydrogenase (SDH) and citrate synthase (CS), two functional mitochondrial enzymes, were reduced by ethanol but rescued by NR supplementation. Same picture was observed for mitochondrial DNA number."
 

revenant

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Awesome. Are the other types of damage we should be mitigating when consuming alcohol?
 

S.Holmes

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The study below is a true gem due to both its broadness of impact, as well as the ease and low-cost of the therapeutic intervention it studied. Chronic endotoxemia, a cause and a result of increased gut permeability (aka "leaky gut") is now known to be a major cause of virtually all chronic degenerative conditions, and many of the acute ones as well (including seemingly unrelated issues such as viral/bacterial infections). Thus, one of the main goals of the pro-metabolic approach is to heal the gut and reduce both the production and systemic absorption of endotoxin (LPS). While tools such as charcoal, insoluble fiber, antibiotics, etc have their use in achieving this goal, the mechanism through which leaky gut develops had so far been largely unknown. As the study below demonstrated, leaky gut is nothing but energetic deficiency in disguise. Namely, since apparently intestinal epithelial cells (forming the bulk of the gut barrier) consume at least 20% of the ATP we synthesize daily, any sizable drop in ATP levels results in massive dysfunction in both the structure and function of these cells. On a related note, something similar has already been demonstrated to happen in the brain (a similarly highly-energetically-sensitive organ) - i.e. a mere 20% drop in brain ATP levels leads to violent, homicidal aggression in the organism experiencing this energetic drop. Endotoxin (LPS), produced by the gram-negative members of out microbiome, is known to deplete ATP levels in the epithelial cells. The study used another known ATP depleting agent - ethanol - to cause the energetic deficiency in the epithelial cells and, unsurprisingly, found that endotoxin levels in the blood massively increased. However, the study found that administering niacinamide at a human-equivalent dose (HED) of 30mg/kg daily, for 10 days, fully prevented the endotoxemia caused by ethanol, and reversed all the energetic (ATP, NAD, Krebs cycle function) deficits as well, thereby restoring the gut barrier function. In fact, niacinamide supplementation reversed the energetic deficits to a level surpassing the healthy control group! As I mentioned above, the study is relevant even for people who do not drink alcohol since endotoxin naturally formed in our intestines in response to feeding can also cause similar energetic depletion in the intestinal cells and thus cause the same state of "leaky gut" as ethanol. While 30mg/kg of niacinamide daily is not a small dose, it is below the daily dose even mainstream medicine considers toxic, and the duration of usage was just 10 days. Furthermore, the treatment lasted 10 days since ethanol was also administered for 10 days. If a person is not drinking daily, then the niacinamide treatment would also likely not be needed daily. In the absence of daily drinking, I think a reasonable protocol would be to take 30mg/kg on weekends (2 days), maybe twice a month, as a general prophylactic and/or gut-repair regimen. A daily dose of 200mg-300mg would probably have similar beneficial effects as the larger doses taken sporadically. Several human studies already demonstrated that a daily dose of 300mg niacinamide raises NAD levels to the same degree as 1,000mg daily.

NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function
NAD+ Supplement Protects Intestines from Alcohol in Mice

"...The permeability of the epithelial intestinal barrier is known to increase with age. The resulting condition, also known as “leaky gut,” can be exacerbated by dietary, lifestyle, and environmental factors, such as alcohol consumption [2]. While not lethal, like cancer or cardiovascular diseases, leaky gut is not a trifling matter. Recent studies have shown that intestinal contents, such as the bacterial byproduct lipopolysaccharide, become potent immune system triggers in the bloodstream. This is how a leaky gut causes inflammaging: the persistent systemic inflammation that drives multiple diseases of aging [3]."

"...In this new study, the researchers investigated the deleterious effects of ethanol on gut permeability in mice and whether they can be alleviated by NR. Over the course of the experiment, mice fed an ethanol-rich diet experienced intestinal barrier deterioration. However, in mice who also received NR, this effect, as measured by lipopolysaccharide (LPS) concentration in serum, was largely abolished."

"...Recent studies show that energy homeostasis is important for tight junction formation between intestinal epithelial cells [6]. The researchers confirmed that NAD+ levels were greatly depleted in those cells by ethanol, but elevated by NR supplementation – amazingly, above those of healthy controls. Levels of ATP, the molecule considered cellular “energy currency”, showed a similar dynamic."

"...Since most of the energy production in cells occurs in mitochondria, the researchers also analyzed mitochondrial health. As expected, levels of succinate dehydrogenase (SDH) and citrate synthase (CS), two functional mitochondrial enzymes, were reduced by ethanol but rescued by NR supplementation. Same picture was observed for mitochondrial DNA number."

Sadly niacinamide inhibits SIRT3.
Is that a bad thing?

Posted by Haidut:
"In the last couple of years there has been a lot of "noise" in the media about how the SIRT-family of genes can extend lifespan when activated by things like exercise or, preferably, by certain chemical compounds like resveratrol (which putatively acts on SIRT-1). Ray Peat has stated his opinion that activating those genes is not likely to lead to life extension and may even be implicated in some cancers. In one is his articles he talks about how niacinamice/nicotinamide (vitamin B3) acts in a way approximately opposite to resveratrol. Also, there are independent studies that found niacinamide silences SIRT-1 and SIRT-2 in high doses. An interesting study came out recently that seems to corroborate Ray's views. It looks like it's niacinamide that actually extends life while resveratrol so far has been a bust (several clinical trials halted due to resveratrol increasing mortality in patients). The sirtuins putative life extension (if any) seems to be due to their ability to convert niacinamide into NAD+ and MNA."
 

Regina

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The study below is a true gem due to both its broadness of impact, as well as the ease and low-cost of the therapeutic intervention it studied. Chronic endotoxemia, a cause and a result of increased gut permeability (aka "leaky gut") is now known to be a major cause of virtually all chronic degenerative conditions, and many of the acute ones as well (including seemingly unrelated issues such as viral/bacterial infections). Thus, one of the main goals of the pro-metabolic approach is to heal the gut and reduce both the production and systemic absorption of endotoxin (LPS). While tools such as charcoal, insoluble fiber, antibiotics, etc have their use in achieving this goal, the mechanism through which leaky gut develops had so far been largely unknown. As the study below demonstrated, leaky gut is nothing but energetic deficiency in disguise. Namely, since apparently intestinal epithelial cells (forming the bulk of the gut barrier) consume at least 20% of the ATP we synthesize daily, any sizable drop in ATP levels results in massive dysfunction in both the structure and function of these cells. On a related note, something similar has already been demonstrated to happen in the brain (a similarly highly-energetically-sensitive organ) - i.e. a mere 20% drop in brain ATP levels leads to violent, homicidal aggression in the organism experiencing this energetic drop. Endotoxin (LPS), produced by the gram-negative members of out microbiome, is known to deplete ATP levels in the epithelial cells. The study used another known ATP depleting agent - ethanol - to cause the energetic deficiency in the epithelial cells and, unsurprisingly, found that endotoxin levels in the blood massively increased. However, the study found that administering niacinamide at a human-equivalent dose (HED) of 30mg/kg daily, for 10 days, fully prevented the endotoxemia caused by ethanol, and reversed all the energetic (ATP, NAD, Krebs cycle function) deficits as well, thereby restoring the gut barrier function. In fact, niacinamide supplementation reversed the energetic deficits to a level surpassing the healthy control group! As I mentioned above, the study is relevant even for people who do not drink alcohol since endotoxin naturally formed in our intestines in response to feeding can also cause similar energetic depletion in the intestinal cells and thus cause the same state of "leaky gut" as ethanol. While 30mg/kg of niacinamide daily is not a small dose, it is below the daily dose even mainstream medicine considers toxic, and the duration of usage was just 10 days. Furthermore, the treatment lasted 10 days since ethanol was also administered for 10 days. If a person is not drinking daily, then the niacinamide treatment would also likely not be needed daily. In the absence of daily drinking, I think a reasonable protocol would be to take 30mg/kg on weekends (2 days), maybe twice a month, as a general prophylactic and/or gut-repair regimen. A daily dose of 200mg-300mg would probably have similar beneficial effects as the larger doses taken sporadically. Several human studies already demonstrated that a daily dose of 300mg niacinamide raises NAD levels to the same degree as 1,000mg daily.

NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function
NAD+ Supplement Protects Intestines from Alcohol in Mice

"...The permeability of the epithelial intestinal barrier is known to increase with age. The resulting condition, also known as “leaky gut,” can be exacerbated by dietary, lifestyle, and environmental factors, such as alcohol consumption [2]. While not lethal, like cancer or cardiovascular diseases, leaky gut is not a trifling matter. Recent studies have shown that intestinal contents, such as the bacterial byproduct lipopolysaccharide, become potent immune system triggers in the bloodstream. This is how a leaky gut causes inflammaging: the persistent systemic inflammation that drives multiple diseases of aging [3]."

"...In this new study, the researchers investigated the deleterious effects of ethanol on gut permeability in mice and whether they can be alleviated by NR. Over the course of the experiment, mice fed an ethanol-rich diet experienced intestinal barrier deterioration. However, in mice who also received NR, this effect, as measured by lipopolysaccharide (LPS) concentration in serum, was largely abolished."

"...Recent studies show that energy homeostasis is important for tight junction formation between intestinal epithelial cells [6]. The researchers confirmed that NAD+ levels were greatly depleted in those cells by ethanol, but elevated by NR supplementation – amazingly, above those of healthy controls. Levels of ATP, the molecule considered cellular “energy currency”, showed a similar dynamic."

"...Since most of the energy production in cells occurs in mitochondria, the researchers also analyzed mitochondrial health. As expected, levels of succinate dehydrogenase (SDH) and citrate synthase (CS), two functional mitochondrial enzymes, were reduced by ethanol but rescued by NR supplementation. Same picture was observed for mitochondrial DNA number."
Outstanding!

I might even try sending the study to family members.
 

CastorTroy

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Is that a bad thing?

Posted by Haidut:
"In the last couple of years there has been a lot of "noise" in the media about how the SIRT-family of genes can extend lifespan when activated by things like exercise or, preferably, by certain chemical compounds like resveratrol (which putatively acts on SIRT-1). Ray Peat has stated his opinion that activating those genes is not likely to lead to life extension and may even be implicated in some cancers. In one is his articles he talks about how niacinamice/nicotinamide (vitamin B3) acts in a way approximately opposite to resveratrol. Also, there are independent studies that found niacinamide silences SIRT-1 and SIRT-2 in high doses. An interesting study came out recently that seems to corroborate Ray's views. It looks like it's niacinamide that actually extends life while resveratrol so far has been a bust (several clinical trials halted due to resveratrol increasing mortality in patients). The sirtuins putative life extension (if any) seems to be due to their bility to convert niacinamide into NAD+ and MNA."

Activating it not being good, doesn't imply artificially inhibiting it through supplements to be good. I wouldn't take resveratrol or any other drug with the purpose of amplifying SIRT3 activity, the same I'd be cautious with anything that directly inhibits it.

SIRT3 is involved in metabolism, and a study with mice lacking SIRT3 had greater obesity and insulin resistance on a high-fat diet. Reduced SIRT3 function leads to mitochondrial dysfunction and metabolic syndrome.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563434/
 

LadyRae

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Awesome. Are the other types of damage we should be mitigating when consuming alcohol?
I'm reminded of the saying:
"Penny wise, but pound foolish"

Consuming alcohol is so detrimental to our health, it's fascinating that people who are hyper aware of their diet and health and all the nuances of individual vitamins and minerals and supplements, still want to consume alcohol.
 

HeyThere

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I would so love to do this, but for someone hyper-sensitive to everything there's no way I'm taking 10x 100mg pills. I'll never know if this would have "fixed me". I see so much of myself in the symptoms though.
 

revenant

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I'm reminded of the saying:
"Penny wise, but pound foolish"

Consuming alcohol is so detrimental to our health, it's fascinating that people who are hyper aware of their diet and health and all the nuances of individual vitamins and minerals and supplements, still want to consume alcohol.

But it's fun, and having fun is important. And it has benefits too, people who abstain just don't like to admit it.
 

Perry Staltic

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Thus, one of the main goals of the pro-metabolic approach is to heal the gut and reduce both the production and systemic absorption of endotoxin (LPS). While tools such as charcoal, insoluble fiber, antibiotics, etc have their use in achieving this goal, the mechanism through which leaky gut develops had so far been largely unknown. As the study below demonstrated, leaky gut is nothing but energetic deficiency in disguise. Namely, since apparently intestinal epithelial cells (forming the bulk of the gut barrier) consume at least 20% of the ATP we synthesize daily, any sizable drop in ATP levels results in massive dysfunction in both the structure and function of these cells.

FWIW, those who take antibiotics should know that they can destroy beneficial gut bacteria, potentially those that produce butyrate, directly or indirectly (eg, bacterial crossfeeding), which increases mitochrondrial ATP synthesis in colonocytes


View: https://twitter.com/raymondnichols_/status/1627326276464771072

FpcBk83aIAUKiCa

 
Last edited:

Perry Staltic

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I'm reminded of the saying:
"Penny wise, but pound foolish"

Consuming alcohol is so detrimental to our health, it's fascinating that people who are hyper aware of their diet and health and all the nuances of individual vitamins and minerals and supplements, still want to consume alcohol.

Take some probiotics and B vitamins for the gut and NAC for the liver and enjoy. The thing that keeps me away from alcohol is the glyphosate used in the growth of hops, grapes, grains, etc.
 
Last edited:

LadyRae

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But it's fun, and having fun is important. And it has benefits too, people who abstain just don't like to admit it.
Well I absolutely understand wanting to have fun of course. And I definitely had plenty of fun.

There's no need to go into the vast evidence detailing how alcohol wrecks us here, but I do think my point is valid for those that have longstanding health issues. It is not easy or convenient or socially acceptable in our culture to stop drinking alcohol... But the health benefits are immense and I just couldn't be happier.

That said, I do indulge in nicotine lozenges several times a day so I'm not trying to self-righteously preach to anyone..
 
OP
haidut

haidut

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are fancy ones like Nicotinamide Riboside or NMN better than niacinamide?

Not really. When ingesting NR or NMN they get broken down in the stomach to niacinamide and the whatever else was attached to in the more complex molecule. In the case of NR it breaks down to niacinamide and D-ribose. Since humans produce plenty of D-ribose (from carbs) taking just niacinamide is expected to have the same effects as taking NR, as far as NAD elevation is concerned and, in confirmation, ChromaDex (purveyor or NR) own humans studies showed that niacinamide and NR do not have statistically significant difference in regards to raising NAD - i.e. they both raise NAD more than placebo but are about equally effective.
This is somewhat similar to the studies on raising total glutathione (GSH+GSSG) - the rate-limiting ingredient is glycine, not NAC. So, taking just glycine seems to raise total glutathione at least as much as glycine+NAC combo. More importantly, glycine raises GSSG more than it raises GSH, while taking NAC or glycine+NAC raises GSH more than GSSG. In other words, taking glycine raises total glutathione pool and shifts the redox balance in favor of oxidation, while the other combos or NAC by itself shift the balance towards reduction. This is one reason most human studies seem to (mistakenly) glorify NAC supplements - i.e. those studies invariably measure only GSH, which is not indicative of total glutathione pool and is also not a really good biomarker as it shows increased reduction.
 
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Not really. When ingesting NR or NMN they get broken down in the stomach to niacinamide and the whatever else was attached to in the more complex molecule. In the case of NR it breaks down to niacinamide and D-ribose. Since humans produce plenty of D-ribose (from carbs) taking just niacinamide is expected to have the same effects as taking NR, as far as NAD elevation is concerned and, in confirmation, ChromaDex (purveyor or NR) own humans studies showed that niacinamide and NR do not have statistically significant difference in regards to raising NAD - i.e. they both raise NAD more than placebo but are about equally effective.
This is somewhat similar to the studies on raising total glutathione (GSH+GSSG) - the rate-limiting ingredient is glycine, not NAC. So, taking just glycine seems to raise total glutathione at least as much as glycine+NAC combo. More importantly, glycine raises GSSG more than it raises GSH, while taking NAC or glycine+NAC raises GSH more than GSSG. In other words, taking glycine raises total glutathione pool and shifts the redox balance in favor of oxidation, while the other combos or NAC by itself shift the balance towards reduction. This is one reason most human studies seem to (mistakenly) glorify NAC supplements - i.e. those studies invariably measure only GSH, which is not indicative of total glutathione pool and is also not a really good biomarker as it shows increased reduction.

thank you. But there is that Baylor study of glycine and NAC and a few others, and they seem to point to glycine and NAC, not just glycine, for improving biomarkers of aging or lowering cancer risk or reducing cancer growths.

So money on the fancy schmancy niacinamides is just wasted?
 
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haidut

haidut

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thank you. But there is that Baylor study of glycine and NAC and a few others, and they seem to point to glycine and NAC, not just glycine, for improving biomarkers of aging or lowering cancer risk or reducing cancer growths.

So money on the fancy schmancy niacinamides is just wasted?

Yes, I think most of the premium paid for NR and NMN is a waste...and now FDA has also said NMN is a "drug" and cannot be sold OTC. Won't be surprised if FDA comes after NR soon as well.
As far as the Baylor study - did they compared glycine only to glycine+NAC?
 
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Yes, I think most of the premium paid for NR and NMN is a waste...and now FDA has also said NMN is a "drug" and cannot be sold OTC. Won't be surprised if FDA comes after NR soon as well.
As far as the Baylor study - did they compared glycine only to glycine+NAC?

no they didn't. But a few other studies seem to but it's very haphazard. Glycine is very helpful on its own. NAC maybe not so much. Hard to say.
 

sunny

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Ray Peat was not a resveratrol fan.
 

Herbie

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Maybe this explains why red bull and vodka is a drink enjoyed by many
 

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