94 replies to this topic

[Phoebus]

 

Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota.

 

PubMed

 

The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera Lactobacillus and Bifidobacterium, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE(-/-) mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis. Recently, trimethylamine-N-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports

 

[albedo]

 

 

Thank you. Good information with a possible explication impact via the gut microbiota mediation also on the known low bioavailability of resveratrol in humans.

For some reason I could not find the dosage of the resveratrol arm of the study. Did I overlooked it?

[Phoebus]

Thank you. Good information with a possible explication impact via the gut microbiota mediation also on the known low bioavailability of resveratrol in humans.

For some reason I could not find the dosage of the resveratrol arm of the study. Did I overlooked it?

 

honestly cant find any reference to a dosage in the whole study! Weird 

 

also if anyone knows about the microbiome this is really fascinating info Re: resveratrol's influence on the gut. If someone know more about this, feel free to chime in.  

 

 

 

Analysis at the phylum level revealed that the bacterial population of vehicle-treated mice was dominated by Bacteroidetes (35.1%) and Firmicutes (50.3%), with a low level of Proteobacteria (11.2%) (Fig. 2D). The proportion of sequences assigned to Bacteroidetes was significantly increased in metagenomes of RSV-fed animals at the expense of Firmicutes (Fig. 2D). Genus-level analysis showed that RSV induced an increase in the relative abundances of Bacteroides, Lactobacillus, Bifidobacterium, and Akkermansia in mice (Fig. 2E and ​andF).F). RSV administration resulted in a decrease in the relative abundances of Prevotella, uncultured Ruminococcaceae (Ruminococcaceae_uncultured), Anaerotruncus, Alistipes, Helicobacter, and uncultured Peptococcaceae (Peptococcaceae_uncultured) (Fig. 2E and ​andF).F).

[MankindRising]

I wouldnt be surprised it would be due to unique aryl hydrocarbon receptor manipulation, lots of flavonoids can have different effects on it (weak agonists by acting as antagonists, antagonists or agonists). Afaik addressing cyp1a2 activity is a good marker of how a herb/phytochemical/med could affect metabolism of toxins.

 

It is well known that probiotics (including l. reuteri atcc 6475 and also other probiotics) create beneficial 'leftover products' such as unique indoles

 

Also resveratrol seems AHr modulatory effects (depending on the study, some note its an antagonist, some say weak agonistic activity, my uneducated guess it will depend on the organism its microbiome make up).

 

See here:

 

Tryptophan as source of ligands for the AhR

https://dspace.libra...e=2&isAllowed=y

 

"It is now suggested that the ligands that activate the AhR can also derive from the metabolism of food by the microbiome. Proposed ligands derive from tryptophan metabolism, resveratrol, eicosanoids, cytokines, dioxins, phytochemicals and flavonoids such as grapes"

 

"Indole-3-aldehyde and the link to L. reuteri Indole-3-aldehyde (IAld) is a well-known metabolite of trp and can arise via various degrading pathways. One of the main pathways is the indole-pyruvate-pathway that is catalyzed by the aromatic amino acid transferase (ArAT). ArAT is conserved in many bacterial species such as the Lactobacilli. In contrast to other bacterial species Lactobacilli showed to be the main bacterial species to metabolize Trp7 . Further research with L. reuteri showed that there is a direct link between the metabolism of trp into IAld by L. reuteri and the increase in IL-22. This was not visible in the same tests with other intestinal bacteria strains such as the L. Johnsonii or Clostridia species7 ."

 

"In IDO-/-mice the administration of IALd (i3a) even lead to the recovery of the Treg and Th1 cellular immune response that was decreased to the IDO-/- knock-out7 ."

 

"All these data show that microbial metabolism of trp can lead to reactivation or improvement of the intestinal immunity. Especially the metabolite IAld is a very potent AhR agonist and could therefore be considered for therapeutic purposes"

 

 

"Kynurenine in brain can lead to suppression of the immune response As described earlier the trp metabolite kynurenine is a ligand for the AhR. This ligand is mainly taken up from food but Opitz et al. recently described that tumor cells are also able to produce kynurenine and activate the AhR25. This activation then leads to the suppression of antitumor immune responses. Although this mechanism has mainly been described in the brain25, this could also play a role in the intestine"

 

 

Interesting study:

 

Kynurenic acid is a nutritional cue that enables behavioral plasticity

https://www.ncbi.nlm...les/PMC4334586/

 

Now PQQ also induces alterations in immune functions, I cant find the paper right now but it showed that PQQ has ligand binding for kynurenic acid. Btw PQQ was shown to reduce TMAO in humans, but its a strong immunsupressant (I had quite severe skin eruptions and all that to PQQ). Also if you look at the structure of both PQQ and Kynurenic acid you will notice they have a lot of similarities.

 

 

Any way going too far offtopic...

 

 

 

https://en.wikipedia...-carboxaldehyde

 

Indole-3-carboxaldehyde (I3A), also known as indole-3-aldehyde and 3-formylindole, is a metabolite of dietary l-tryptophan which is synthesized by human gastrointestinal bacteria, particularly species of the Lactobacillus genus.^[2][3] I3A is a biologically active metabolite which acts as a receptor agonist at the aryl hydrocarbon receptor in intestinal immune cells, in turn stimulating the production of interleukin-22 which facilitates mucosal reactivity.^[2]

 

 

 

 

 

So as most of you know by now is that the tryptophan has 2 fates, one is to go into the serotonin pathway, the other is into the kyna/quin pathway.

 

Resveratrol intake enhances indoleamine-2 3-dioxygenase activity in humans

https://www.ncbi.nlm...pubmed/27552061

 

"METHODS:

Healthy volunteers were orally administrated 5g resveratrol (n=8) or placebo (n=2) in a pilot study. IDO activity was determined by analyzing plasma levels of tryptophan and kynurenine. Determination of the immune activation marker neopterin was included in the analysis."

RESULTS:

Resveratrol administration significantly reduced tryptophan levels 2.5h (p<0.001) and 5h (p<0.001) after treatment. Kynurenine levels were slightly, but not significantly, elevated 2.5h after the intervention, which resulted in an 1.33- and 1.30-fold increase of the kynurenine to tryptophan ratio at 2.5h (p<0.01) and 5h (p<0.01), respectively. Neopterin levels were not affected by resveratrol administration.

CONCLUSION: This is the first evidence of a modulatory effect of orally administered resveratrol on tryptophan metabolism in humans. Since IDO has been shown to play a crucial role in immunity, cancer development and regulation of vascular tone, the modulation of this enzyme might be involved in resveratrol's diverse biological effects.

 

Resveratrol suppresses tumor progression via the regulation of indoleamine 2,3-dioxygenase

https://www.ncbi.nlm...pubmed/23291179

"Taken together, resveratrol not only regulates immune response through the regulation of IDO in a JAK/STAT1- and PKCδ-dependent manner, but also modulates the IDO-mediated immune tolerance in EG7 thymoma."

 

 

Bidirectional communication between the Aryl Hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism

https://www.ncbi.nlm...les/PMC5515264/

 

 

My guess is that research into the metabolites that resveratrol creates in the gut opens new possibilities, I do think though that chances are high that certain intact strains of gut are required for effects. Different gut microbiome make up may either render people sensitive or insensitive to the effects of resveratrol? thoughts on this?

 

One last thing, I am very curious to see which metabolite/ahr ligand science will eventually link to resveratrols benefit. No doubt it will be some indole or quinone like structure. These can module the immune system and turn on defenses against cancer and such.

Edited by MankindRising, 21 February 2019 - 03:31 PM.

[MankindRising]

To add:

 

Feces of Resveratrol-Fed Mice Improves Glucose Homeostasis in Obese Mice Through Reduction of Intestinal Inflammation

https://www.canadian...0854-7/abstract

 

Could it be that for example dogs (Im an owner) know which poop contains an abundance of certain strains? For example my dog used to eat poop, but only selectively. He would for example not binge on any turd he would come accross. FYI their smell is thought to be as powerfull as 40.000 times as much that of ours, I wouldnt be surprised that if they could smell strain abundance and subconsciously link this to their own gut 'disbalance'.

Edited by MankindRising, 21 February 2019 - 06:01 PM.