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Resveratrol's most significant MOA may have nothing to do with SIRT1


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#1 FunkOdyssey

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Posted 05 October 2016 - 06:19 PM

I guess we shouldn't be surprised -- it seems all roads lead to the gut microbiome:



mBio. 2016 Mar-Apr; 7(2): e02210-15.

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


Ming-liang Chen, Long Yi, Yong Zhang, Xi Zhou, Li Ran, Jining Yang, Jun-dong Zhu, Qian-yong Zhang, and Man-tian Mi


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 the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.


Free full text: https://www.ncbi.nlm...les/PMC4817264/



The implications are interesting.  Advanced formulations of resveratrol that increase its bioavailability might actually reduce its efficacy for atherosclerosis prevention, if less remains in the gut to act on the microbiota.




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#2 Darryl

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Posted 05 October 2016 - 11:43 PM

Assumes TMAO has meaningful effects at physiological concentrations.


McCarty, M.F., 2013. L-carnitine consumption, its metabolism by intestinal microbiota, and cardiovascular health. In Mayo Clinic Proceedings (Vol. 88, No. 8, p. 786)


The plasma TMAO level achieved in the TMAO-fed mice averaged approximately 150 mM, whereas the plasma TMAO level in the top quartile of patients in the epidemiologic analysis was 6.18 mM and higher; the median value of the whole group was 3.67 mM. Hence, the values of TMAO achieved in the TMAO-fed mice were at least an order of magnitude higher than those occurring ambiently in humans. The TMAO could simply be functioning as a marker for habitual ingestion of foods rich in carnitine and choline, which include animal products such as red meat and eggs linked to increased vascular risk.

Beefsteak contains no more than 350 mg of carnitine per pound, some minor fraction of which might be converted to TMAO after ingestion.9 In contrast, ocean fish contains approximately 1.7 g of preformed TMAO per pound; the TMAO content of deepwater fish is even higher. So, human exposure to TMAO will be approximately an order of magnitude higher from ingesting a given weight of fish than of beef; yet, as is well known, fish-rich diets are far more compatible with vascular health than those high inred meats.
I will say, in general it appears most polyphenols, like resveratrol, may exert their most important effects modulating the gut microbiota and reducing intestinal permeability to endotoxins. Some microsome and liposome forumlations to increase polyphenol bioavailability closely resemble the emulsified fats that increase endotoxin transport from the gut.

Edited by Darryl, 05 October 2016 - 11:48 PM.

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#3 normalizing

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Posted 09 October 2016 - 05:36 AM

"Some microsome and liposome forumlations to increase polyphenol bioavailability closely resemble the emulsified fats that increase endotoxin transport from the gut"


more detail information on this part if possible please

#4 Darryl

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Posted 09 October 2016 - 08:12 AM



The common thought on dietary polyphenols for 15 years has been "these have interesting effects in vitro, but are very poorly absorbed. Why don't we improve their oral bioavailability using an emulsion-like preparation (puting the polyphenol, a surfactant emulsifier, and sometimes lipid into a blender to make microscopic liposomes or micelles carrying the polyphenol in the interior). I erred above in mentioning microsomes (ER vesicles isolated in lab work), actual terms in use are "liposomes, proliposomes; micelles and micelle-based hybrid delivery systems; nanosuspensions; microemulsions; selfemulsifying, self-microemulsifying, and self-nanoemulsifying drug delivery systems" according to:


Lewandowska et al, 2013. Overview of metabolism and bioavailability enhancement of polyphenolsJournal of agricultural and food chemistry61(50), pp.12183-12199.


Biovailability can be improved with liposomal formulation, which is great, but what if the polyphenol is exerting its heath benefits primarily through effects on the gut microbiome, intestinal barrier, or through binding other gut chemical species (all found in studies). Then all the effort to improve intestinal absorption is besides the point. Moreover, emulsions don't just improve absorption of drugs of interest, they also drag along inflammatory bacterial detritus (endotoxins) from the gut, a topic I've been fascinated with for the past year or two.


Michalski et al, 2016. Dietary lipid emulsions and endotoxemiaOilseeds and Fats, Crops and Lipids23(3).

In the rat, we revealed that gavage with an emulsion of sunflower oil using soybean lecithin increased postprandial endotoxemia compared with gavage with the unemulsified sunflower oil. Moreover, postprandial endotoxin accumulation was positively correlated with that of plasma triglycerides after these different products. In the long term, we explored the impact of different lipid emulsifiers in the diet on metabolic inflammation. Mice were fed a high-fat diet containing 20% of lipids (mostly palm oil) or modified diets in which 1.2% of oil has been replaced with 1.2% soybean phospholipids or 1.2% milk phospholipids. The diet containing soybean phospholipids (commonly called soybean lecithin) induced adipose tissue hypertrophy and increased markers of inflammation, including circulating lipopolysaccharide-binding protein concentration and its expression by the adipose tissue, compared with the high fat diet devoid of phospholipids.


Giving it more thought, increased endotoxin uptake from liposome formulations isn't a valid concern, as the amount of liposomes used to enhance polyphenol bioavailability would tiny compared to the amount of fatty emulsions commonly consumed as homogenized milk, ice cream, mayonnaise, creamy dressings etc.


I will say that i've viewed almond milk, mayonnaise, etc. in a harsher light with the emulsion studies, as if endotoxins mediate much of the harm of high fat diets, then mayo could multiply the harms of its oil content several fold.



Edited by Darryl, 09 October 2016 - 08:17 AM.

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#5 Castiel

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Posted 17 October 2016 - 06:35 AM

Resveratrol activates other protective molecules besides sirt1 at near 1 thousandth of the dose, so it has multiple mechanisms of action, not all of the mechanisms have been fully elucidated, afaik.



The team's experiments showed, however, that the TyrRS-PARP-1 pathway can be measurably activated by much lower doses of resveratrol -- as much as 1,000 times lower -- than were used in some of the more celebrated prior studies, including those focused on SIRT1...TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6.-source link


It extended the lifespan of multiple simple life forms, even vertebrates.   It may be that failure in longer lived vertebrates is related to age related NAD depletion or it may not.

#6 bixbyte

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Posted 26 October 2016 - 07:49 PM

Here is some tied in Meta type info I found why obesity and the Gut bacteria and their influence of Liver and Adipose result in toxins that make Arteriosclerosis AS.

And this might all be benefited supplementing with what Dose? of Resveratrol that changes the Gut microbes that are transported through your liver and adipose.

Results in Inflammation that causes Heart Disease are cytokine based.



On a metabolic standpoint, both forms of CD14 are able to bind the LPS-LBP complex, which can then fix on the TLR4 receptor (toll-like receptor 4) and the co-receptor MD2 (myeloid differenciation protein-2) and then mediate signal transduction via the activation of NF-κB (Nuclear Factor-κB). This signalization cascade results in the secretion of proinflammatory cytokines (IL-6, TNF-α, IL-1β, etc.) (Fig. 1).





Edited by bixbyte, 26 October 2016 - 07:53 PM.

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#7 malbecman

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Posted 04 November 2016 - 05:23 PM

 Wow, that is certainly a different avenue of research into resveratrol's pleiotropic effects.  Thanks for sharing.    All roads do seem to lead to the gut microbiome....

#8 bixbyte

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Posted 07 November 2016 - 11:27 PM

Not exactly related except for Heart Disease.

Any opinions? Resveratrol reported to Reverse heart disease symptoms caused by Chagas?  

Need Efficacy studies how Resveratrol reversed Heart Disease?

Does Res change your Gut Microbiomes that leads to a healthy heart?

Maybe Res is a new therapy for Heart disease or Blockbuster in the future?



However, one third of people with Chagas disease eventually develop chronic Chagas cardiomyopathy, in which T. cruzidamages heart tissue and may eventually cause  arrhythmias and heart  failure.

Currently, there is no effective treatment to reverse heart damage in chronic Chagas cardiomyopathy. Based on previous evidence that T. cruzi harms the heart through oxidative stress, the group lead by Claudia N. Paiva from Universidade Federal do Rio de Janeiro, tested whether the antioxidant supplement resveratrol could combat this condition.


In the study, mice were infected with T. cruzi, and they quickly transitioned from initial symptoms to a chronic stage of heart damage. The researchers then treated the mice with resveratrol and monitored their hearts with electro- and echocardiography.

Resveratrol reversed mouse heart dysfunction in several measurable  ways, including improvement of heart pumping efficiency and the heart electrical cycle. It also reduced oxidative damage and decreased amounts of T. cruzi in the heart. These effects occurred even in mice treated late after infection (120-160 days after infection).



Edited by bixbyte, 07 November 2016 - 11:32 PM.

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#9 normalizing

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Posted 08 November 2016 - 03:36 AM

another mice study. any human studies yet please

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