Grape Seed Extract and The Gut Microbiota – A New Understanding of The Interplays and Their Impact on Health

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GrapeseedGrape seed extract by no means is “new” to the nutraceutical world, however, we are learning more about the potential broad benefits of this antioxidant-like nutritional compound, and starting to gain broader knowledge of mechanisms by which individual responses to this substance may vary. Grape seed extract is high in antioxidants in the form of polyphenols, which contribute to its potential therapeutic action.[i]  Resveratrol, the grape’s greatest claim to fame, is found primarily in the skins of grapes, with gallic acid, catechin, and epicatechin being the main polyphenols found in GSE.[ii] The amount of each of these substances in Grape seed extract varies widely by the variety of grape from which the seeds are sourced. Studies have shown that some of the compounds sourced from grapes, such as catechin and epicatechin, have a synergistic antioxidant effect.[iii]

The bioavailability of polyphenols varies, and studies have shown that there is very little relation between the quantity of polyphenols in foods and their bioavailability in human body.[iv] One of the factors that plays a significant role in the absorption and availability of these compounds is the intestinal micro-environment – the enzymes present and the intestinal flora.[v] In the process of absorption, polyphenols are modified significantly, being conjugated both in intestines and the liver by methylation, sulphation and/or glucuronidation.[vi] Thus, quantifying bioavailability also requires assessing various metabolites and their levels in blood as well as the tissues. Many of these metabolites may possess more bioactivity than their precursors, shedding light on the importance of their quantification.[vii] Polyphenols also impact the balance of gastrointestinal flora, a mechanism by which their effects may be seen, but also another factor which may contribute to variable bioavailability.[viii] In circulation, polyphenol metabolites bind to blood proteins, primarily albumin, which also affects their bioavailability in the tissues.[ix] Studies suggest that some albumin-bound polyphenols are capable of having biological activity, but it is unknown if this is true for all polyphenols or if these substances need to be in their free, unbound form.[x],[xi]

The polyphenols derived from Grape seed extract are no different from the group as a whole, and we are starting to understand that the variability that has been seen in the efficacy of these compounds for a variety of conditions such as hypertension may be due to differences in metabolism and biological levels of the bioactive metabolites. A wide variety of factors have been shown to influence this, including gender,[xii] age,[xiii] and health status.[xiv]

Substantial differences in the metabolism and distribution of Grape seed extract -derived polyphenols have been observed between male and female rats.12 The plasma, liver, and brain distribution and types of flavanol metabolites has been shown to be significantly different. The only tissue in which similarities was seen was mesenteric white adipose tissue. As an example, in the plasma of male rats the distribution of polyphenol was 64% glucuronidated metabolites, 20% methyl-glucuronidated metabolites, and 7% methylated-sulphated metabolites, followed by lower levels of other metabolites while in females the distribution of these same metabolites was 56%, 12%, and 20% respectfully.  Differences as remarkable as this were also seen in the liver, while in the brain, there was even more stark differences as in males the primary fraction was methylated metabolites at 61% followed by 24% glucuronidated metabolites, while in females the level of methylated metabolites was below the detection threshold, with highest amounts of glucuronidated metabolites at 50% and the second highest category being flavanols at 34% (which were found to be 6% in the males).  These significant differences were suggested to be due to the modulating effect that progesterone and oestrogen may have on uptake of flavanols through the blood-brain barrier as well as differences in catechol-o-methyltransferase (COMT) activity between males and females in the brain.[xv],[xvi]

Age, as a second factor of consideration, also has been shown to contribute to significant differences between young and older (adult) rats.13 Factors which are anticipated to impact polyphenol metabolism with age are gastrointestinal bacterial population, liver and kidney function as well as circulatory volume, and expression and activity of xenobiotic metabolizing enzymes.[xvii] In a gender-limited population of male rats, total flavanol concentration in plasma was found to be about 3 times lower in adult rats than that of the young rats in the 2 – 7 hour time period after dosage. However, the older rats were shown to have much higher concentrations of GSE microbial metabolites at all time points, suggested to be because reduced absorption in the small intestine allowed more of the GSE compounds to reach the large intestine intact and available for microbiota metabolism. Additionally, the plasma levels of phase II flavanol metabolites were found to decrease much faster in young rats.

Finally, health status also has been shown to impact Grape seed extract flavanol bioavailability and metabolism.14 In spontaneously hypertensive rats, oral administration of Grape seed extract was shown to lead to a significant reduction in blood pressure at 6 hours post-consumption, while it didn’t impact the blood pressure of healthy rats. Although total plasma flavanol metabolites showed similar levels, quantitative and qualitative differences in microbial metabolites were shown in the healthy and disease state. The most noteworthy differences were plasma gallic acid levels, which were found to be approximately 10 times more concentrated in diseased rats, and methyl-epicatechin-O-sulfate which was 4 times higher in diseased than in healthy rats.  Additionally, some flavanol microbial metabolites were shown to be increased in the aortas of spontaneously hypertensive rats compared to healthy rats, although aorta total concentrations were lower in the diseased rat population.

The more we understand the impact that our microbiota has on our health, the more this understanding opens up further study of how diet and botanically derived substances may affect us each, individually.[xviii] There is no doubt that studies such as this will continue to further pique our interest in further understanding of the impacts of nutritional substances on our health, and in cases such as GSE more directed application of these findings.


[i] Shi J, et al. Polyphenolics in grape seeds-biochemistry and functionality. J Med Food. 2003 Winter;6(4):291-9. View Abstract

[ii] Yilmaz Y, Toledo RT. Major flavonoids in grape seeds and skins: antioxidant capacity of catechin, epicatechin, and gallic acid. J Agric Food Chem. 2004 Jan 28;52(2):255-60. View Abstract

[iii] Iacopini P, et al. Catechin, epicatechin, quercetin, rutin and resveratrol in red grape: Content, in vitro antioxidant activity and interactions. Journal of Food Composition and Analysis. 2008 Dec 31;21(8):589-98. View Abstract

[iv] Manach C, et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004 May;79(5):727-47. View Full Paper

[v] Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009 Nov-Dec;2(5):270-8. View Full Paper

[vi] Day AJ, Williamson G. Biomarkers for exposure to dietary flavonoids: a review of the current evidence for identification of quercetin glycosides in plasma. Br J Nutr. 2001 Aug;86 Suppl 1:S105-10. View Abstract

[vii] Chiou YS, et al. Metabolic and colonic microbiota transformation may enhance the bioactivities of dietary polyphenols. J Func Foods. 2014 Mar 31;7:3-25. View Abstract

[viii] Ozdal T, et al. The Reciprocal Interactions between Polyphenols and Gut Microbiota and Effects on Bioaccessibility. Nutrients. 2016 Feb 6;8(2):78. View Full Paper

[ix] Dangles O, et al. Binding of flavonoids to plasma proteins. Methods Enzymol. 2001;335:319-33. View Abstract

[x] Dufour C, et al. Inhibition of the peroxidation of linoleic acid by the flavonoid quercetin within their complex with human serum albumin. Free Radic Biol Med. 2007;43:241–252. View Abstract

[xi] Filipe P, et al. Albumin-bound quercetin repairs vitamin E oxidized by apolipoprotein radicals in native HDL3 and LDL. Biochemistry. 2007 Dec 11;46(49):14305-15. View Abstract

[xii] Margalef M, et al. Gender-related similarities and differences in the body distribution of grape seed flavanols in rats. Mol Nutr Food Res. 2016 Apr;60(4):760-72. View Full Paper

[xiii] Margalef M, et al. Age related differences in the plasma kinetics of flavanols in rats. J Nutr Biochem. 2016 Mar;29:90-6. View Abstract

[xiv] Margalef M, et al. Rat health status affects bioavailability, target tissue levels, and bioactivity of grape seed flavanols. Mol Nutr Food Res. 2017 Feb;61(2). View Abstract

[xv] Faria A, et al. Insights into the putative catechin and epicatechin transport across blood-brain barrier. Food Funct. 2011;2(1):39-44. View Full Paper

[xvi] Harrison PJ, Tunbridge EM. Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology. 2008 Dec 1;33(13):3037-45. View Full Paper

[xvii] Lee JS, et al. Coordinated changes in xenobiotic metabolizing enzyme gene expression in aging male rats. Toxicol Sci. 2008 Nov;106(1):263-83. View Abstract

[xviii] Chen F, et al. Could the gut microbiota reconcile the oral bioavailability conundrum of traditional herbs? J Ethnopharmacol. 2016 Feb 17;179:253-64. View Full Paper

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