Polyphenols as prebiotics

The gut is home to trillions of microbes collectively known as the gut microbiota. The growth of these microbes ultimately depends upon food entering via the host’s diet. Microbes directly metabolise food components and mucus lining the GI tract ¹, generated metabolites are further available to other microbes and the host ². In this way trophic chains underlie the symbiosis between microbes and the host. Not surprisingly then many food components have been shown to alter the balance and metabolic activities of the gut microbiota. Basic macronutrients (i.e. protein, carbohydrates and fats) can alter the balance and activity of specific bacterial communities ^3–5. Poorly digestible food components such as fibre pass through the entire intestines directly feeding bacteria. Soluble fibres in particular (e.g. FOS/inulin, GOS, MOS, etc.) are well known for their prebiotic effects (i.e. their ability to preferentially promote the growth of beneficial bacteria).

However less well recognised is the ability of other poorly absorbed plant phytochemicals such as polyphenols to modulate the gut microbiota. Polyphenols are a group of chemicals containing multiple phenol (C₆H₅OH) structural units. Phenolic compounds are abundant in many plant food stuffs highly revered for their health-promoting effects such as berries, green tea, cocoa and nuts ⁶. Common phenolic compounds include flavanols, flavonoids and anthrocyanins (for a full list see Wiki). Most polyphenols are poorly digested and have low bioavailability in humans although some can be partially absorbed ⁶. As such substantial quantities of polyphenols pass into the colon and are metabolised by the gut microbiota which can generate smaller absorbable molecules ^6–8. Several studies have begun to show that phenolic compounds exert prebiotic effects. Consumption of high-flavanol cocoa versus low-flavanol cocoa was reported to increase Lactobacilli and Bifidobacteria while decreasing Clostridia levels in humans ⁹. These microbial changes were paralleled by significant reductions in plasma triacylglycerol and C-reactive protein (CRP) concentrations ⁹. Blueberries (rich in anthocyanins) have been shown to possess prebiotic effects in vitro and in rats ^10,11. In humans consumption of a wild blueberry powder drink was shown to boost Bifidobacteria levels ¹². Consumption of red wine polyphenols increased the levels of several bacterial genera including Bifidobacteria which correlated changes to blood markers in humans ¹³. Selenium-rich green tea increased Lactobacilli and Bifidobacteria while decreasing Clostridia and Bacteroides levels in rats ¹⁴. Green tea consumption has also been reported to increase Bifidobacteria levels in humans ¹⁵. In an animal model of obesity administration of a polyphenol-rich extract of pomegranate peel increased Bifidobacteria levels and alleviated tissue inflammation and hypercholesterolaemia ¹⁶. In addition to the prebiotic effects reviewed above plant phenolic compounds have also been reported to preferentially inhibit important pathogens (e.g. Salmonella, C. perfringens, C. difficile and H. pylori) ^17–23.

Prebiotics have never (knowingly) been trialled in ME/CFS however it is notable that in a small study consumption of a high-cocoa/polyphenol-rich chocolate improved fatigue and mood symptoms in CFS patients ²⁴. Beneficial effects were attributed to the polyphenol content in this chocolate although it is not clear what the levels of other important nutrients were (e.g. magnesium). Polyphenols in cocoa do have some bioavailability and so could mediate some direct effects such as antioxidant activity  ⁶. However much of the polyphenol content in cocoa may pass into the colon ⁹. As described above cocoa exhibits robust prebiotic activity in humans which correlates with systemic blood markers ⁹. Indeed pre and probiotics favourably modulate many facets of host immune, metabolic and neurological function. The prebiotic effects of cocoa have been found to correlate with blood CRP levels ⁹; CRP is a marker of inflammation and is often slightly increased in ME/CFS ^25–28. Hence it seems logical to suppose the beneficial effects of cocoa reported in CFS patients may involve modulation of the gut microbiota.

References

1.         Kim, Y. S. & Ho, S. B. Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr. Gastroenterol. Rep. 12, 319–30 (2010).

2.         Bourriaud, C. et al. Lactate is mainly fermented to butyrate by human intestinal microfloras but inter-individual variation is evident. J. Appl. Microbiol. 99, 201–12 (2005).

3.         Brown, K., DeCoffe, D., Molcan, E. & Gibson, D. L. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4, 1095–119 (2012).

4.         Carbonero, F., Benefiel, A. C., Alizadeh-Ghamsari, A. H. & Gaskins, H. R. Microbial pathways in colonic sulfur metabolism and links with health and disease. Front. Physiol. 3, 448 (2012).

5.         Ghosh, S. et al. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis. PLoS One 8, e55468 (2013).

6.         Del Rio, D. et al. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal. 18, 1818–92 (2013).

7.         Bolca, S., Van de Wiele, T. & Possemiers, S. Gut metabotypes govern health effects of dietary polyphenols. Curr. Opin. Biotechnol. 24, 220–5 (2013).

8.         Van Duynhoven, J. et al. Metabolic fate of polyphenols in the human superorganism. Proc. Natl. Acad. Sci. U. S. A. 108 Suppl , 4531–8 (2011).

9.         Tzounis, X. et al. Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study. Am. J. Clin. Nutr. 93, 62–72 (2011).

10.       Molan, A., Lila, M. & Ravindran, G. Blueberries: Genotype-dependent variation in antioxidant, free-radical scavenging, and prebiotic activities. 427–434 (2010). at

11.       Molan, A. L., Lila, M. A., Mawson, J. & De, S. In vitro and in vivo evaluation of the prebiotic activity of water-soluble blueberry extracts. World J. Microbiol. Biotechnol. 25, 1243–1249 (2009).

12.       Vendrame, S. et al. Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the human gut. J. Agric. Food Chem. 59, 12815–20 (2011).

13.       Queipo-Ortuño, M. I. et al. Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am. J. Clin. Nutr. 95, 1323–34 (2012).

14.       Molan, A.-L., Liu, Z. & Tiwari, R. The ability of green tea to positively modulate key markers of gastrointestinal function in rats. Phytother. Res. 24, 1614–9 (2010).

15.       Jin, J.-S., Touyama, M., Hisada, T. & Benno, Y. Effects of green tea consumption on human fecal microbiota with special reference to Bifidobacterium species. Microbiol. Immunol. 56, 729–39 (2012).

16.       Neyrinck, A. M. et al. Polyphenol-rich extract of pomegranate peel alleviates tissue inflammation and hypercholesterolaemia in high-fat diet-induced obese mice: potential implication of the gut microbiota. Br. J. Nutr. 109, 802–9 (2013).

17.       Puupponen-Pimiä, R. et al. Antimicrobial properties of phenolic compounds from berries. J. Appl. Microbiol. 90, 494–507 (2001).

18.       Puupponen-Pimiä, R. et al. Berry phenolics selectively inhibit the growth of intestinal pathogens. J. Appl. Microbiol. 98, 991–1000 (2005).

19.       Chatterjee, A., Yasmin, T., Bagchi, D. & Stohs, S. J. Inhibition of Helicobacter pylori in vitro by various berry extracts, with enhanced susceptibility to clarithromycin. Mol. Cell. Biochem. 265, 19–26 (2004).

20.       Ankolekar, C. et al. Inhibitory potential of tea polyphenolics and influence of extraction time against Helicobacter pylori and lack of inhibition of beneficial lactic acid bacteria. J. Med. Food 14, 1321–9 (2011).

21.       Juneja, V. K., Bari, M. L., Inatsu, Y., Kawamoto, S. & Friedman, M. Control of Clostridium perfringens spores by green tea leaf extracts during cooling of cooked ground beef, chicken, and pork. J. Food Prot. 70, 1429–33 (2007).

22.       Taguri, T., Tanaka, T. & Kouno, I. Antimicrobial activity of 10 different plant polyphenols against bacteria causing food-borne disease. Biol. Pharm. Bull. 27, 1965–9 (2004).

23.       Lee, H. C., Jenner, A. M., Low, C. S. & Lee, Y. K. Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Res. Microbiol. 157, 876–84 (2006).

24.       Sathyapalan, T., Beckett, S., Rigby, A. S., Mellor, D. D. & Atkin, S. L. High cocoa polyphenol rich chocolate may reduce the burden of the symptoms in chronic fatigue syndrome. Nutr. J. 9, 55 (2010).

25.       Groeger, D. et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes 4, (2013).

26.       Spence, V. A., Kennedy, G., Belch, J. J. F., Hill, A. & Khan, F. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin. Sci. (Lond). 114, 561–6 (2008).

27.       Newton, D. J. et al. Large and small artery endothelial dysfunction in chronic fatigue syndrome. Int. J. Cardiol. 154, 335–6 (2012).

28.       Hokama, Y. et al. Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J. Clin. Lab. Anal. 22, 99–105 (2008).