Cocoa, Green Tea & Grape Seed | Polyphenols
Proanthocyanidins, or condensed tannins, are a class of polyphenols, including catechin and epicatechin and their esters. They are well-known for their antioxidant capacity, but more recent research also indicates their ability to alter the microbiome and the gastrointestinal environment.
Cocoa proanthocyanidins are metabolised down to catechin and epicatechin in the gut. Many animal studies have shown cocoa to reduce circulating endotoxin (1, 2), reduce inflammation, improve gut barrier function, and alter the microbiome (3).
Lipopolysaccharides (LPS) are the primary ligand for toll like receptor 4 (TLR4), which is found on the cell surface of immune cells, skeletal muscle and many other tissues. LPS binding to TLR4 initiates an inflammatory cascade that leads to nuclear translocation of nuclear factor kappa B (NF-κB), resulting in production of inflammatory cytokines. Poor gut barrier function may lead to elevated plasma endotoxin levels and metabolic disease (4).
In human studies, cocoa and cocoa flavanols improved insulin sensitivity and reduced blood glucose, insulin, HbA1c, oxidative stress and inflammation in subjects with varying degrees of glucose homeostasis (normoglycemic, pre-diabetic or T2DM) within 2–4 weeks (5-8).
It is unknown if reduced endotoxemia is due solely to alterations of the gut microbiota and barrier function, or if flavanols can directly bind and inactivate LPS in the gut, blood, or modulate LPS-TLR4 binding and downstream signalling at the levels of skeletal muscle cells.
Epidemiological studies show an inverse relationship of green tea consumption with risk of gastric cancers (9-11). The mechanisms may involve inhibition of Helicobacter pylori, the implicated microorganism in gastric carcinogenesis and the development of gastric and duodenal ulcers (12).
Tea catechins, particularly (_)-epigallocatechin gallate, inactivate urease (13). This enzyme is required for the conversion of urea into ammonia, which buffers the bacteria from digestion by gastric juice. In this way, tea catechins help to suppress proliferation of bacteria (14). Indeed, the incidence of gastric disorders and infection with H. pylori has been found to be lower in subjects who consumed tea regularly (15).
Green tea has been shown to be preventative of chronic active gastritis (16,17,18). Tea catechins reduce gastric levels of nitrosating substances and inhibits the formation of carcinogenic nitrosamines and nitrosamides (19). Green tea also inhibits the formation of heterocyclic amines (20).
Green tea inhibits the expression of cyclooxygenases and inducible nitric oxide synthase in colonic tissues, which are constantly found to be elevated in subjects with ulcerative colitis (21). Additionally, green tea polyphenols consistently inhibit cyclooxygenase-2 activity in human colon tumour tissue (22) and tea co-administration produced an enhancing effect with cyclooxygenase inhibitors (22, 23).
Green tea has also been shown to modulate the gut microbiota by selectively increasing the growth of Bifidobacteria and Lactobacilli in the gut wall (24, 25).
In vitro analysis showed grape seed to have the highest inhibitory activity of lipase and LPS binding compared to cranberry, avocado and apple, which strongly correlated with the proanthocyanidin content of the polyphenol extracts (p<0.001) (26).
In a mouse-model of menopause, grape seed extract was shown to normalise the ratio of Firmicutes:Bacteroidetes populations to that of control. Additionally, grape seed prevented ovariectomised animals from increasing body weight (27).
A parallel human trial (n=29 on normal weight and overweight subjects) confirmed the inhibitory activity of grape seed on LPS binding. The postprandial increase in plasma LPS was significantly prevented by the grape seed extract at 4 hours (p=0.0039), compared with placebo. When comparing normal weight with overweight subjects, grape seed extract significantly decreased LPS (p=0.0077), supporting the use of proanthocyanidins in the management of low-grade inflammation in the overweight population (26).
References1. Gu Y., Yu S., Park J.Y., et al. (2014) Dietary cocoa reduces metabolic endotoxemia and adipose tissue inflammation in high-fat fed mice. J Nutr Biochem 25:439–45
2. Dorenkott M.R., Griffin L.E., Goodrich K.M., et al. (2014) Oligomeric cocoa procyanidins possess enhanced bioactivity compared to monomeric and polymeric cocoa procyanidins for preventing the development of obesity, insulin resistance, and impaired glucose tolerance during high-fat feeding. J Agric Food Chem 62:2216–27
3. Massot-Cladera M., Perez-Berezo T., Franch A., et al. (2012) Cocoa modulatory effect on rat faecal microbiota and colonic crosstalk. Arch Biochem Biophys 527:105–12
4. Takeda K., Kaisho T., Akira S. (2003) Toll-like receptors. Annu Rev Immunol 21 335–76
5. Grassi D., Necozione S., Lippi C., et al. (2005) Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 46:398–405
6. Grassi D., Desideri G., Necozione S., et al. (2008) Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J Nutr 138:1671–6
7. Haghighat N., Rostami A., Eghtesadi S., et al. (2013) The effects of dark chocolate on glycemic control and blood pressure in hypertensive diabetic patients: a randomized clinical trial. Razi J Med Sci 20:78–86
8. Davison K., Coates A.M., Buckley J.D., et al. (2008) Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes (Lond) 32:1289–96
9. Gao C.M., Takezaki T., Wu, J.Z. et al. (2002) Glutathione-Stransferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case-control study of a high-incidence area in Jiangsu Province. China. Cancer Lett. 188, 95– 102
10. Inoue M., Tajima K., Hirose K., et al. (1998) Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan. Cancer Causes Control 9, 209– 216
11. Setiawan V.W., Zhang Z.F., Yu G.P., et al. (2001) Protective effect of green tea on the risks of chronic gastritis and stomach cancer. Int. J. Cancer 92, 600– 604
12. Graham D.Y., Lew G.M., Klein, P.D. (1992) Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer: randomized controlled study. Ann. Intern. Med. 116, 705–708
13. Matsubara S., Shibata H., Ishikawa F., et al. (2003) Suppression of Helicobacter pylori-induced gastritis by green tea extract in Mongolian gerbils. Biochem. Biophys. Res. Commun. 310, 715– 719
14. Tsujii M., Kawano S., Tsuju S., et al. (1992) Mechanism of gastric mucosal damage induced by ammonia. Gastroenterology 102, 1881–1888
15. Yee, Y.K., Koo, M.W.L., Szeto, M.L. (2002) Helicobacter pylori infection: risk and virulence. Chinese tea consumption and lower risk of Helicobacter infection. J. Gastroenterol. Hepatol. 17, 552– 555
16. Kuwahara Y., Kono S., Eguchi H. (2000) Relationship between serologically diagnosed chronic active gastritis, Helicobacter pylori and environmental factors in Japanese men. Scand. J. Gastroenterol. 35, 476
17. Setiawan V.W., Zhang Z.F., Yu G.P., et al. (2001) Protective effect of green tea on the risks of chronic gastritis and stomach cancer. Int. J. Cancer 92, 600– 604
18. Shibata K., Moriyama M., Fukushima T., et al. (2000) Green tea consumption and chronic active gastritis: a cross-sectional study in a green tea production village. J. Epidemiol. 10, 310– 316
19. Tanaka K., Hayatsu T., Negishi, T. (1998) Inhibition of nitrosation of secondary amines in vitro by tea extracts and catechins. Mutat. Res. 412, 91– 98
20. Weisburger J.H., Nagao M., Wakabayashi K., et al. (1994) Prevention of heterocyclic amine formation by tea and tea polyphenols. Cancer Lett. 83, 143– 147
21. Hendel J., Nielsen O.H. (1997) Expression of cyclooxygenase-2 mRNA in active inflammatory bowel disease. Am. J. Gastroenterol. 92, 1170– 1173
22. Ohishi T., Kishimoto Y., Miura N., et al. (2002) Synergistic effects of (_)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane. Cancer Lett. 177, 49–56
23. Suganuma M., Okabe S., Kai Y., et al. (1999) Synergistic effects of (_)-epigallocatechin gallate with (_)-epicatechin, Sulindac, or tamoxifen on cancer-preventive activity in human lung cancer cell line PC-9. Cancer Res. 59, 44– 47
24. Weisburger J.H., 1999. Tea and health: the underlying mechanisms. Proc. Soc. Exp. Biol. Med. 220, 271– 275.
25. Yamamoto T., Juneja L.R., Chu, D.C., et al. (1997) Chemistry and Applications of Green Tea. CRC Press LLC, Boca Raton, USA.
26. Bouhnik Y., Alain S., Attar A., et al. (1999). Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome. The American Journal of Gastroenterology, 94, 1327–1331
27. Guangwen J., Yoshinori A., Kirika I., et al. (2018). Proanthocyanidin-Rich Grape Seed Extract Modulates Intestinal Microbiota in Ovariectomized Mice. Jour. Food Sci. 83.