Gut/Oral Bacteria Variability May Explain the High Efficacy of Green Tea in Rodent Tumor Inhibition and Its Absence in Humans

Consumption of green tea (GT) and GT polyphenols has prevented a range of cancers in rodents but has had mixed results in humans. Human subjects who drank GT for weeks showed changes in oral microbiome. However, GT-induced changes in RNA in oral epithelium were subject-specific, suggesting GT-induced changes of the oral epithelium occurred but differed across individuals. In contrast, studies in rodents consuming GT polyphenols revealed obvious changes in epithelial gene expression. GT polyphenols are poorly absorbed by digestive tract epithelium. Their metabolism by gut/oral microbial enzymes occurs and can alter absorption and function of these molecules and thus their bioactivity. This might explain the overall lack of consistency in oral epithelium RNA expression changes seen in human subjects who consumed GT. Each human has different gut/oral microbiomes, so they may have different levels of polyphenol-metabolizing bacteria. We speculate the similar gut/oral microbiomes in, for example, mice housed together are responsible for the minimal variance observed in tissue GT responses within a study. The consistency of the tissue response to GT within a rodent study eases the selection of a dose level that affects tumor rates. This leads to the theory that determination of optimal GT doses in a human requires knowledge about the gut/oral microbiome in that human.

[1]  J. Vincken,et al.  Reciprocal Interactions between Epigallocatechin-3-gallate (EGCG) and Human Gut Microbiota In Vitro , 2020, Journal of agricultural and food chemistry.

[2]  A. Rahmani,et al.  Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer , 2020, Molecules.

[3]  A. Atanasov,et al.  Health Functions and Related Molecular Mechanisms of Tea Components: An Update Review , 2019, International journal of molecular sciences.

[4]  A. Minihane,et al.  Future prospects for dissecting inter-individual variability in the absorption, distribution and elimination of plant bioactives of relevance for cardiometabolic endpoints , 2019, European Journal of Nutrition.

[5]  P. Stehle,et al.  Microbial Metabolites of Flavan-3-Ols and Their Biological Activity , 2019, Nutrients.

[6]  D. Angelino,et al.  Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. , 2019, Natural product reports.

[7]  Yuerong Liang,et al.  Inhibitory Effects of (−)-Epigallocatechin-3-gallate on Esophageal Cancer , 2019, Molecules.

[8]  J. Griffin,et al.  Inter-individual variability in the production of flavan-3-ol colonic metabolites: preliminary elucidation of urinary metabotypes , 2019, European Journal of Nutrition.

[9]  Yuerong Liang,et al.  Bioavailability of Tea Catechins and Its Improvement , 2018, Molecules.

[10]  A. Goldstein,et al.  Microbiome Composition in Both Wild-Type and Disease Model Mice Is Heavily Influenced by Mouse Facility , 2018, Front. Microbiol..

[11]  J. Vincken,et al.  Green and Black Tea Phenolics: Bioavailability, Transformation by Colonic Microbiota, and Modulation of Colonic Microbiota. , 2018, Journal of agricultural and food chemistry.

[12]  W. Reygaert Green Tea Catechins: Their Use in Treating and Preventing Infectious Diseases , 2018, BioMed research international.

[13]  M. Garcia-Conesa,et al.  Critical Evaluation of Gene Expression Changes in Human Tissues in Response to Supplementation with Dietary Bioactive Compounds: Moving Towards Better-Quality Studies , 2018, Nutrients.

[14]  K. Kaliannan,et al.  Green Tea Liquid Consumption Alters the Human Intestinal and Oral Microbiome , 2018, Molecular nutrition & food research.

[15]  Xiaofeng Meng,et al.  Effects of gut microbiota and time of treatment on tissue levels of green tea polyphenols in mice , 2018, BioFactors.

[16]  C. Lutz,et al.  Acclimation and Institutionalization of the Mouse Microbiota Following Transportation , 2018, Front. Microbiol..

[17]  Jinbao Liu,et al.  Perspectives on the recent developments with green tea polyphenols in drug discovery , 2018, Expert opinion on drug discovery.

[18]  Jessica L. Tang,et al.  Effects of green tea on miRNA and microbiome of oral epithelium , 2018, Scientific Reports.

[19]  T. Nielsen,et al.  Impact of a vegan diet on the human salivary microbiota , 2018, Scientific Reports.

[20]  Eivind Almaas,et al.  A composite network of conserved and tissue specific gene interactions reveals possible genetic interactions in glioma , 2017, PLoS Comput. Biol..

[21]  G. Williamson,et al.  Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols , 2017, Biochemical pharmacology.

[22]  J. Espín,et al.  The gut microbiota: A key factor in the therapeutic effects of (poly)phenols , 2017, Biochemical pharmacology.

[23]  Jian-Min Yuan,et al.  Effect of Green Tea Supplements on Liver Enzyme Elevation: Results from a Randomized Intervention Study in the United States , 2017, Cancer Prevention Research.

[24]  Jessica L. Tang,et al.  Improving accuracy of RNA-based diagnosis and prognosis of oral cancer by using noninvasive methods. , 2017, Oral oncology.

[25]  S. A. Jacob,et al.  The Effect of Green Tea Consumption on Prostate Cancer Risk and Progression: A Systematic Review , 2017, Nutrition and cancer.

[26]  H. Mo,et al.  Therapeutic properties of green tea against environmental insults. , 2017, The Journal of nutritional biochemistry.

[27]  A. Minihane,et al.  The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids , 2016, The American journal of clinical nutrition.

[28]  Y. Yamashita,et al.  The oral microbiome and human health. , 2017, Journal of oral science.

[29]  Hong Wang,et al.  Cancer Preventive Activities of Tea Catechins , 2016, Molecules.

[30]  D. Otzen,et al.  Epigallocatechin Gallate Remodels Overexpressed Functional Amyloids in Pseudomonas aeruginosa and Increases Biofilm Susceptibility to Antibiotic Treatment* , 2016, The Journal of Biological Chemistry.

[31]  J. Messenger,et al.  Impact of Proton Pump Inhibitor Use on the Comparative Effectiveness and Safety of Prasugrel Versus Clopidogrel: Insights From the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE‐ACS) Study , 2016, Journal of the American Heart Association.

[32]  S. Zeissig,et al.  Analysis of factors contributing to variation in the C57BL/6J fecal microbiota across German animal facilities. , 2016, International journal of medical microbiology : IJMM.

[33]  P. Saha,et al.  Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice. , 2016, Toxicology and applied pharmacology.

[34]  Hong Wang,et al.  Lessons learned from cancer prevention studies with nutrients and non-nutritive dietary constituents. , 2016, Molecular nutrition & food research.

[35]  M. Westerterp-Plantenga,et al.  Long-Term Green Tea Supplementation Does Not Change the Human Gut Microbiota , 2016, PloS one.

[36]  R. Mckinnon,et al.  Manipulation of the gut microbiota using resistant starch is associated with protection against colitis-associated colorectal cancer in rats. , 2016, Carcinogenesis.

[37]  A. Braune,et al.  Bacterial species involved in the conversion of dietary flavonoids in the human gut , 2016, Gut microbes.

[38]  A. Goel,et al.  Epigallocatechin-3-gallate targets cancer stem-like cells and enhances 5-fluorouracil chemosensitivity in colorectal cancer , 2016, Oncotarget.

[39]  E. Çapanoğlu,et al.  The Reciprocal Interactions between Polyphenols and Gut Microbiota and Effects on Bioaccessibility , 2016, Nutrients.

[40]  J. Raes,et al.  Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design , 2015, FEMS microbiology reviews.

[41]  C. Panda,et al.  Tea polyphenols epigallocatechin gallete and theaflavin restrict mouse liver carcinogenesis through modulation of self-renewal Wnt and hedgehog pathways. , 2016, The Journal of nutritional biochemistry.

[42]  G. Panagiotou,et al.  A Molecular-Level Landscape of Diet-Gut Microbiome Interactions: Toward Dietary Interventions Targeting Bacterial Genes , 2015, mBio.

[43]  Akiko Takagaki,et al.  Effects of Metabolites Produced from (-)-Epigallocatechin Gallate by Rat Intestinal Bacteria on Angiotensin I-Converting Enzyme Activity and Blood Pressure in Spontaneously Hypertensive Rats. , 2015, Journal of agricultural and food chemistry.

[44]  Akiko Takagaki,et al.  Bioconversion of (-)-epicatechin, (+)-epicatechin, (-)-catechin, and (+)-catechin by (-)-epigallocatechin-metabolizing bacteria. , 2015, Biological & pharmaceutical bulletin.

[45]  B. Bartolomé,et al.  A Survey of Modulation of Gut Microbiota by Dietary Polyphenols , 2015, BioMed research international.

[46]  J. Lambert,et al.  Differential prooxidative effects of the green tea polyphenol, (-)-epigallocatechin-3-gallate, in normal and oral cancer cells are related to differences in sirtuin 3 signaling. , 2015, Molecular nutrition & food research.

[47]  A. Collins,et al.  Redox-linked effects of green tea on DNA damage and repair, and influence of microsatellite polymorphism in HMOX-1: results of a human intervention trial. , 2015, Mutagenesis.

[48]  Hong Wang,et al.  Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer , 2014, BMC Genomics.

[49]  N. Chia,et al.  Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility , 2014, Microbiome.

[50]  Christine Morand,et al.  Interindividual variation in response to consumption of plant food bioactives and determinants involved (POSITIVe) , 2014 .

[51]  I. Benzie,et al.  Effects of single dose and regular intake of green tea (Camellia sinensis) on DNA damage, DNA repair, and heme oxygenase-1 expression in a randomized controlled human supplementation study. , 2014, Molecular nutrition & food research.

[52]  B. Halliwell Cell culture, oxidative stress, and antioxidants: Avoiding pitfalls , 2014, Biomedical journal.

[53]  B. Hennig,et al.  Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes. , 2014, The Journal of nutritional biochemistry.

[54]  Mina Sakuma,et al.  Effect of dietary supplementation of (-)-epigallocatechin gallate on gut microbiota and biomarkers of colonic fermentation in rats. , 2014, Journal of nutritional science and vitaminology.

[55]  Se Jin Song,et al.  Cohabiting family members share microbiota with one another and with their dogs , 2013, eLife.

[56]  M. Fani,et al.  Inhibitory Activity of Green Tea (Camellia sinensis) Extract on Some Clinically Isolated Cariogenic and Periodontopathic Bacteria , 2013, Medical Principles and Practice.

[57]  J. Buer,et al.  Anti‐infective properties of epigallocatechin‐3‐gallate (EGCG), a component of green tea , 2013, British journal of pharmacology.

[58]  Falk Hildebrand,et al.  Inflammation-associated enterotypes, host genotype, cage and inter-individual effects drive gut microbiota variation in common laboratory mice , 2013, Genome Biology.

[59]  M. Hattori,et al.  Isolation and characterization of a human intestinal bacterium Eggerthella sp. CAT-1 capable of cleaving the C-ring of (+)-catechin and (-)-epicatechin, followed by p-dehydroxylation of the B-ring. , 2012, Biological & pharmaceutical bulletin.

[60]  P. Zheng,et al.  Green tea consumption and risk of esophageal cancer: a meta-analysis of epidemiologic studies , 2012, BMC Gastroenterology.

[61]  Y. Benno,et al.  Effects of green tea consumption on human fecal microbiota with special reference to Bifidobacterium species , 2012, Microbiology and immunology.

[62]  Rob Knight,et al.  Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood , 2012, Genome research.

[63]  B. Bartolomé,et al.  Capability of Lactobacillus plantarum IFPL935 to catabolize flavan-3-ol compounds and complex phenolic extracts. , 2012, Journal of agricultural and food chemistry.

[64]  E. Choi,et al.  Green tea (-)-epigallocatechin-3-gallate inhibits HGF-induced progression in oral cavity cancer through suppression of HGF/c-Met. , 2011, The Journal of nutritional biochemistry.

[65]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[66]  A. Braune,et al.  Isolation of catechin‐converting human intestinal bacteria , 2011, Journal of applied microbiology.

[67]  Hong Wang,et al.  Mechanistic issues concerning cancer prevention by tea catechins. , 2011, Molecular nutrition & food research.

[68]  V. Adhami,et al.  Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[69]  N. Pace,et al.  Disease phenotype and genotype are associated with shifts in intestinal‐associated microbiota in inflammatory bowel diseases , 2011, Inflammatory bowel diseases.

[70]  N. Pellegrini,et al.  Bioavailability and catabolism of green tea flavan-3-ols in humans. , 2010, Nutrition.

[71]  A. Fuente,et al.  From ‘differential expression’ to ‘differential networking’ – identification of dysfunctional regulatory networks in diseases , 2010 .

[72]  Akiko Takagaki,et al.  Metabolism of (-)-epigallocatechin gallate by rat intestinal flora. , 2010, Journal of agricultural and food chemistry.

[73]  Diane D. Liu,et al.  Phase II Randomized, Placebo-Controlled Trial of Green Tea Extract in Patients with High-Risk Oral Premalignant Lesions , 2009, Cancer Prevention Research.

[74]  Markus Horneber,et al.  Green tea (Camellia sinensis) for the prevention of cancer. , 2009, The Cochrane database of systematic reviews.

[75]  Xin Wang,et al.  Cancer prevention by tea: animal studies, molecular mechanisms and human relevance , 2009, Nature Reviews Cancer.

[76]  Takuji Tanaka,et al.  (−)-Epigallocatechin Gallate Suppresses Azoxymethane-Induced Colonic Premalignant Lesions in Male C57BL/KsJ-db/db Mice , 2008, Cancer Prevention Research.

[77]  B. Halliwell Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies? , 2008, Archives of biochemistry and biophysics.

[78]  S. Narayan,et al.  Chemopreventive and therapeutic modulation of green tea polyphenols on drug metabolizing enzymes in 4-Nitroquinoline 1-oxide induced oral cancer. , 2008, Chemico-biological interactions.

[79]  Chung S. Yang,et al.  Green tea polyphenols inhibit colorectal aberrant crypt foci (ACF) formation and prevent oncogenic changes in dysplastic ACF in azoxymethane-treated F344 rats. , 2007, Carcinogenesis.

[80]  A. Tamakoshi,et al.  A prospective study of green tea consumption and oral cancer incidence in Japan. , 2007, Annals of epidemiology.

[81]  Gang Lu,et al.  Inhibition of Intestinal Tumorigenesis in Apc Min/+ Mice by Green Tea Polyphenols (Polyphenon E) and Individual Catechins , 2007, Nutrition and cancer.

[82]  Shu-Chun Lin,et al.  The repressive effect of green tea ingredients on amyloid precursor protein (APP) expression in oral carcinoma cells in vitro and in vivo. , 2007, Cancer letters.

[83]  Andy H. Lee,et al.  Does the Consumption of Green Tea Reduce the Risk of Lung Cancer Among Smokers? , 2006, Evidence-based complementary and alternative medicine : eCAM.

[84]  D. Threadgill,et al.  Quantitative PCR assays for mouse enteric flora reveal strain-dependent differences in composition that are influenced by the microenvironment , 2006, Mammalian Genome.

[85]  Yuan-Kun Lee,et al.  Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. , 2006, Research in microbiology.

[86]  Ming You,et al.  A gene expression signature that can predict green tea exposure and chemopreventive efficacy of lung cancer in mice. , 2006, Cancer research.

[87]  E. Fiala,et al.  Induction of preneoplastic lung lesions in guinea pigs by cigarette smoke inhalation and their exacerbation by high dietary levels of vitamins C and E. , 2005, Carcinogenesis.

[88]  J. Liao,et al.  Information Of Lung Tumorigenesis By Tea , 2004, Experimental lung research.

[89]  Joseph Rafter,et al.  Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not? , 2005, The American journal of clinical nutrition.

[90]  A. Scalbert,et al.  Metabolism of dietary procyanidins in rats. , 2003, Free radical biology & medicine.

[91]  C. Dawes,et al.  Estimates, from salivary analyses, of the turnover time of the oral mucosal epithelium in humans and the number of bacteria in an edentulous mouth. , 2003, Archives of oral biology.

[92]  Richard M. Simon,et al.  Methods for assessing reproducibility of clustering patterns observed in analyses of microarray data , 2002, Bioinform..

[93]  Chi Han,et al.  Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters by tea and curcumin. , 2002, Carcinogenesis.

[94]  L. Juneja,et al.  Improvement of intestinal microflora balance and prevention of digestive and respiratory organ diseases in calves by green tea extracts , 2001 .

[95]  H. Witschi,et al.  SUCCESSFUL AND NOT SO SUCCESSFUL CHEMOPREVENTION OF TOBACCO SMOKE-INDUCED LUNG TUMORS , 2000, Experimental lung research.

[96]  J. Chen,et al.  The chemopreventive effects of tea on human oral precancerous mucosa lesions. , 1999, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[97]  J. Chen,et al.  Tea preparations protect against DMBA-induced oral carcinogenesis in hamsters. , 1999, Nutrition and cancer.

[98]  Laishun Chen,et al.  Human salivary tea catechin levels and catechin esterase activities: implication in human cancer prevention studies. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[99]  N. Willits,et al.  The effects of phenethyl isothiocyanate, N-acetylcysteine and green tea on tobacco smoke-induced lung tumors in strain A/J mice. , 1998, Carcinogenesis.

[100]  May-Chen Kuo,et al.  Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[101]  S. Wiseman,et al.  The chemistry of tea flavonoids. , 1997, Critical reviews in food science and nutrition.

[102]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[103]  Y. Hara Influence of tea catechins on the digestive tract , 1997, Journal of cellular biochemistry. Supplement.

[104]  V. Steele,et al.  Effects of theaflavins on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis. , 1997, Nutrition and cancer.

[105]  T. Mitsuoka,et al.  Effect of tea polyphenols on fecal flora and fecal metabolic products of pigs. , 1995, The Journal of veterinary medical science.

[106]  J K McLaughlin,et al.  Reduced risk of esophageal cancer associated with green tea consumption. , 1994, Journal of the National Cancer Institute.

[107]  T. Mitsuoka,et al.  In Vivo Effects of Tea Polyphenol Intake on Human Intestinal Microflora and Metabolism. , 1992, Bioscience, biotechnology, and biochemistry.