Gut-level Antiinflammatory Activities of Green Tea in Metabolic Syndrome

Overview

This study evaluates dietary green tea extract to improve gut health and inflammation in persons with metabolic syndrome and healthy adults. Participants will complete two phases of intervention in random order in which they will consume green tea extract or placebo for one month and then switch to the opposite treatment for an additional month.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Prevention
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: March 1, 2021

Detailed Description

Tea is the most abundantly consumed prepared beverage in the world. Green tea, containing catechins, exerts antiinflammatory activities. However, a fundamental gap exists concerning its intestinal-level targets that can prevent metabolic syndrome (MetS) development and progression. Studies in obese rodents indicate that green tea inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activation by limiting gut-derived endotoxin translocation to the portal circulation and decreasing hepatic Toll-like receptor-4 (TLR4) pro-inflammatory signaling. The objective of this clinical investigation is to establish evidence-based recommendations for green tea, based on improvements in endotoxemia and restored gut barrier function, that promote optimal health. The hypothesis is that green tea catechins function to limit metabolic endotoxemia by ameliorating gut dysbiosis-mediated inflammation that otherwise provokes intestinal permeability. This will be tested by conducting a double-blind, placebo-controlled, randomized-order, crossover trial in MetS and healthy persons to examine the efficacy of green tea on metabolic endotoxemia. Each treatment will be one-month in duration and separated by a washout period. The anticipated outcomes are expected to be of significance, because they will advance a dietary strategy to help avert MetS complications attributed to metabolic endotoxemia by establishing antiinflammatory prebiotic and antimicrobial bioactivities of catechins that promote intestinal health.

Interventions

  • Dietary Supplement: Green Tea Extract
    • A gummy confection with catechin-rich green tea extract (1 g/d)
  • Dietary Supplement: Placebo
    • A matched gummy confection formulated without green tea extract

Arms, Groups and Cohorts

  • Experimental: Green Tea
    • Participants consuming gummy confections with catechin-rich green tea extract daily for 4 weeks
  • Placebo Comparator: Placebo
    • Participants consuming matched gummy confections formulated without green tea extract daily for 4 weeks

Clinical Trial Outcome Measures

Primary Measures

  • Change in metabolic endotoxemia
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Serum endotoxin concentration (EU/mL) will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.

Secondary Measures

  • Gastrointestinal permeability
    • Time Frame: Day 28 of the 28-day intervention
    • Lactulose/mannitol ratio will be measured in urine collected 0-5 h post-ingestion to assess small intestinal permeability. Sucralose (%) will be measured in urine collected 0-24 h post-ingestion to assess colonic permeability. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Plasma inflammatory biomarker: C-reactive protein
    • Time Frame: Day 28 of the 28-day intervention
    • Plasma concentration (mg/L) of C-reactive protein will be measured at the end of each treatment. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Plasma inflammatory biomarkers: interleukin-6, interleukin-8, and tumor necrosis factor alpha
    • Time Frame: Day 28 of the 28-day intervention
    • Plasma concentrations (pg/mL) of interleukin-6, interleukin-8, and tumor necrosis factor alpha will be measured individually at the end of each treatment. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Plasma inflammatory biomarker: myeloperoxidase
    • Time Frame: Day 28 of the 28-day intervention
    • Plasma concentration (ng/mL) of myeloperoxidase will be measured at the end of each treatment. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Pro-inflammatory gene expression from peripheral blood mononuclear cells
    • Time Frame: Day 28 of the 28-day intervention
    • Relative expression of toll-like receptor 4, myeloid differentiation factor 88, p65 subunit of NF-kappa B, interleukin-6, interleukin-8, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 will be measured individually at the end of each treatment. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Intestinal inflammatory biomarker: calprotectin
    • Time Frame: Days 25-27 of the 28-day intervention
    • Fecal concentration (μg/g) of calprotectin will be measured in samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Intestinal inflammatory biomarker: myeloperoxidase
    • Time Frame: Days 25-27 of the 28-day intervention
    • Fecal concentration (ng/g) of myeloperoxidase will be measured in samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Changes in plasma catechins and their metabolites
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Plasma concentrations (nmol/L) of epigallocatechin gallate, epicatechin gallate, epigallocatechin, epicatechin, gamma-valerolactones, and catechin-derivates will be measured individually at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Fecal catechins and their metabolites
    • Time Frame: Days 25-27 of the 28-day intervention
    • Fecal concentrations (μmol/kg) of epigallocatechin gallate, epicatechin gallate, epigallocatechin, epicatechin, gamma-valerolactones, and catechin-derivates will be measured individually in samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Fecal short-chain fatty acids
    • Time Frame: Days 25-27 of the 28-day intervention
    • Fecal concentrations (mmol/kg) of butyrate, acetate, propionate, isobutyric acid, and isovaleric acid will be measured individually in samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Gut microbiota diversity indices
    • Time Frame: Days 25-27 of the 28-day intervention
    • Gut microbiota diversity indices (Shannon species and Chao1) will be measured in fecal samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Gut microbiota Firmicutes/Bacteroidetes ratio
    • Time Frame: Days 25-27 of the 28-day intervention
    • Gut microbiota Firmicutes/Bacteroidetes ratio will be measured in fecal samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Gut microbiota relative abundance
    • Time Frame: Days 25-27 of the 28-day intervention
    • Gut microbiota relative abundance (% order, genus, and species level) will be measured in fecal samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Gut microbiota function proportions
    • Time Frame: Days 25-27 of the 28-day intervention
    • Gut microbiota function proportions (%) based on microbial genome analysis will be measured in fecal samples collected over 3 consecutive days and pooled prior to analysis. Between-treatment differences will be measured in MetS vs. healthy individuals.
  • Change in plasma glucose
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Plasma concentration (mg/dL) of glucose will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Change in plasma insulin
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Plasma concentration (μIU/mL) of insulin will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Change in plasma lipids
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Plasma concentrations (mg/dL) of triglyceride and HDL-cholesterol will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Changes in serum alanine transaminase and aspartate transaminase
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Serum concentrations (U/L) of alanine transaminase and aspartate transaminase will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Changes in serum creatinine and blood urea nitrogen
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Serum concentrations (U/L) of creatinine and blood urea nitrogen will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.
  • Change in blood hematocrit
    • Time Frame: Day 0, 14, and 28 of the 28-day intervention
    • Blood hematocrit (%) will be measured at the beginning, in the middle, and at the end of each treatment. Time-dependent changes relative to baseline (day 0) in each treatment and between-treatment differences will be measured in MetS vs. healthy individuals.

Participating in This Clinical Trial

Inclusion Criteria

Individuals with ≥3 of the following established criteria for metabolic syndrome:

  • Fasting glucose 100-126 mg/dL – Waist circumference >89/>102 cm for females/males – HDL-C <50/<40 mg/dL for females/males – Triglyceride >150 mg/dL – Blood pressure >130/85 mmHg Healthy adults: – Body weight 19-25 kg/m2 – Fasting glucose <100 mg/dL – HDL-C >50/>40 mg/dL for females/males – Triglyceride <150 mg/dL – Blood pressure <120/80 mmHg Exclusion criteria:

  • Concurrent tea consumption – Use of dietary supplements, prebiotics, or probiotics – Use of antibiotics or antiinflammatory agents – History of liver disease, cardiovascular disease, hypertension (blood pressure >140/90 mmHg), or cancer – History of gastrointestinal disorders, chronic diarrhea, or surgeries – Hemochromatosis – Parkinson's disease – Use of medications to manage diabetes, hypertension, or hyperlipidemia – Use of antipsychotic medications [Clozapine, lithium, Diazepam] – Use of blood thinning medications [Warfarin] – Use of high blood pressure medications [nadolol] – Use of monoamine oxidase inhibitors [selegiline] – Alcohol consumption >2 drinks/d – Smoking tobacco – Vegetarian – Pregnancy, lactation, or recent changes in birth control use for women

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Ohio State University
  • Collaborator
    • USDA Beltsville Human Nutrition Research Center
  • Provider of Information About this Clinical Study
    • Principal Investigator: Richard Bruno, Principal Investigator – Ohio State University
  • Overall Official(s)
    • Richard S Bruno, PhD, RD, Principal Investigator, Ohio State University

References

Dey P, Sasaki GY, Wei P, Li J, Wang L, Zhu J, McTigue D, Yu Z, Bruno RS. Green tea extract prevents obesity in male mice by alleviating gut dysbiosis in association with improved intestinal barrier function that limits endotoxin translocation and adipose inflammation. J Nutr Biochem. 2019 May;67:78-89. doi: 10.1016/j.jnutbio.2019.01.017. Epub 2019 Feb 8.

Li J, Sasaki GY, Dey P, Chitchumroonchokchai C, Labyk AN, McDonald JD, Kim JB, Bruno RS. Green tea extract protects against hepatic NFkappaB activation along the gut-liver axis in diet-induced obese mice with nonalcoholic steatohepatitis by reducing endotoxin and TLR4/MyD88 signaling. J Nutr Biochem. 2018 Mar;53:58-65. doi: 10.1016/j.jnutbio.2017.10.016. Epub 2017 Nov 3.

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