Assessing Gut Microbiota Mediated Health Outcomes of Whole Wheat and Its Major Bioactive Components

Sponsor

Ohio State University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05318183

Collaborator

USDA Beltsville Human Nutrition Research Center (U.S. Fed)

Enrollment

Location

Arms

34.1

Anticipated Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will investigate the gut microbiota-mediated effects of whole wheat consumption on human health in adults with pre-diabetes. Participants will complete two phases of intervention in random order in which they will consume either whole wheat bread (4 servings) or white bread a day for two weeks prior to collecting specimens (stool, urine, and plasma/serum).

Condition or Disease	Intervention/Treatment	Phase
PreDiabetes Dysbiosis Endotoxemia Inflammation	Other: Whole Wheat Bread Other: White Bread (control)	N/A

Detailed Description

Accumulating clinical evidence suggests positive effects of whole grain on cardiometabolic risk. However, outcomes of controlled trials indicate that substantial interpersonal variation occurs in these studies with regard to glucose homeostasis, with some persons being unaffected and others experiencing glucose-lowering effects due to whole wheat bread consumption. Whole grain (whole wheat) contains bioactive phytochemicals in addition to its well-recognized fiber content, and these constituents have not received adequate study to inform dietary recommendations. The objective of this study is to investigate the glucose-lowering effects of whole wheat bread in persons with prediabetes using multi-omics platforms that can provide an understanding of the complex interactions among the gut microbiome, gut metabolome, host metabolome, and gut barrier function. The hypothesis is that gut microbial metabolism of whole wheat and its major bioactive components is a determining factor of human health benefits. This will be tested by conducting a randomized, controlled crossover trial in persons with pre-diabetes who follow a controlled diet containing whole wheat bread or white bread for 2-weeks. Outcomes are expected to significantly advance an understanding of personalized, gut microbiome-mediated approaches in individuals with pre-diabetes to help guide dietary recommendations of whole wheat intake. In addition, novel evidence that maps out the differential functions of diverse genus/species of microbiota to biotransform whole wheat nutrients into more bioactive metabolites are expected.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Participants will be randomized to receive 4 servings per day of whole wheat bread (WWB) or white bread (WB) for 2 weeks. During each study arm, participants will be provided eucaloric standardized diets that are devoid of whole wheat products, probiotic-containing foods, and fermented foods. Before and after each study arm, a fasting blood sample and fecal sample will be obtained for metabolomic and clinical measures. Anthropometric measurements and blood pressure will be assessed at days 0, 7, and 14 of each study arm. On day 14, participants will complete an oral glucose tolerance test (OGTT) with collection of blood samples every 30 minutes for 3 hours and a simultaneous gut permeability test that entails ingesting non-digestible sugar probes and subsequent 24-h collection of urine. Upon completion of these procedures, participants will undergo a ~1 month washout before repeating the study identically, with the crossover to the alternate bread diet.Participants will be randomized to receive 4 servings per day of whole wheat bread (WWB) or white bread (WB) for 2 weeks. During each study arm, participants will be provided eucaloric standardized diets that are devoid of whole wheat products, probiotic-containing foods, and fermented foods. Before and after each study arm, a fasting blood sample and fecal sample will be obtained for metabolomic and clinical measures. Anthropometric measurements and blood pressure will be assessed at days 0, 7, and 14 of each study arm. On day 14, participants will complete an oral glucose tolerance test (OGTT) with collection of blood samples every 30 minutes for 3 hours and a simultaneous gut permeability test that entails ingesting non-digestible sugar probes and subsequent 24-h collection of urine. Upon completion of these procedures, participants will undergo a ~1 month washout before repeating the study identically, with the crossover to the alternate bread diet.

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Assessing Gut Microbiota Mediated Health Outcomes of Whole Wheat and Its Major Bioactive Components

Anticipated Study Start Date :

Apr 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Feb 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Whole Wheat Bread Participants consuming 128 g of whole wheat bread (4 slices of bread) daily for two weeks	Other: Whole Wheat Bread Standardized whole wheat bread (128 g daily)
Placebo Comparator: White Bread (control) Participants consuming 128 g of white bread (4 slices of bread) daily for two weeks	Other: White Bread (control) Standardized white bread (128 g daily)

Arm

Intervention/Treatment

Experimental: Whole Wheat Bread

Participants consuming 128 g of whole wheat bread (4 slices of bread) daily for two weeks

Other: Whole Wheat Bread

Standardized whole wheat bread (128 g daily)

Placebo Comparator: White Bread (control)

Participants consuming 128 g of white bread (4 slices of bread) daily for two weeks

Other: White Bread (control)

Standardized white bread (128 g daily)

Outcome Measures

Primary Outcome Measures

Change in fasting plasma glucose [Day 0, Day 14]
Fasting plasma glucose concentrations (mg/dL) will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.

Secondary Outcome Measures

Change in plasma insulin [Day 0, Day 14]
Plasma concentration (μIU/mL) of insulin will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Change in insulin sensitivity [Day 14]
Evaluated through an oral glucose tolerance test and quantified using the area under the curve (AUC) of the temporal changes in blood glucose and insulin conducted at the end of each intervention arm to assess between-treatment effects.
Small gastrointestinal permeability [Day 14]
Lactulose/mannitol ratio will be measured in urine collected 0-5 h following the digestion of non-digestible sugar probes to assess small intestinal permeability. Excretion ratios will be measured at the end of each intervention arm to assess between-treatment effects.
Colonic gastrointestinal permeability [Day 14]
Sucralose/erythritol ratio will be measured in urine collected 6-24 h following digestion of non-digestible sugar probes to access colonic permeability. Excretion ratios will be measured at the end of each intervention arm to assess between-treatment effects.
Metabolic Endotoxemia [Day 0, Day 14]
Serum endotoxin concentration (EU/mL) will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Serum myeloperoxidase [Day 0, Day 14]
Serum concentration (ng/mL) of myeloperoxidase will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of toll-like receptor 4 gene expression [Day 0, Day 14]
Expression of pro-inflammatory toll-like receptor 4 gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of myeloid differentiation factor 88 gene expression [Day 0, Day 14]
Expression of pro-inflammatory myeloid differentiation factor 88 gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of tumor necrosis factor alpha gene expression [Day 0, Day 14]
Expression of pro-inflammatory tumor necrosis factor alpha gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of p65 subunit of nuclear factor kappa B gene expression [Day 0, Day 14]
Expression of pro-inflammatory p65 subunit of nuclear factor kappa B gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of interleukin-6 gene expression [Day 0, Day 14]
Expression of pro-inflammatory interleukin-6 gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of interleukin-8 gene expression [Day 0, Day 14]
Expression of pro-inflammatory interleukin-8 gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of myeloperoxidase gene expression [Day 0, Day 14]
Expression of pro-inflammatory myeloperoxidase gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Level of monocyte chemoattractant protein-1 gene expression [Day 0, Day 14]
Expression of pro-inflammatory monocyte chemoattractant protein-1 gene from peripheral blood mononuclear cells will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal calprotectin [Day 0, Day 14]
Fecal concentration (μg/g) of calprotectin will be measured in samples collected and the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal myeloperoxidase [Day 0, Day 14]
Fecal concentration (ng/g) of myeloperoxidase will be measured in samples collected at the beginning and end of each study arm to assess within-treatment and between-treatment effects.
Fecal short-chain fatty acid: butyrate [Day 0, Day 14]
Fecal concentrations (mmol/kg) of butyrate will be measured in samples collected at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal short-chain fatty acid: acetate [Day 0, Day 14]
Fecal concentrations (mmol/kg) of acetate will be measured in samples collected at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal short-chain fatty acid: propionate [Day 0, Day 14]
Fecal concentrations (mmol/kg) of propionate will be measured individually in samples collected at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal short-chain fatty acid: isobutyric acid [Day 0, Day 14]
Fecal concentrations (mmol/kg) of isobutyric acid will be measured in samples collected at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Fecal short-chain fatty acid: isovaleric acid [Day 0, Day 14]
Fecal concentrations (mmol/kg) of isovaleric acid will be measured in samples collected at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Serum whole wheat bread phytochemical: alkylersorcinols [Day 0, Day 14]
Serum concentrations of (nmol/L) alkylresorcinol and alkylresorcinol derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Serum whole wheat bread phytochemical: benoxazinods [Day 0, Day 14]
Serum concentrations of (nmol/L) benoxazinoids and benoxazinoids derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Serum whole wheat bread phytochemical: phenolic compounds [Day 0, Day 14]
Serum concentrations of (nmol/L) phenolic compounds and phenolic derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Intestinal whole wheat phytochemical: alkylresorcinols [Day 0, Day 14]
Fecal concentrations of (μmol/L) alkylresorcinols and alkylresorcinol derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Intestinal whole wheat phytochemical: benoxazinoids [Day 0, Day 14]
Fecal concentrations of (μmol/L) benoxazinoids and benoxazinoids derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Intestinal whole wheat phytochemical: phenolic compounds [Day 0, Day 14]
Fecal concentrations of (μmol/L) phenolic compounds and phenolic derivatives will be measured at the beginning and end of each intervention arm to assess within-treatment and between treatment effects.

Other Outcome Measures

Plasma triglyceride levels [Day 0, Day 14]
Plasma triglyceride concentrations (mg/dL) will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Plasma cholesterol levels [Day 0, Day 14]
Plasma cholesterol concentrations (mg/dL) will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Plasma HDL-cholesterol levels [Day 0, Day 14]
Plasma HDL-cholesterol concentrations (mg/dL) will be measured at the beginning and end of each intervention arm to assess within-treatment and between-treatment effects.
Serum alanine transaminase [Day 0, Day 14]
Serum concentrations (U/L) of alanine transaminase will be measured at the beginning and end of each intervention arm to assess within-treatment and between treatment effects.
Serum inflammatory biomarker: C-reactive protein [Day 14]
Serum concentration (mg/L) of C-reactive protein will be measured at the end of each intervention arm to assess between-treatment effects.
Serum inflammatory biomarker: interleukin-6 [Day 14]
Serum interleukin-6 concentrations (pg/mL) of interleukin-6 will be measured at the end of each intervention arm to assess between-treatment effects.
Serum inflammatory biomarker: interleukin-8 [Day 14]
Serum interleukin-8 concentrations (pg/mL) will be measured at the end of each intervention arm to assess between-treatment effects.
Serum inflammatory biomarker: tumor necrosis factor alpha [Day 14]
Serum tumor necrosis factor alpha concentrations (pg/mL) will be measured at the end of each intervention arm to assess between-treatment effects.
Gut microbiota alpha-diversity indices [Day 0, Day 14]
Within-treatment and between-treatment effects regarding alpha-diversity will be determined based on the Shannon-Wiener diversity index. Fecal samples collected at the beginning and end of each intervention period will be used to perform microbiota assessments and the subsequent determinations of alpha-diversity.
Gut microbiota beta-diversity indices [Day 0, Day 14]
Within-treatment and between-treatment effects regarding beta-diversity will be determined based on the Bray-Curtis diversity index. Fecal samples collected at the beginning and end of each intervention period will be used to perform microbiota assessments and the subsequent determinations of beta-diversity.
Gut microbiota relative abundance [Day 0, Day 14]
Gut microbiota relative abundance (percent order, genus, and species level) will be measured in fecal samples collected at the beginning and end of each intervention arm to assess within-treatment and between treatment effects.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Fasting blood glucose between 100-125 mg/dL
BMI of 30-35 kg/m2

Exclusion Criteria:

History of liver disease, cardiovascular disease, overt diabetes, or cancer
Prescribed medications for hyperglycemia or dyslipidemia
Use of dietary supplements, prebiotics, or probiotics
Usage of antibiotics or anti-fungals within 3 months prior to enrollment
Smoker
Alcohol consumption greater than 2 drinks per day
Aerobic exercise greater than 5 hours per week
Pregnancy or fertility treatments
History of chronically active inflammatory or neoplastic disease in 3 years prior to enrollment
History of chronic gastrointestinal disorder including diarrhea, inflammatory bowel disease, celiac disease; coagulation disorders, chronic immunosuppressive medication usage
History of myocardial infarction or cerebrovascular accident within 6 months prior to participation