Dysbiosis, Endotoxemia, Inflammation, PreDiabetes
Conditions
Keywords
Gut microbiota, Microbiome, Metabolomics, Prediabetes, Glycemic response, Intestinal permeability, Gut dysbiosis, Microbiome metabolism, Whole Wheat, Phytochemicals
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).
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.
Interventions
OTHERWhole Wheat Bread
Standardized whole wheat bread (128 g daily)
Standardized white bread (128 g daily)
Sponsors
United States Department of Agriculture (USDA)
Ohio State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Glucose | Day 14 (0, 30, 60, 90, 120, 150, 180 minutes post oral glucose tolerance test) | Data are biomarker area under the time-concentration curve (0-3 hours) on day 14 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Level of Toll-like Receptor 4 Gene Expression | Day 14 | Data are expression of toll-like receptor 4 gene from peripheral blood mononuclear cells. |
| Fecal Isobutyric Acid | Day 14 | Data are biomarker fecal concentrations. |
| Fecal Isovaleric Acid | Day 14 | Data are biomarker fecal concentrations of isovaleric acid. |
| Serum Alkylersorcinols | Day 14 | Data are biomarker serum concentrations of alkylresorcinol and alkylresorcinol derivatives. |
| Serum Benoxazinods | Day 14 | Data are biomarker serum concentrations of benoxazinoids and benoxazinoids derivatives. |
| Serum Phenolic Compounds | Day 14 | Data are biomarker serum concentrations of phenolic compounds and phenolic derivatives. |
| Fecal Alkylresorcinols | Day 14 | Data are biomarker fecal concentrations of alkylresorcinols and alkylresorcinol derivatives. |
| Fecal Benoxazinoids | Day 14 | Data are biomarker fecal concentrations of benoxazinoids and benoxazinoids derivatives. |
| Fecal Phenolic Compounds | Day 14 | Data are fecal concentrations of phenolic compounds and phenolic derivatives. |
| Plasma Insulin | Day 14 | Data are biomarker fasting concentrations |
| Plasma Glucose | Day 14 | Data are biomarker fasting concentrations. |
| Serum C-reactive Protein | Day 14 | Data are the biomarker serum concentration of C-reactive protein. |
| Serum Tumor Necrosis Factor Alpha | Day 14 | Data are biomarker serum tumor necrosis factor alpha concentrations. |
| Serum Interleukin-6 | Day 14 | Data are biomarker serum interleukin-6 concentrations. |
| Fecal Calprotectin | Day 14 | Data are biomarker fecal concentrations. |
| Fecal Myeloperoxidase | Day 14 | Data are biomarker fecal concentrations. |
| Urine Lactulose/Mannitol | Day 14 | Data are the 24-hour urinary excretion ratio of lactulose relative to mannitol collected 0-5 h following the digestion of non-digestible sugar probes. |
| Urine Sucralose/Erythritol | Day 14 | Data are the sucralose/erythritol ratio measured in urine collected 6-24 h following the digestion of non-digestible sugar probes. |
| Serum Endotoxin | Day 14 | Data are biomarker fasting concentrations. |
| Serum Myeloperoxidase | Day 14 | Data are biomarker serum concentrations. |
| Myeloid Differentiation Factor 88 Gene Expression | Day 14 | Expression of myeloid differentiation factor 88 gene from peripheral blood mononuclear cells. |
| Tumor Necrosis Factor Alpha Gene Expression | Day 14 | Expression of tumor necrosis factor alpha gene from peripheral blood mononuclear cells. |
| p65 Subunit of Nuclear Factor Kappa B Gene Expression | Day 14 | Expression of p65 subunit of nuclear factor kappa B gene from peripheral blood mononuclear cells. |
| Interleukin-6 Gene Expression | Day 14 | Expression of interleukin-6 gene from peripheral blood mononuclear cells. |
| Interleukin-8 Gene Expression | Day 14 | Expression of interleukin-8 gene from peripheral blood mononuclear cells. |
| Myeloperoxidase Gene Expression | Day 14 | Expression of myeloperoxidase gene from peripheral blood mononuclear cells. |
| Monocyte Chemoattractant Protein-1 Gene Expression | Day 14 | Expression of monocyte chemoattractant protein-1 gene from peripheral blood mononuclear cells. |
| Fecal Butyrate | Day 14 | Data are biomarker fecal concentrations. |
| Fecal Acetate | Day 14 | Data are biomarker fecal concentrations. |
| Fecal Propionate | Day 14 | Data are biomarker fecal concentrations. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Gut Microbiota Relative Abundance | Day 14 | Gut microbiota relative abundance (percent order, genus, and species level) will be measured in fecal samples. |
| Plasma Triglyceride | Day 0, Day 14 | Data are biomarker fasting plasma concentrations. |
| Plasma Cholesterol Levels | Day 14 | Data are biomarker fasting plasma concentrations. |
| Plasma HDL-cholesterol | Day 14 | Data are biomarker fasting plasma concentrations. |
| Serum Alanine Transaminase | Day 14 | Data are biomarker serum concentrations of alanine transaminase. |
| Serum Interleukin-8 | Day 14 | Data are biomarker serum interleukin-8 concentrations. |
| Gut Microbiota Beta-diversity Indices | Day 14 | Beta-diversity will be determined based on the Bray-Curtis diversity index. Fecal microbiota assessments and the subsequent determinations of beta-diversity. |
| Gut Microbiota Alpha-diversity Indices | Day 14 | Alpha-diversity will be determined based on the Shannon-Wiener diversity index. Fecal microbiota assessments and the subsequent determinations of alpha-diversity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Baseline characteristics of participants at screening | 39 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (2 Weeks) | Lost to Follow-up | 2 | 0 |
| First Intervention (2 Weeks) | Withdrawal by Subject | 2 | 3 |
| Second Intervention (2 Weeks) | Protocol Violation | 0 | 2 |
| Second Intervention (2 Weeks) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Overall | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 39 Participants | — |
| BMI | 34.7 kg/m^2 STANDARD_DEVIATION 5.2 | — |
| Diastolic blood pressure | 81.9 mmHg STANDARD_DEVIATION 7.5 | — |
| Fasting plasma glucose | 108.7 mg/dL STANDARD_DEVIATION 6.3 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 39 participants | — |
| Sex: Female, Male Female | 18 Participants | — |
| Sex: Female, Male Male | 21 Participants | — |
| Systolic blood pressure | 122.6 mmHg STANDARD_DEVIATION 10.3 | — |
| Waist circumference | 106.1 cm STANDARD_DEVIATION 12.3 | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 45 |
| other Total, other adverse events | 0 / 46 | 0 / 45 |
| serious Total, serious adverse events | 0 / 46 | 0 / 45 |
Outcome results
Primary
Plasma Glucose
Data are biomarker area under the time-concentration curve (0-3 hours) on day 14
Time frame: Day 14 (0, 30, 60, 90, 120, 150, 180 minutes post oral glucose tolerance test)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Plasma Glucose | 4092.15 mg/dL x min | Standard Error 597.81 |
| White Bread (Control) | Plasma Glucose | 5622.96 mg/dL x min | Standard Error 644.59 |
Secondary
Fecal Acetate
Data are biomarker fecal concentrations.
Time frame: Day 14
Secondary
Fecal Alkylresorcinols
Data are biomarker fecal concentrations of alkylresorcinols and alkylresorcinol derivatives.
Time frame: Day 14
Secondary
Fecal Benoxazinoids
Data are biomarker fecal concentrations of benoxazinoids and benoxazinoids derivatives.
Time frame: Day 14
Secondary
Fecal Butyrate
Data are biomarker fecal concentrations.
Time frame: Day 14
Secondary
Fecal Calprotectin
Data are biomarker fecal concentrations.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Fecal Calprotectin | 32.8 ug/g | Standard Error 4.6 |
| White Bread (Control) | Fecal Calprotectin | 35.84 ug/g | Standard Error 5.2 |
Secondary
Fecal Isobutyric Acid
Data are biomarker fecal concentrations.
Time frame: Day 14
Secondary
Fecal Isovaleric Acid
Data are biomarker fecal concentrations of isovaleric acid.
Time frame: Day 14
Secondary
Fecal Myeloperoxidase
Data are biomarker fecal concentrations.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Fecal Myeloperoxidase | 116 ng/g | Standard Error 31.5 |
| White Bread (Control) | Fecal Myeloperoxidase | 157 ng/g | Standard Error 20.9 |
Secondary
Fecal Phenolic Compounds
Data are fecal concentrations of phenolic compounds and phenolic derivatives.
Time frame: Day 14
Secondary
Fecal Propionate
Data are biomarker fecal concentrations.
Time frame: Day 14
Secondary
Interleukin-6 Gene Expression
Expression of interleukin-6 gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Interleukin-8 Gene Expression
Expression of interleukin-8 gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Level of Toll-like Receptor 4 Gene Expression
Data are expression of toll-like receptor 4 gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Monocyte Chemoattractant Protein-1 Gene Expression
Expression of monocyte chemoattractant protein-1 gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Myeloid Differentiation Factor 88 Gene Expression
Expression of myeloid differentiation factor 88 gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Myeloperoxidase Gene Expression
Expression of myeloperoxidase gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
p65 Subunit of Nuclear Factor Kappa B Gene Expression
Expression of p65 subunit of nuclear factor kappa B gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Plasma Glucose
Data are biomarker fasting concentrations.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Plasma Glucose | 93.5 mg/dL | Standard Error 2.6 |
| White Bread (Control) | Plasma Glucose | 85.6 mg/dL | Standard Error 2.3 |
Secondary
Plasma Insulin
Data are biomarker fasting concentrations
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Plasma Insulin | 18.9 uIU/mL | Standard Error 2.8 |
| White Bread (Control) | Plasma Insulin | 16.0 uIU/mL | Standard Error 1.6 |
Secondary
Serum Alkylersorcinols
Data are biomarker serum concentrations of alkylresorcinol and alkylresorcinol derivatives.
Time frame: Day 14
Secondary
Serum Benoxazinods
Data are biomarker serum concentrations of benoxazinoids and benoxazinoids derivatives.
Time frame: Day 14
Secondary
Serum C-reactive Protein
Data are the biomarker serum concentration of C-reactive protein.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Serum C-reactive Protein | 0.47 mg/dL | Standard Error 0.1 |
| White Bread (Control) | Serum C-reactive Protein | 0.53 mg/dL | Standard Error 0.1 |
Secondary
Serum Endotoxin
Data are biomarker fasting concentrations.
Time frame: Day 14
Secondary
Serum Interleukin-6
Data are biomarker serum interleukin-6 concentrations.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Serum Interleukin-6 | 1.88 pg/mL | Standard Error 0.2 |
| White Bread (Control) | Serum Interleukin-6 | 1.94 pg/mL | Standard Error 0.2 |
Secondary
Serum Myeloperoxidase
Data are biomarker serum concentrations.
Time frame: Day 14
Secondary
Serum Phenolic Compounds
Data are biomarker serum concentrations of phenolic compounds and phenolic derivatives.
Time frame: Day 14
Secondary
Serum Tumor Necrosis Factor Alpha
Data are biomarker serum tumor necrosis factor alpha concentrations.
Time frame: Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Whole Wheat Bread | Serum Tumor Necrosis Factor Alpha | 6.39 pg/mL | Standard Error 1 |
| White Bread (Control) | Serum Tumor Necrosis Factor Alpha | 5.63 pg/mL | Standard Error 0.6 |
Secondary
Tumor Necrosis Factor Alpha Gene Expression
Expression of tumor necrosis factor alpha gene from peripheral blood mononuclear cells.
Time frame: Day 14
Secondary
Urine Lactulose/Mannitol
Data are the 24-hour urinary excretion ratio of lactulose relative to mannitol collected 0-5 h following the digestion of non-digestible sugar probes.
Time frame: Day 14
Secondary
Urine Sucralose/Erythritol
Data are the sucralose/erythritol ratio measured in urine collected 6-24 h following the digestion of non-digestible sugar probes.
Time frame: Day 14
Other Pre-specified
Gut Microbiota Alpha-diversity Indices
Alpha-diversity will be determined based on the Shannon-Wiener diversity index. Fecal microbiota assessments and the subsequent determinations of alpha-diversity.
Time frame: Day 14
Other Pre-specified
Gut Microbiota Beta-diversity Indices
Beta-diversity will be determined based on the Bray-Curtis diversity index. Fecal microbiota assessments and the subsequent determinations of beta-diversity.
Time frame: Day 14
Other Pre-specified
Gut Microbiota Relative Abundance
Gut microbiota relative abundance (percent order, genus, and species level) will be measured in fecal samples.
Time frame: Day 14
Other Pre-specified
Plasma Cholesterol Levels
Data are biomarker fasting plasma concentrations.
Time frame: Day 14
Other Pre-specified
Plasma HDL-cholesterol
Data are biomarker fasting plasma concentrations.
Time frame: Day 14
Other Pre-specified
Plasma Triglyceride
Data are biomarker fasting plasma concentrations.
Time frame: Day 0, Day 14
Other Pre-specified
Serum Alanine Transaminase
Data are biomarker serum concentrations of alanine transaminase.
Time frame: Day 14
Other Pre-specified
Serum Interleukin-8
Data are biomarker serum interleukin-8 concentrations.
Time frame: Day 14