Elucidating the Role of Human Small Intestine Microbiota in Explaining Differences in Postprandial Glucose Responses

Study Overview
=================
Brief Summary
-----------------
It has been shown that person-specific factors, such as the fecal microbiome, influenced postprandial glycemia. The small intestine is the site of nutrient digestion and absorption. The small intestine microbiota is amendable by dietary changes, and plays a key role in host adaptability to dietary variations. The role of the human small intestine microbiota in regulating postprandial glycemic responses towards food products will be investigated. First a screening will take place with to choose the test products that elicit most differential glucose responses and to select subjects with differential postprandial response to the same food product. The study will be a 6-day randomized cross-over trial with two test days. Four test (food) products, each containing 50 gram carbohydrates, and an oral glucose tolerance test will be provided to participants. Twenty men or women (BMI≥25 kg/m2, 40-75 years old) will be included. The main study parameters/endpoints are the food product-induced plasma glucose responses (iAUC) and the small intestine microbiota.

Detailed Description
-----------------
Rationale: It has been shown that person-specific factors, such as the fecal microbiome, influenced postprandial glycemia. The small intestine is the site of nutrient digestion and absorption. The small intestine microbiota is amendable by dietary changes, and plays a key role in host adaptability to dietary variations. Differences in small intestine microbiota are hypothesized to be key in explaining the interpersonal differences in glycemic responses. Objective: To investigate the role of the human small intestine microbiota in regulating postprandial glycemic responses towards food products. Study design: The subjects will wear a continuous glucose monitor during the screening and the study. First a screening (14 days in total) will take place with to choose the test products (2 out of 4) that elicit most differential glucose responses and to select subjects with differential postprandial response to the same food product. Also an OGTT will be performed. The study will be a randomized cross-over trial with two test days (length of trial is 6 days in total). During the trial, the subjects will be intubated with a naso-jejunum catheter. Study population: Twenty men or women (BMI≥25 kg/m2, 40-75 years old). Intervention (if applicable): Four test (food) products, each containing 50 gram carbohydrates, and an oral glucose tolerance test. Main study parameters/endpoints: test (food) product-induced plasma glucose responses (iAUC), small intestine microbiota.

Official Title
-----------------
Elucidating the Role of Human Small Intestine Microbiota in Interpersonal Differences in GLYcemic Responses Upon Consumption of Food Products: A Proof of Principle Study

Conditions
-----------------
Metabolic Syndrome, Obesity, Overweight, Microbiota, Small Intestine, Digestion

Intervention / Treatment
-----------------
* Other: food product


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females BMI≥25 kg/m2 Age 40-75 years Signed informed consent Exclusion Criteria: Having a history of medical or surgical events that may either put the subject at risk because of participation in the study, or influence the results of the study, including diabetes type 1, a swallowing disorder, gastrointestinal or liver disease, renal failure, cancer, nose/throat diseases, gastric bypass surgery, use of anticoagulants; Having a bleeding/coagulation disorder, including hemophilia, Von Willebrand disease, Bernard-Soulier, Glanzmann thrombasthenia or thrombocytopenia; Use of antibiotics within 2 months of starting the study or planned during the study; Use of medication that could influence the study results, such as diabetes treatment; Use of pro- and prebiotic supplements; Sensitive to medical skin adhesives; Having an allergy or intolerance towards compounds in the test products; Follows a vegan diet; Excessive alcohol consumption (on average >21 glasses/week for men and >14 glasses/week for women); Currently a research subject in another clinical trial; Having blood vessels that are too difficult for inserting a cannula/blood drawing' Having a hemoglobin level <8.5 mmol/l (men) or <7.5 mmol/l (women); Being a blood donor during the duration of the study; Not having a General Practitioner (GP); Being an employee of Wageningen University, division Human Nutrition and Health.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carbohydrate-rich food product (to be determined)<br>This is a nutritional product, such as bread or cake, containing 50 gram carbohydrates. | Other: food product<br>* a food product containing 50 gram carbohydrates<br>|
| Experimental: Another carbohydrate-rich food product (to be determined)<br>This is a nutritional product, such as bread or cake, containing 50 gram carbohydrates. | Other: food product<br>* a food product containing 50 gram carbohydrates<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| postprandial glucose response (iAUC) per test product | iAUC glucose | 0-120 minutes | 
| small intestine microbiome | the relative composition (%) and the functional capacity (%) of the small intestine microbiota | at baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| macronutrients in the small intestinal aspirates | amounts of carbohydrates, proteins, fats | 0-240 minutes | 
| presence and production of (bacterial) degradation products in the small intestinal aspirates | concentrations of organic acids and short-chain fatty acids | 0-240 minutes | 
| digestive enzymes in the small intestinal aspirates | concentrations of amylase | 0-240 minutes | 
| non-absorbable marker in the small intestinal aspirates | peg-4000 concentrations | 0-240 minutes | 
| blood HbA1c | concentrations of HbA1c | 0-240 minutes | 
| blood glucose | concentrations glucose (e.g. GLP-1, PYY) | 0-240 minutes | 
| blood insulin | concentrations of insulin | 0-240 minutes | 
| blood glucagon | concentrations of glucagon | 0-240 minutes | 
| blood total triglycerides | concentrations of triglycerides | 0-240 minutes | 
| blood total free fatty acids | concentrations of free fatty acids | 0-240 minutes | 
| plasma gut hormones | concentrations of gut hormones (e.g. GLP-1, PYY) | 0-240 minutes | 
| breath 13C-lactosyl ureide | concentrations of 13C-lactosyl ureide | 0-240 minutes | 
| breath hydrogen | concentrations of hydrogen (ppm) | 0-240 minutes | 
| breath methane | concentrations of methane (ppm) | 0-240 minutes | 
| Oral microbiome composition | microbiota relative composition (%) | baseline | 
| Salivary α-amylase | concentrations of a-amylase | 0-240 minutes | 
| Fecal microbiota composition | microbiota relative composition (%) | baseline |