Effects of Changing Intestinal Transit Time on Gut Microbial Composition and Metabolism

Study Overview
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Brief Summary
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The aim of this study is to investigate how a short versus a long transit time impacts the gut microbiome's response to a high-fiber and a low-fiber diet, respectively. Such insights could help us understand personal responses to diets and be a first step towards personalized dietary recommendations targeting the gut microbiome.

Detailed Description
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The study consists of two parallel arms of whole-meal diets, a low-fiber diet, and a high-fiber diet, respectively. Each arm is designed as a cross-over where participants, in random order, are administered a laxative (Movicol) along with the provided diet to shorten their intestinal transit time or simply consume the provided whole-meal diet (control). The two intervention periods both involve the following: One week of run-in where participants consume the provided whole-meal diet. One week where participants either consume Movicol with the provided whole-meal diet or simply continue consuming the provided whole-meal diet (control). Both arms begin with a screening visit and one week where participants consume and record their habitual diets. Subsequently, the first intervention period follows with one visit before and after each of the two weeks (visit 1-3) followed by the second intervention period with one visit before and after each of the two weeks (visit 4-6). The two cross-over periods are split by a washout of at least two weeks. The study thus runs for approximately 7-8 weeks depending on the length of the washout and consists of seven visits (one screening visit and six regular visits) in total.

Official Title
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Effects of Changing Intestinal Transit Time on Gut Microbial Composition and Metabolism During a Dietary Intervention With Low and High Fiber.

Conditions
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Diet, Healthy, Metabolic Disease

Intervention / Treatment
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* Drug: Diet + laxative
* Other: Diet only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18.5-30.0 kg/m2 BMI Self-reported ≤3.5 spontaneous bowel movements per week Willing to collect urine and stool samples at home and able to temporarily store them in their own freezer in a provided container. Willing to eat the foods provided. Owns a smartphone (iOS 11.0 and later or Android 5.0 and up) with access to the internet. Exclusion Criteria: Pregnant or lactating women. Diagnosis of irritable bowel syndrome (IBS), small intestinal bacterial overgrowth (SIBO), inflammatory bowel diseases (IBD), Gastrointestinal obstruction, or Ischemic colitis Diagnosed constipation according to the ROME IV criteria Intake of antibiotics ˂ 1month, or any medication that can affect the outcomes of the study Regular use of diarrhea inhibitors or laxatives Dysphagia Any chronic disease that can affect the outcomes of the study or pose a risk when consuming Movicol Intake of medications potentially altering gastric pH (proton pump inhibitors, histamine receptor antagonists, antacids) Intake of medications potentially altering the gastrointestinal motility (prokinetics, antiemetic agents, anti-cholinergic agents, narcotic analgetics, nonsteroidal anti-inflammatory drugs, and peroral glucocorticoids) Concurrent participation in another trial Any condition that makes the project responsible researcher to doubt the feasibility of the volunteer´s participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Overall, there are two parallel arms (low- and high-fiber diet) to which the participants will be randomized with an allocation ratio 1:1. In each arm participants will be exposed to a crossover design where participants in random order will continue on the meal intervention alone (control) or receive Movicol (a laxative) along with the meal intervention to shorten intestinal transit time.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-fiber diet<br>The high-fiber diet will consist of foods rich in dietary fiber such as coarse vegetables, wholegrain bread, and fruits representing a broad range of dietary fibers aiming for ≈40 g of fiber/10 MJ. | Drug: Diet + laxative<br>* The participants will start by consuming one sacket of Movicol powder (13 g macrogol 3350) on the first day. On day 2, the participants will consume two sackets of Movicol powder (26 g macrogol 3350), one with breakfast in the morning and one before sleep in the evening. The participants will continue consuming two sackets per day (one morning, one evening) until the following study visit, day 8 (seven days in total). If the participants have a very loose stomach (recorded as Bristol stool scale ≥6), they will be instructed to reduce Movicol by one sacket/day. In case the participants have not passed a stool on day 2 or in the morning of day 3, the participants will increase the dose to a maximum of three sackets of Movicol powder (39 g macrogol 3350) per day (morning, noon, and evening) and continue this until the following study visit at day 8. If three sackets cause very loose stomach the participants will decrease the number of sackets consumed.<br>Other: Diet only<br>* This is only a control and participants will not receive Movicol.<br>* Other names: Control;|
| Experimental: Low-fiber diet<br>The low-fiber diet will consist of foods poor in fiber such as white bread and refined foods aiming for ≈10 g of fiber/10 MJ. | Drug: Diet + laxative<br>* The participants will start by consuming one sacket of Movicol powder (13 g macrogol 3350) on the first day. On day 2, the participants will consume two sackets of Movicol powder (26 g macrogol 3350), one with breakfast in the morning and one before sleep in the evening. The participants will continue consuming two sackets per day (one morning, one evening) until the following study visit, day 8 (seven days in total). If the participants have a very loose stomach (recorded as Bristol stool scale ≥6), they will be instructed to reduce Movicol by one sacket/day. In case the participants have not passed a stool on day 2 or in the morning of day 3, the participants will increase the dose to a maximum of three sackets of Movicol powder (39 g macrogol 3350) per day (morning, noon, and evening) and continue this until the following study visit at day 8. If three sackets cause very loose stomach the participants will decrease the number of sackets consumed.<br>Other: Diet only<br>* This is only a control and participants will not receive Movicol.<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal butyrate over urine p-cresol sulfate ratio | Changes in ratio between fecal butyrate (reflecting saccharolytic fermentation) and urine p-cresol sulfate (reflecting proteolytic fermentation) between interventions. | From visit 1 through to study completion, an average of 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole gut transit time measured by sweet corn | Changes in whole gut transit time between interventions determined by the passage time of sweet corn. | From visit 1 through to study completion, an average of 7 weeks | 
| Whole gut transit time measured by blue muffins | Changes in whole gut transit time between interventions determined by the passage time of muffins with blue dye. | From visit 1 through to study completion, an average of 7 weeks | 
| Stool consistency | Changes in stool consistency determined by Bristol Stool Scale. The Bristol Stool Scale measures stool consistency on a scale from 1-7 with high numbers reflecting loose stool. | From visit 1 through to study completion, an average of 7 weeks | 
| Change in bowel movement frequency | Changes in bowel movement frequency will be measured by the participants recording every bowel movement in a defecation diary during the study. | From visit 1 through to study completion, an average of 7 weeks | 
| Fecal water content in percentage of stool weight | Change in fecal water content between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fecal concentration of short-chain fatty acids | Change in concentration of short-chain fatty acids between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fecal pH | Change in fecal pH level between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fecal ammonia concentration | Change in ammonia content between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Concentration of fasting plasma short-chain fatty acids | Change in concentration of short-chain fatty acids between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fasting plasma concentrations of bile acids | Change in concentration of bile acids in fasting blood between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fasting breath methane and hydrogen levels in parts per million | Changes in fasting breath methane and hydrogen concentration measured in parts per million (PPM) in exhalations between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Microbial metabolites in urine from proteolytic fermentation as assessed by mass spectrometry | Changes in the urine concentration of metabolites of microbial proteolysis between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Microbial metabolites in blood from proteolytic fermentation as assessed by mass spectrometry | Changes in the blood concentration of metabolites of microbial proteolysis between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Fecal metabolome as assessed by untargeted metabolomics | Changes in the fecal metabolome between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Gut microbiome assessed by shotgun sequencing | Changes in gut microbiota composition between interventions. | From visit 1 through to study completion, an average of 7 weeks | 
| Gut microbiome assessed by 16S amplicon sequencing | Changes in gut microbiota composition between interventions. | From visit 1 through to study completion, an average of 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiome, Metabolomics, Transit time, Nutrition, Dietary fibre