Gut-microbiota Targeted Nutritional Intervention for Gut Barrier Integrity at High Altitude

Study Overview
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Brief Summary
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The aim of this randomized, crossover clinical trial is to determine the efficacy of a gut microbiota-targeted nutritional intervention containing a blend of fermentable fibers and polyphenols (FP) for mitigating increases in GI permeability, and decrements in immune function and neuropsychologic performance following rapid ascent to simulated high altitude. Fifteen healthy young adults will participate in each of three study phases that include a 14-day supplementation period in which participants will consume 1 of 2 supplement bars: placebo (PL, will be consumed during 2 phases) and FP supplementation (will be consumed during one phase only). During the final 2-d of each phase, participants will live in a hypobaric chamber under sea level or high altitude conditions.

Detailed Description
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The collection of microbes inhabiting the human gastrointestinal (GI) tract, known as the gut microbiota, is increasingly recognized as a mediator of GI, immunologic, and neuropsychologic responses to various environmental and physiologic stressors. The hypobaric hypoxia characteristic of high altitude environments is a stressor that has recently been associated with increased GI permeability, and which has been shown to cause decrements in immune, neuropsychological and physical function. To what extent modulation of the human gut microbiota can mitigate these responses during high altitude exposure is undetermined. The aim of this randomized, crossover clinical trial is to determine the efficacy of a gut microbiota-targeted nutritional intervention containing a blend of fermentable fibers and polyphenols (FP) for mitigating increases in GI permeability, and decrements in immune function and neuropsychologic performance following rapid ascent to simulated high altitude. Fifteen healthy young adults will participate in each of three study phases in random order. Each phase will include a 14-day supplementation period in which participants will consume 1 of 2 supplement bars: placebo (PL, will be consumed during 2 phases) and FP supplementation (will be consumed during one phase only). During the final 2-d of each phase, participants will live in a hypobaric chamber. During one phase the chamber environment will mimic low-altitude conditions (SHAM). During two phases the chamber environment will mimic the barometric pressure at Pike's Peak CO (460 mmHg; HA).

Official Title
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Efficacy of a Gut-microbiota Targeted Nutritional Intervention for Promoting Gut Barrier Integrity During Short-term Exposure to Hypobaric Hypoxia.

Conditions
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Gastrointestinal Injury, Acute Mountain Sickness

Intervention / Treatment
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* Dietary Supplement: FP
* Dietary Supplement: Placebo
* Other: High altitude
* Other: Sea level


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Men and women aged 18 - 39 years (active duty personnel who are 17 yr of age will also be allowed to participate) In good health Physically active For active duty, passed most recent body composition assessment; for civilians, body mass index (BMI) ≤ 30.0 kg/m2. Self-reports having a bowel movement at least as frequently as every-other-day Self-reports normal vision (with or without glasses) and hearing Exclusion Criteria: Born at altitudes greater than 2,100 m ( 7,000 feet) Living in areas that are more than 1,200 m ( 4,000 feet), or have traveled to areas that are more than 1,200 m for five days or more within the last 2 mo Pregnant, expecting to become pregnant during study, or breastfeeding Any of the following medical conditions: Musculoskeletal injuries that compromise exercise capability Metabolic or cardiovascular abnormalities (e.g., kidney disease, diabetes, cardiovascular disease, etc.) Suspected or known strictures, fistulas, or physiological/mechanical GI obstruction Evidence of apnea or other sleeping disorders Evidence of prior high altitude pulmonary or cerebral edema diagnosis Disease of the GI tract including, but not limited to diverticulitis, inflammatory bowel disease, peptic ulcer disease, Crohn's disease, ulcerative colitis Anemia or Sickle Cell Anemia/Trait Alcoholism or other substance abuse issues History of gastric bezoar Swallowing disorders; severe dysphagia to food or pills Implanted or portable electro-mechanical medical devices Allergy to skin adhesive Past GI surgery Colonoscopy within 3 months of study participation Taking prescription medications other than a contraceptive (unless approved by Medical Office and study PI) Regular use of over-the-counter medications (including antacids, laxatives, stool softeners, and anti-diarrheals) unless approved by Medical Office and study PI Any use of antibiotics, except topical antibiotics, within 3 months of study participation Not willing to refrain from using non-steroidal anti-inflammatory medications (NSAIDs) or antihistamine during the study Not willing to stop consumption of prebiotic- or probiotic-containing supplements (e.g.,VSL#3, PRO-15, etc.), or other dietary supplements at least 2 weeks before and throughout study participation Not willing to stop consumption of probiotic-containing foods (e.g., yogurt, etc.) during study participation. Not willing to refrain from smoking any nicotine product (includes e-cigarettes), vaping, and chewing tobacco during controlled-diet periods. Not willing to abstain from caffeine and alcohol during controlled-diet periods. Allergies, intolerances, unwillingness or inability to eat provided foods and beverages Following vegetarian/vegan diet Unable to regularly sleep for 7-10 hr/night Any previous blood donation, within 8 weeks of the first blood draw of the study, of a volume that when combined with the amount of blood to be collected during the study would exceed 550 mL

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 39 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: PL+SHAM<br>Placebo intervention + sea level exposure | Dietary Supplement: Placebo<br>* Matched placebo<br>Other: Sea level<br>* Sea level environment in altitude chamber<br>|
| Placebo Comparator: PL+HA<br>Placebo intervention + high altitude exposure | Dietary Supplement: Placebo<br>* Matched placebo<br>Other: High altitude<br>* Simulated high altitude in altitude chamber using hypobaric hypoxia<br>|
| Experimental: FP+HA<br>Fiber and polyphenol supplementation + high altitude exposure | Dietary Supplement: FP<br>* Fiber and polyphenol blend<br>Other: High altitude<br>* Simulated high altitude in altitude chamber using hypobaric hypoxia<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in intestinal permeability | Intestinal permeability measured by the ratio of the urinary excretion of sucralose and erythrirol | Study days 20, 40 and 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in lipopolysaccharide binding protein concentrations | Fasting serum lipopolysaccharide binding protein concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in zonulin concentrations | Fasting serum zonulin concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in glucagon-like peptide-2 concentrations | Fasting serum glucagon-like peptide-2 concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in intestinal fatty acid binding protein concentrations | Fasting and post-exercise serum intestinal fatty acid binding protein concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in claudin-3 concentrations | Fasting and post-exercise serum claudin-3 concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in S100B concentrations | Fasting and post-exercise serum S100B concentration | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in systemic inflammation | Fasting serum interleukin (IL) IL-6, IL-8, IL-10, IL-17, IL-1β, IL-1ra, tumor necrosis factor-α, interferon-γ concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in intestinal inflammation | Fecal calprotectin concentration | Study days 6, 18, 21, 23, 27, 39, 42, 44, 48, 60, 63, 65 | 
| Difference in glucose concentrations | Fasting and post-exercise serum glucose concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in insulin concentrations | Fasting and post-exercise serum insulin concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in lactate concentrations | Fasting and post-exercise serum lactate concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in glycerol concentrations | Fasting and post-exercise serum glycerol concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in cortisol concentrations | Fasting and post-exercise serum cortisol concentrations | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in bone specific alkaline phosphatase concentrations | Fasting serum bone specific alkaline phosphatase concentration | Study days 20, 41, 62 | 
| Difference in carboxy-terminal collagen crosslinks concentrations | Fasting serum carboxy-terminal collagen crosslinks concentration | Study days 20, 41, 62 | 
| Difference in tartrate resistant acid phosphatase concentrations | Fasting serum tartrate resistant acid phosphatase concentration | Study days 20, 41, 62 | 
| Difference in procollagen type 1 N-terminal propeptide concentrations | Fasting serum procollagen type 1 N-terminal propeptide concentration | Study days 20, 41, 62 | 
| Difference in osteocalcin concentrations | Fasting serum osteocalcin concentration | Study days 20, 41, 62 | 
| Difference in secretory immunoglobulin A concentrations | Secretory immunoglobulin A concentrations in tear fluid and saliva | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in immune cell phenotypes | Immune cell phenotype by flow cytometry | Study days 21, 42, 63 | 
| Difference in T-cell simulated cytokine production | T-cell simulated cytokine production by cell culture and flow cytometry | Study days 21, 42, 63 | 
| Difference in natural killer-cell cytotoxicity | Natural killer-cell cytotoxicity by cell culture and flow cytometry | Study days 21, 42, 63 | 
| Difference in development of acute mountain sickness | Environmental Symptoms Questionnaire-short form. Acute Mountain Sickness will be measured multiple times daily using the Lake Louise scoring system wherein higher scores indicate more severe symptoms. AMS severity cutoffs will use mild (0.7-1.53), moderate (1.53-2.63), severe >=2.63 | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in gastrointestinal symptoms; quality of life | Gastrointestinal symptoms measure by modified version of the gastrointestinal quality of life index wherein lower scores indicate more severe symptoms. | Study weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 | 
| Difference in gastrointestinal symptoms; irritable bowel syndrome | Gastrointestinal symptoms measure by modified version of the irritable bowel syndrome symptom severity scale score wherein higher scores indicate more severe symptoms. Scored on scale of 0-500; symptom severity scored as mild (75-174), moderate (175-300), severe (>300). | Study weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 | 
| Difference in appetite | Hunger, fullness, desire to eat, and prospective consumption measured by 100 mm visual analog scale. Scored from 0-100 with higher scores indicating greater sensation. | Study weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 | 
| Difference in changes in mood state | Measured by Profile of Mood States Questionnaire; a 65-item inventory of self-reported mood states which factor into six mood sub-scales (tension/anxiety (0-36), depression/dejection (0-60), anger/hostility (0-48), vigor/activity (0-32), fatigue/inertia (0-28), confusion/bewilderment (0-28), and total mood disturbance (0-200) wherein higher scores indicate greater mood state. | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in changes in feeling | Measured by Feeling Scale; a one-item inventory measuring the extent to which participants feel pleasant or unpleasant. Higher scores indicate more unpleasant feeling. Scored from -5 (very bad) to 5 (very good) | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in changes arousal | Measured by Felt Arousal Scale; a one-item inventory measuring the extent to which participants feel aroused. Higher scores indicate greater arousal (low=1 to high =6). | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in willingness to take risks | Measured by Evaluation of Risks Questionnaire; a 24-item questionnaire providing scores on five scales: self-control, danger seeking, energy, impulsivity, and invincibility. | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in risk taking behavior | Measured by Balloon Analogue Risk Task | Study days 7, 20, 21, 41, 42, 62, 63 | 
| Difference in resting metabolic rate | Resting metabolic rate measured by indirect calorimetry | Study days 7, 21, 42, 63 | 
| Difference in physical activity energy expenditure | Energy expenditure measured by indirect calorimetry during 60-minute steady state exercise | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in gastrointestinal transit time | Gastric, small intestine and large intestine transit time measured by SmartPill | Study days 20, 41, 62 | 
| Difference in gastrointestinal pH | Gastric, small intestine and large intestine pH measured by SmartPill | Study days 20, 41, 62 | 
| Difference in changes in working memory | Measured by N-Back task before, during and after exercise | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in changes in spatial working memory | Measured by emotional Interference task before, during and after exercise | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in changes in spatial memory | Measured by Matching to Sample test in the morning and afternoon | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in change in reaction time | Measured by reaction time task before, during and after exercise | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in change in response inhibition | Measured by Go/No-Go task before, during and after exercise | Study days 20, 21, 41, 42, 62, 63 | 
| Difference in vigilance | Measured by scanning visual vigilance task | Study days 20, 21, 23, 41, 42, 44, 62, 63, 65 | 
| Difference in simple visual reaction time | Measured by psychomotor vigilance test | Study days 20, 21, 23, 41, 42, 44, 62, 63, 65 | 
| Difference in language-based logical reasoning | Measured by grammatical Reasoning task | Study days 20, 21, 23, 41, 42, 44, 62, 63, 65 | 
| Difference in ambulatory vigilance | Measured by wrist-worn vigilance monitor | 48-hours/day during study weeks 0, 2, 3, 5, 6, 8, 9 | 
| Difference in fecal short chain fatty acids | Fecal short chain fatty acid concentrations | Study days 6, 18, 21, 23, 27, 39, 42, 44, 48, 60, 63, 65 | 
| Difference in gut microbiota composition | Fecal bacterial community diversity and relative abundance measured by 16S rRNA gene sequencing | Study days 6, 18, 21, 23, 27, 39, 42, 44, 48, 60, 63, 65 | 
| Differences in microRNA concentrations | Fasting and post-exercise circulating and exosomal microRNA | Study days 20, 21, 41, 42, 62, 63 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiome, Intestinal permeability, Cognition, Immune, Fiber, Military, Altitude, Polyphenol