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

United States Army Research Institute of Environmental Medicine33 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Eligibility

Sex: ALLMin age: 17 YearsMax age: 39 YearsHealthy volunteers:

Medical Language ↔ Plain English

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: 1. Musculoskeletal injuries that compromise exercise capability 2. Metabolic or cardiovascular abnormalities (e.g., kidney disease, diabetes, cardiovascular disease, etc.) 3. Suspected or known strictures, fistulas, or physiological/mechanical GI obstruction 4. Evidence of apnea or other sleeping disorders 5. Evidence of prior high altitude pulmonary or cerebral edema diagnosis 6. Disease of the GI tract including, but not limited to diverticulitis, inflammatory bowel disease, peptic ulcer disease, Crohn's disease, ulcerative colitis 7. Anemia or Sickle Cell Anemia/Trait 8. Alcoholism or other substance abuse issues 9. History of gastric bezoar 10. Swallowing disorders; severe dysphagia to food or pills 11. Implanted or portable electro-mechanical medical devices 12. 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

Outcomes

Primary Outcomes

Difference in intestinal permeability

Intestinal permeability measured by the ratio of the urinary excretion of sucralose and erythrirol

Time frame: Study days 20, 40 and 60

Secondary Outcomes

Difference in lipopolysaccharide binding protein concentrations

Fasting serum lipopolysaccharide binding protein concentration

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in zonulin concentrations

Fasting serum zonulin concentration

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in glucagon-like peptide-2 concentrations

Fasting serum glucagon-like peptide-2 concentration

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in claudin-3 concentrations

Fasting and post-exercise serum claudin-3 concentration

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in S100B concentrations

Fasting and post-exercise serum S100B concentration

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in intestinal inflammation

Fecal calprotectin concentration

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in insulin concentrations

Fasting and post-exercise serum insulin concentrations

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in lactate concentrations

Fasting and post-exercise serum lactate concentrations

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in glycerol concentrations

Fasting and post-exercise serum glycerol concentrations

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in cortisol concentrations

Fasting and post-exercise serum cortisol concentrations

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in bone specific alkaline phosphatase concentrations

Fasting serum bone specific alkaline phosphatase concentration

Time frame: Study days 20, 41, 62

Difference in carboxy-terminal collagen crosslinks concentrations

Fasting serum carboxy-terminal collagen crosslinks concentration

Time frame: Study days 20, 41, 62

Difference in tartrate resistant acid phosphatase concentrations

Fasting serum tartrate resistant acid phosphatase concentration

Time frame: Study days 20, 41, 62

Difference in procollagen type 1 N-terminal propeptide concentrations

Fasting serum procollagen type 1 N-terminal propeptide concentration

Time frame: Study days 20, 41, 62

Difference in osteocalcin concentrations

Fasting serum osteocalcin concentration

Time frame: Study days 20, 41, 62

Difference in secretory immunoglobulin A concentrations

Secretory immunoglobulin A concentrations in tear fluid and saliva

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in immune cell phenotypes

Immune cell phenotype by flow cytometry

Time frame: Study days 21, 42, 63

Difference in T-cell simulated cytokine production

T-cell simulated cytokine production by cell culture and flow cytometry

Time frame: Study days 21, 42, 63

Difference in natural killer-cell cytotoxicity

Natural killer-cell cytotoxicity by cell culture and flow cytometry

Time frame: 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

Time frame: 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.

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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).

Time frame: 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.

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in risk taking behavior

Measured by Balloon Analogue Risk Task

Time frame: Study days 7, 20, 21, 41, 42, 62, 63

Difference in resting metabolic rate

Resting metabolic rate measured by indirect calorimetry

Time frame: Study days 7, 21, 42, 63

Difference in physical activity energy expenditure

Energy expenditure measured by indirect calorimetry during 60-minute steady state exercise

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in gastrointestinal transit time

Gastric, small intestine and large intestine transit time measured by SmartPill

Time frame: Study days 20, 41, 62

Difference in gastrointestinal pH

Gastric, small intestine and large intestine pH measured by SmartPill

Time frame: Study days 20, 41, 62

Difference in changes in working memory

Measured by N-Back task before, during and after exercise

Time frame: 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

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in change in reaction time

Measured by reaction time task before, during and after exercise

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

Difference in vigilance

Measured by scanning visual vigilance task

Time frame: Study days 20, 21, 23, 41, 42, 44, 62, 63, 65

Difference in simple visual reaction time

Measured by psychomotor vigilance test

Time frame: Study days 20, 21, 23, 41, 42, 44, 62, 63, 65

Difference in language-based logical reasoning

Measured by grammatical Reasoning task

Time frame: Study days 20, 21, 23, 41, 42, 44, 62, 63, 65

Difference in ambulatory vigilance

Measured by wrist-worn vigilance monitor

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Study days 20, 21, 41, 42, 62, 63

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes