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

Acute Mountain Sickness Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04111263
• Other study ID #: 19-02-HC
• Secondary ID: M-10783
• Status: Completed
• Phase: N/A
• Start date: October 6, 2019
• Est. completion date: November 5, 2022

Study information

• Verified date: December 2022
• Source: United States Army Research Institute of Environmental Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: November 5, 2022
• Est. primary completion date: November 5, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 17 Years to 39 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Mountain Sickness
• Altitude Sickness
• Gastrointestinal Injury

Intervention

Dietary Supplement:
• FP
Fiber and polyphenol blend
• Placebo
Matched placebo

Other:
• High altitude
Simulated high altitude in altitude chamber using hypobaric hypoxia
• Sea level
Sea level environment in altitude chamber

Locations

Country	Name	City	State
United States	USARIEM	Natick	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
United States Army Research Institute of Environmental Medicine	University of Reading, US Army Combat Capabilities Development Command- Soldier Center, Walter Reed Army Institute of Research (WRAIR)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Difference in lipopolysaccharide binding protein concentrations	Fasting serum lipopolysaccharide binding protein concentration	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in zonulin concentrations	Fasting serum zonulin concentration	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in glucagon-like peptide-2 concentrations	Fasting serum glucagon-like peptide-2 concentration	Study days 20, 21, 41, 42, 62, 63
Secondary	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
Secondary	Difference in claudin-3 concentrations	Fasting and post-exercise serum claudin-3 concentration	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in S100B concentrations	Fasting and post-exercise serum S100B concentration	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in systemic inflammation	Fasting serum interleukin (IL) IL-6, IL-8, IL-10, IL-17, IL-1ß, IL-1ra, tumor necrosis factor-a, interferon-? concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in intestinal inflammation	Fecal calprotectin concentration	Study days 6, 18, 21, 23, 27, 39, 42, 44, 48, 60, 63, 65
Secondary	Difference in glucose concentrations	Fasting and post-exercise serum glucose concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in insulin concentrations	Fasting and post-exercise serum insulin concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in lactate concentrations	Fasting and post-exercise serum lactate concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in glycerol concentrations	Fasting and post-exercise serum glycerol concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in cortisol concentrations	Fasting and post-exercise serum cortisol concentrations	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in bone specific alkaline phosphatase concentrations	Fasting serum bone specific alkaline phosphatase concentration	Study days 20, 41, 62
Secondary	Difference in carboxy-terminal collagen crosslinks concentrations	Fasting serum carboxy-terminal collagen crosslinks concentration	Study days 20, 41, 62
Secondary	Difference in tartrate resistant acid phosphatase concentrations	Fasting serum tartrate resistant acid phosphatase concentration	Study days 20, 41, 62
Secondary	Difference in procollagen type 1 N-terminal propeptide concentrations	Fasting serum procollagen type 1 N-terminal propeptide concentration	Study days 20, 41, 62
Secondary	Difference in osteocalcin concentrations	Fasting serum osteocalcin concentration	Study days 20, 41, 62
Secondary	Difference in secretory immunoglobulin A concentrations	Secretory immunoglobulin A concentrations in tear fluid and saliva	Study days 20, 21, 41, 42, 62, 63
Secondary	Difference in immune cell phenotypes	Immune cell phenotype by flow cytometry	Study days 21, 42, 63
Secondary	Difference in T-cell simulated cytokine production	T-cell simulated cytokine production by cell culture and flow cytometry	Study days 21, 42, 63
Secondary	Difference in natural killer-cell cytotoxicity	Natural killer-cell cytotoxicity by cell culture and flow cytometry	Study days 21, 42, 63
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Difference in risk taking behavior	Measured by Balloon Analogue Risk Task	Study days 7, 20, 21, 41, 42, 62, 63
Secondary	Difference in resting metabolic rate	Resting metabolic rate measured by indirect calorimetry	Study days 7, 21, 42, 63
Secondary	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
Secondary	Difference in gastrointestinal transit time	Gastric, small intestine and large intestine transit time measured by SmartPill	Study days 20, 41, 62
Secondary	Difference in gastrointestinal pH	Gastric, small intestine and large intestine pH measured by SmartPill	Study days 20, 41, 62
Secondary	Difference in changes in working memory	Measured by N-Back task before, during and after exercise	Study days 20, 21, 41, 42, 62, 63
Secondary	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
Secondary	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
Secondary	Difference in change in reaction time	Measured by reaction time task before, during and after exercise	Study days 20, 21, 41, 42, 62, 63
Secondary	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
Secondary	Difference in vigilance	Measured by scanning visual vigilance task	Study days 20, 21, 23, 41, 42, 44, 62, 63, 65
Secondary	Difference in simple visual reaction time	Measured by psychomotor vigilance test	Study days 20, 21, 23, 41, 42, 44, 62, 63, 65
Secondary	Difference in language-based logical reasoning	Measured by grammatical Reasoning task	Study days 20, 21, 23, 41, 42, 44, 62, 63, 65
Secondary	Difference in ambulatory vigilance	Measured by wrist-worn vigilance monitor	48-hours/day during study weeks 0, 2, 3, 5, 6, 8, 9
Secondary	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
Secondary	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
Secondary	Differences in microRNA concentrations	Fasting and post-exercise circulating and exosomal microRNA	Study days 20, 21, 41, 42, 62, 63