Fiber Metabolism in Chronic Obstructive Pulmonary Disease

• ClinicalTrials.gov Identifier: NCT04459156
• Recruitment Status: Recruiting
• First Posted: July 7, 2020
• Last Update Posted: July 7, 2020
• Sponsor: Texas A&M University
• Information provided by (Responsible Party): Marielle PKJ Engelen, PhD, Texas A&M University

Study Description

Brief Summary:

The impact of fiber intake on short chain fatty acid (SCFA) metabolism has not been studied in subjects suffering from COPD. The purpose of this study is to compare changes in SCFA metabolism after inulin vs. placebo intake in COPD patients to healthy matched controls. This protocol is an extension of a recent study about whole-body SCFA production rates in COPD patients. The investigators hypothesize that a short-term fiber supplementation increases SCFA production in COPD patients.

Condition or disease	Intervention/treatment	Phase
Chronic Obstructive Pulmonary Disease	Dietary Supplement: Fiber Inulin; Dietary Supplement: Placebo Maltodextrin	Not Applicable

Detailed Description:

Dietary fibers are indigestible carbohydrates, which are present in several daily foods such as beans, legumes, whole grain products, and whole fruits and vegetables. The Food and Drug Administration recommends a daily fiber uptake of 25 g. However, in 2009-2010 the mean fiber intake of US adults was 17 g/day. Fiber cannot be digested by human enzymes and reach the colon undigested. Depending on the chemical structure (solubility, degree of polymerization) of the fiber, it can or cannot be fermented by the intestinal bacteria. Insoluble, unfermented fibers such as cellulose help to prevent constipation by enhancing bowel movement and the transit time of the feces. Most soluble fibers like inulin can be fermented by intestinal bacteria. During the bacterial fermentation short-chain fatty acids (SCFA) such as acetate (C2), propionate (C3), and butyrate (C4) are produced. The production is highest in the proximal colon where the abundance of fiber is the highest. The colonocytes absorb more than 90 % of the SCFAs, the rest is excreted with the feces. Most of the butyrate is oxidized in the colonocytes, being their main energy source. Propionate gets metabolized by the liver. In particular acetate enters the systemic circulation and might have anti-inflammatory and immune modulating effects. Indole and isovalerate are products of bacterial amino acid fermentation. Indole is solely produced by bacterial enzymes from the essential amino acid tryptophan (TRP) and isovalerate from branched-chain amino acids.

In COPD an enhanced pulmonary inflammatory response causes a combination of small airways disease (e.g., obstructive bronchiolitis) and/or a destruction of lung parenchyma (emphysema). This leads to a progressive and persistent airflow limitation. It has been shown that a healthy overall diet as well as a diet high in fiber can be associated with a good lung function and a decreased COPD prevalence. A diet rich in fermentable fiber altered the gut and lung microbiota composition in mice, mainly through a decrease in the Firmicutes-to-Bacteroidetes-ratio, which was accompanied by elevated concentrations of circulating SCFAs. These mice were protected against allergic inflammation in the lungs. Previous human research has demonstrated that the composition of the intestinal microbiota influences the asthma risk and it was associated with early life exacerbations in cystic fibrosis, which demonstrates a gut-lung cross-talk. Halnes et al. found a significantly reduced airway inflammation in asthma patients four hours after the ingestion of a meal containing soluble fiber and prebiotics compared to a placebo meal. Stable tracer studies are needed to examine the colonic production and metabolic fate of SCFAs in healthy and ill subjects.

Study Design

• Study Type: Interventional
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Fiber Metabolism in Chronic Obstructive Pulmonary Disease
• Actual Study Start Date: June 23, 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Healthy Participants; healthy control subjects	Dietary Supplement: Fiber Inulin; Commercially available inulin is provided as powder. The following doses will be administered twice daily (with breakfast and dinner): Day 1-2: 5-g; Day 3: 7.5-g; Day 4: 10-g; Day 5: 12.5-g; Day 6-7: 15-g. All supplements are commercially available.; Dietary Supplement: Placebo Maltodextrin; Commercially available maltodextrin is provided as powder. The following doses will be administered twice daily (with breakfast and dinner): Day 1-2: 5-g; Day 3: 7.5-g; Day 4: 10-g; Day 5: 12.5-g; Day 6-7: 15-g. All supplements are commercially available.
Experimental: Chronic Obstructive Pulmonary Disease patients; Established diagnosis of Chronic Obstructive Pulmonary Disease	Dietary Supplement: Fiber Inulin; Commercially available inulin is provided as powder. The following doses will be administered twice daily (with breakfast and dinner): Day 1-2: 5-g; Day 3: 7.5-g; Day 4: 10-g; Day 5: 12.5-g; Day 6-7: 15-g. All supplements are commercially available.; Dietary Supplement: Placebo Maltodextrin; Commercially available maltodextrin is provided as powder. The following doses will be administered twice daily (with breakfast and dinner): Day 1-2: 5-g; Day 3: 7.5-g; Day 4: 10-g; Day 5: 12.5-g; Day 6-7: 15-g. All supplements are commercially available.

Outcome Measures

Primary Outcome Measures :

1. Whole body short-chain fatty acid production rates by plasma samples [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences and changes in whole body SCFA production rates in COPD patients and healthy older adults after administration of stable-isotope labeled short-chain fatty acids.
2. Intestinal microbiota composition by stool sample collection using Shallow Shotgun Sequencing [ Time Frame: Collection up to 24 hours before study visits of weeks 1, 2, 4, and 5 ]
   Differences and changes in intestinal microbiota composition in COPD patients and healthy older adults using Shallow Shotgun Sequencing

Secondary Outcome Measures :

1. Intestinal integrity markers by stool samples [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences and changes in fecal zonulin levels in COPD patients and healthy older adults.
2. Exhalation of CO2 from short-chain fatty acid oxidation [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences and changes in concentrations of exhaled, labeled CO2 originating from intravenously administered stable-isotope labeled short-chain fatty acids.
3. Fecal short-chain fatty acid concentrations by stool samples [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences and changes in fecal SCFA concentrations in COPD patients and healthy older adults.
4. Body composition by DXA [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences in muscle mass (kg), fat mass (kg), and bone mineral density (g/cm^2) between COPD patients and healthy older adults using DXA.
5. Bone mineral density by BIA [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Differences in muscle mass (kg), fat mass (kg), and extra- and intracellular fluid (L) between COPD patients and healthy older adults using BIA.
6. Handgrip strength dynamometry [ Time Frame: Weeks 1, 2, 4, and 5 ]
   Difference and changes in handgrip strength in COPD patients and healthy older adults.
7. 6 minute walk test distance [ Time Frame: Screening visit ]
   With this sub-maximal exercise test, aerobic capacity and endurance will be compared between COPD patients and healthy older adults. The outcome is the distance covered over a time of 6 minutes.
8. Skeletal muscle strength of leg [ Time Frame: Screening visit ]
   Difference in muscle strength of leg using kin-com machine between COPD patients and healthy older adults.
9. Micro-respiratory pressure meter measurement [ Time Frame: Screening visit ]
   Difference and changes in maximum inspiratory and expiratory pressure between COPD patients and healthy older adults.
10. C-reactive protein [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Differences and changes in the concentration of the inflammatory marker C-reactive protein in COPD patients and healthy older adults.
11. Attention and executive functions measured by Trail Making Test (TMT) [ Time Frame: Weeks 1, 2, 4, and 5 ]
    In Part A, the examinee is instructed to connect a set of 25 circles with numbers as quickly as possible while maintaining accuracy. In Part B, the examinee is instructed to connect a set of 25 circles, alternating between numbers and letters, as quickly as possible while maintaining accuracy. Measures attentional resources and is a measure of the frontal lobe "executive" functions of visual search, set-switching and mental flexibility. The total time in seconds will be recorded for each measure.
12. Attention and executive functions measured by Stroop Color-Word Test (SCWT) [ Time Frame: Screening visit ]
    A word page with words printed in black ink, a color page with blocks printed in color, and a color-word page where the color and the word do not match. The examinee reads the words or names the ink colors as quickly as possible within a time limit. Measures selective attention and inhibitory control. The total time in seconds was reported for each trial.
13. Gut function as reported by "The Gastrointestinal Symptom Rating Scale" [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Self-administered questionnaire regarding gut function and associated symptoms. It is composed of 15 items (7-Point Likert Scale) assessing Reflux, Abdominal pain, Indigestion, Diarrhoea and Constipation. Scores range from 15 to 105 with a higher score indicating more discomfort.
14. Physical activity as reported by "Physical Activity Scale for the Elderly" [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Self-administered questionnaire is intended for use in an elderly population and focuses on 3 types of activities: leisure time activities, household activities and work-related activities.
15. State of mood as measured by the Hospital Anxiety and Depression Scale (HADS [ Time Frame: Weeks 1, 2, 4, and 5 ]
    A fourteen item self-assessment scale. Seven of the items related to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression.
16. COPD Assessment Test [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Self-administered questionnaire regarding impact of COPD on daily life
17. 3-day diet diary [ Time Frame: Completion within the week before study visits of weeks 1, 2, 4, and 5 ]
    The subject is asked to note in detail all the food and drinks consumed during 3 days (2 week days and 1 weekend day) in the week prior to each test day.
18. Group differences in learning and memory as measured by Digit Span [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Recall of numbers in the same order (Digit Forward) and in reverse order (Digit Backward). Measures auditory attention and verbal working memory.
19. Group differences in overall cognitive abilities as measured by Montreal Cognitive Assessment (MoCA) [ Time Frame: Screening visit ]
    Assesses several cognitive domains and is used for the screening of mild cognitive impairment. Total scores range from 0-30 with lower scores indicating decreased functioning.
20. Group differences in state of mood as measured by the Profile of Mood State (POMS) [ Time Frame: Weeks 1, 2, 4, and 5 ]
    A psychological distress scale to measure mood disturbance in 6 domains - fatigue-inertia, vigor-activity, tension-anxiety, depression-dejection, anger-hostility, and confusion-bewilderment.
21. Group differences in learning and memory as measured by Controlled Oral Word Association Test (COWAT) [ Time Frame: Weeks 1, 2, and 5 ]
    The examinee is required to say as many words as they can think of in one minute that begin with a given letter of the alphabet. The task contains three trials. Measures phonemic verbal fluency. The raw score (total and mean words recorded across the three trials) will be reported.
22. Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) [ Time Frame: Weeks 1, 2, 4, and 5 ]
    Quality of life concerns related to fatigue will be assessed only in COPD patients with this questionnaire.

Eligibility Criteria

• Ages Eligible for Study: 45 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy male or female according to the investigator's or appointed staff's judgment
• Ability to walk, sit down and stand up independently
• Age 45 - 100 years
• Ability to lay in supine or elevated position for 1.5 hours
• No diagnosis of COPD
• Willingness and ability to comply with the protocol

Exclusion Criteria:

• Any condition that may interfere with the definition 'healthy subject' according to the investigator's judgment (healthy subjects only)
• Insulin dependent diabetes mellitus
• Established diagnosis of malignancy
• History of untreated metabolic diseases including hepatic or renal disorder
• Presence of acute illness or metabolically unstable chronic illness
• Presence of fever within the last 3 days
• Use of short course of oral corticosteroids within 4 weeks preceding study day

• Dietary or lifestyle characteristics:

  • Daily use of fiber supplements 1 week prior to the first test day
  • Daily use of protein supplements 5 days prior to each test day

• Indications related to interaction with study products:

  • Known allergy to inulin or inulin products
  • Known hypersensitivity to inulin or maltodextrin or any of its ingredients
• Failure to give informed consent or Investigator's uncertainty about the willingness or ability of the subject to comply with the protocol requirements
• (Possible) pregnancy
• Already enrolled in another clinical trial and that clinical trial interferes with participating in this study
• Any other condition according to the PI or nurse that was found during the screening visit, that would interfere with the study or safety of the patient

Contacts and Locations

Contacts

Contact: Marielle M Engelen, PhD; 9792202282; mpkj.engelen@ctral.org

Contact: Sarah Kirschner, M.S.; 979.422.1789; sk.kirschner@ctral.org

Locations

United States, Texas

Texas A&M University-CTRAL; Recruiting

College Station, Texas, United States, 77845

Contact: Marielle Engelen, PhD 979-220-2282 mpkj.engelen@ctral.org

Contact: Laura Ruebush, PhD 979-218-5515 le.ruebush@ctral.org

Sponsors and Collaborators

Texas A&M University

Investigators

• Principal Investigator: Marielle Engelen; Texas A&M University - CTRAL

More Information

• Responsible Party: Marielle PKJ Engelen, PhD, Director, Texas A&M University
• ClinicalTrials.gov Identifier: NCT04459156
• Other Study ID Numbers: 2019-0832
• First Posted: July 7, 2020
• Last Update Posted: July 7, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marielle PKJ Engelen, PhD, Texas A&M University:

fiber metabolism; short chain fatty acid production rates

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases