Diet ModificationMetanolsNCT04124016
Metabotypes in the Urinary Excretion of Flavan-3-ol Metabolites: "Metanols"
A study testing Inulin, green tea extract and grape seed in people with Diet Modification, run by University of Parma at 1 site in Italy.
Trial summary
Flavan-3-ols are the main source of flavonoids in Western diets. They are characteristic compounds of tea, cocoa, wine, apple, pears, etc. In plant-based foods, they occur as simple monomers or as oligomers and polymers of up to 50 units (also known as proanthocyanidins or condensed tannins). Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Diet Modification
- What is being tested?
- Inulin, green tea extract and grape seed
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 1 siteItaly
- Study dates
- 2 Sep 2019to 27 Dec 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Adult
- Both genders
- Healthy
- BMI > 18.5
- BMI < 30
Who cannot join
- Metabolic disorder or surgeries of liver, kidney or gastrointestinal tract
- Immunodeficiency
- Food intolerance or allergies
- Regular consumption of medication
- Antibiotic therapy within the last 3 months
- Use of food supplements, including pro- and prebiotics
Show all 9Show fewer
- Intense physical activity (PAL ≥ 2.10)
- Pregnancy
- Lactation
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Metabotypes in the Urinary Excretion of Flavan-3-ol Metabolites
Flavan-3-ols are the main source of flavonoids in Western diets. They are characteristic compounds of tea, cocoa, wine, apple, pears, etc. In plant-based foods, they occur as simple monomers or as oligomers and polymers of up to 50 units (also known as proanthocyanidins or condensed tannins). When ingested, both monomeric and high molecular weight flavan-3-ols are poorly absorbed and metabolized in the first gastrointestinal tract, reaching the colon and becoming a suitable substrate for the local microbiota. These compounds undergo an extensive microbial metabolism leading to the formation of hydroxyphenyl-γ- valerolactones (PVLs), which are then absorbed by colonocytes before reaching the liver and being converted into phase II conjugated metabolites. Since the microbiota composition varies among individuals, it results in differences in the production of PVLs and, consequently, the health effects of flavan-3-ols might change at an individual level.
Another factor of variability might be due to a different asset in the fermentation of indigestible dietary carbohydrates, which are known to modify colonic pH through the production of short-chain fatty acids and may result in different profiles of gas production (i.e. hydrogen and methane), possibly affecting the bioconversion of flavan-3-ols as well. Nevertheless, these multiple variabilities are poorly understood to date.
Read the detailed description
The study will be a single-dose, partially randomized, cross-over design, with 4 consecutive treatments. The study includes 4 phases where each volunteer will consume a specific dose of one of the products chosen for the study. Each volunteer will consume each product once, for a total of 4 different occasions. The products will be a food extract consisting of chicory fermentable fiber (inulin) fractions followed by three food extracts rich in a different type of flavan-3-ols, consumed at three different occasions and in random order.
Volunteers will be asked to provide once a fecal sample, taken from the first daily defecation, which will be analyzed for fecal microbiota composition. They will also undergo a Breath gases day profile in order to evaluate the effect of inulin consumption on colonic fermentation and breath-gases production. These two analyses (fecal samples microbial composition and breath-gases production) will serve to characterize the volunteers' gut microbiota composition and functionality. In detail, during the 48-h before the fecal and breath samples collections, volunteers will be asked to avoid a high level of fiber and (poly)phenols (to facilitate adherence to the dietary restrictions, a list of permitted and forbidden foods will be supplied. To check dietary compliance, a 2- days dietary record of the 2 days prior to each sampling day will be used.
The morning of the first treatment, volunteers will arrive, after an overnight fast, and they will deliver the fresh fecal sample. After that, one sample of forced end-expiratory samples of alveolar air will be collected. Then, they will be given a standardized test breakfast consisting of 12 g of food extract of chicory inulin fractions dissolved into 250 g water and a fermentable fiber-free, (poly)phenol-free, nutritionally-balanced solid meal. They will be asked to consume the entire breakfast within 15 minutes. At hourly intervals for 11 hours after breakfast, forced end-expiratory samples of alveolar air will be collected. During the whole test, all subjects will refrain from smoking, sleeping, exercising and eating foods or meals other than the ones provided by the staff. Five hours after starting the test, volunteers will eat a fermentable fiber-free nutritionally-balanced standardized lunch provided by the study staff.
Subsequently, on three distinct occasions and with one-week wash-out between different treatments, each participant will randomly consume a dose of flavan-3-ol rich extracts. Each test day, participants, after fasting baseline urine collection, will receive the dose of one of the food extract rich in flavan-3-ols (1 mmol of PVL precursors) dissolved into 200 mL of water. Then, the same standardized breakfast (pre-packaged (poly)phenol-free snack) will be provided to subjects. After breakfast, volunteers will be allowed to leave and to perform the successive urine collections on their own. Urine samples will be collected at selected intervals of time along the 24 h following the extract ingestion. In addition, urine sampling will continue in a subgroup of volunteers for the successive 24 h to evaluate the evolution of metabotypes from 24 to 48h. This subgroup will be composed of the first 30 participants enrolled in the study.
Subjects will be asked to follow a (poly)phenol-poor diet 48-h before each test day and while sampling (to facilitate adherence to the dietary restrictions, a list of permitted and forbidden foods will be supplied; to check dietary compliance, a 3/4-days dietary record of the 2 days prior to each sampling day and of the sampling day(s), depending on the subgroup the subject belongs to, will be used.
At the end of all treatments, and on the basis of the results of gas samples analysis, one subgroup of methane producer volunteers (number=5) and one of non-methane producers (numnber=5) will be asked to provide one further faecal sample, taken from the first daily defecation for In Vitro analysis of short-chain fatty acids and gas production after incubation with different mixes of Inulin and Polyphenols used during the In Vivo part of the study . Volunteers will be asked to follow a diet poor in (poly)phenols and fermentable fiber for 2 days before fecal donation.
- Conditions
- Diet Modification
- Being tested
- Inulin, green tea extract, grape seed, grape seed extract
- Keywords
- flavan-3-ol, phenyl-y-valerolactones, catechins, metabotype, gas production, gut microbiota
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InulinDietary supplement
Powder of inulin fractions dissolved into 250 ml of water
green tea extractDietary supplement
Powder of green tea extract dissolved into 200 ml of water
grape seedDietary supplement
Powder of grape seed extract (rich in di-hydroxylated flavan-3-ol monomers) dissolved into 200 ml of water
grape seed extractDietary supplement
Powder of grape seed extract (rich in di-hydroxylated flavan-3-ol oligomers) dissolved into 200 ml of water
| Study group | Role | What they receive |
|---|---|---|
| Inulin | Experimental | Inulin_ extract of chicory fermentable fiber Receives: Dietary Supplement: Inulin |
| green tea extract | Experimental | green tea extract_rich in tri-hydroxylated flavan-3-ol monomers (1 mmol of PVL precursor) Receives: Dietary Supplement: green tea extract |
| grape seed | Experimental | grape seed extract - rich in di-hydroxylated flavan-3-ol monomers (1 mmol of PVL precursors) Receives: Dietary Supplement: grape seed |
| grape seed exctract | Experimental | grape seed extract - rich in di-hydroxylated flavan-3-ol oligomers (1 mmol of PVL precursors) Receives: Dietary Supplement: grape seed extract |
What is being measured
The primary outcome is the main question the study is designed to answer.
Assessing the formation of urinary metabotypes of flavan-3-ol colonic metabolites
Assessing the variability of the area under the curve of the urinary concentration of some phenolic metabolites ( tri- and di-hydroxyphenyl-γ-valerolactones and 3-hydroxyphenylpropionic acids (umol)) after consumption of 3 different sources of flavan-3-ols by using data-driven clustering.
Measured: AUC for 24 hours (sum of 0-180; 180-360; 360-540; 540-720; 720-1440 minutes)
Secondary outcomes (7)
Evolution over the time of the metabolites of flavan-3-ols in urine samples
Assessed by using UHPLC-MSn for individual detection and quantification.
Measured: AUC for 48 hours (sum of 0-180; 180-360; 360-540; 540-720; 720-1440; 1440-2160; 2160-2880; 2880 minutes)
Identification of Firmicutes, bacteroidetes and Archea in faecal samples of participants
Firmicutes, Bacteroidetes and Archea main species assessed by an optimized 16S rRNA gene-based analysis protocol.
Measured: Baseline
Evaluation of inter-individual differences on breath-gases production (hydrogen and methane) on alveolar air samples
Performed by using a hydrogen/methane analyser
Measured: AUC for 12 hours; (sum of 60; 120; 180; 240; 300; 360; 420; 480; 540; 600; 660; 720 minutes)
Correlations between colonic fermentation, gas production and microbiota composition and metabotypes
multiple correlation between in vitro short chain fatty acids and gas production, microbiota composition and metabotype through PCA and PLS-DA.
Measured: 24 hours
In vitro variation of gases production by fermentable dietary fibre in presence of polyphenols using faecal starters
Gasses production will be assessed using a hydrogen/methane analyser
Measured: Baseline
In vitro variation of short chain fatty acids production of fermentable dietary fibre in presence of polyphenols using faecal starters
Short chains fatty acids will be quantified using GC-MS
Measured: Baseline
Untargeted metabolomics on urine samples
Metabolomics will be carried out in urine using HR-LC-MS/MS to unravel the potential metabolic pathways of molecules present after the consumption of the different sources of flavan-3-ols.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2019
- Study start2 Sep 2019
- Primary completionFeb 2022 (estimated)
- Study completion27 Dec 2022 (estimated)
Why it stopped: COVID
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diet ModificationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- single-dose, partially randomized, cross over design with 4 consecutive treatments
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Parma
- Sponsor type
- University, hospital or other
- Collaborators
- Azienda Ospedaliero-Universitaria di Parma
- Responsible party
- Principal investigator, Professor Furio Brighenti, University of Parma
- Investigators
- Furio FB Brighenti, Professor, Principal investigator, University of ParmaDaniele DR Del Rio, Professor, Study director, University of ParmaPedro Miguel PM Mena Parreño, Ph.D., Study director, University of ParmaRossella RD Dodi, M. Sc., Study director, University of Parma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04124016
- Sponsor's protocol ID
- 796/2018/SPER/UNIPR
- Acronym
- Metanols
- Status last verified
- Apr 2021
- First submitted
- 3 Sep 2019
- Last updated
- 30 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metabotypes in the Urinary Excretion of Flavan-3-ol Metabolites
- ClinicalTrials.gov ID
- NCT04124016
- Acronym / sponsor ID
- Metanols / 796/2018/SPER/UNIPR
- Conditions
- Diet Modification
- Keywords
- flavan-3-ol, phenyl-y-valerolactones, catechins, metabotype, gas production, gut microbiota
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: COVID
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- University of ParmaUniversity, hospital or other
- Collaborators
- Azienda Ospedaliero-Universitaria di Parma
- Study start
- 2 Sep 2019 (actual)
- Primary completion
- Feb 2022 (estimated)
- Study completion
- 27 Dec 2022 (estimated)
- First posted
- 11 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Flavan-3-ols are the main source of flavonoids in Western diets. They are characteristic compounds of tea, cocoa, wine, apple, pears, etc. In plant-based foods, they occur as simple monomers or as oligomers and polymers of up to 50 units (also known as proanthocyanidins or condensed tannins). When ingested, both monomeric and high molecular weight flavan-3-ols are poorly absorbed and metabolized in the first gastrointestinal tract, reaching the colon and becoming a suitable substrate for the local microbiota. These compounds undergo an extensive microbial metabolism leading to the formation of hydroxyphenyl-γ- valerolactones (PVLs), which are then absorbed by colonocytes before reaching the liver and being converted into phase II conjugated metabolites. Since the microbiota composition varies among individuals, it results in differences in the production of PVLs and, consequently, the health effects of flavan-3-ols might change at an individual level.
Another factor of variability might be due to a different asset in the fermentation of indigestible dietary carbohydrates, which are known to modify colonic pH through the production of short-chain fatty acids and may result in different profiles of gas production (i.e. hydrogen and methane), possibly affecting the bioconversion of flavan-3-ols as well. Nevertheless, these multiple variabilities are poorly understood to date.
Detailed description
The study will be a single-dose, partially randomized, cross-over design, with 4 consecutive treatments. The study includes 4 phases where each volunteer will consume a specific dose of one of the products chosen for the study. Each volunteer will consume each product once, for a total of 4 different occasions. The products will be a food extract consisting of chicory fermentable fiber (inulin) fractions followed by three food extracts rich in a different type of flavan-3-ols, consumed at three different occasions and in random order.
Volunteers will be asked to provide once a fecal sample, taken from the first daily defecation, which will be analyzed for fecal microbiota composition. They will also undergo a Breath gases day profile in order to evaluate the effect of inulin consumption on colonic fermentation and breath-gases production. These two analyses (fecal samples microbial composition and breath-gases production) will serve to characterize the volunteers' gut microbiota composition and functionality. In detail, during the 48-h before the fecal and breath samples collections, volunteers will be asked to avoid a high level of fiber and (poly)phenols (to facilitate adherence to the dietary restrictions, a list of permitted and forbidden foods will be supplied. To check dietary compliance, a 2- days dietary record of the 2 days prior to each sampling day will be used.
The morning of the first treatment, volunteers will arrive, after an overnight fast, and they will deliver the fresh fecal sample. After that, one sample of forced end-expiratory samples of alveolar air will be collected. Then, they will be given a standardized test breakfast consisting of 12 g of food extract of chicory inulin fractions dissolved into 250 g water and a fermentable fiber-free, (poly)phenol-free, nutritionally-balanced solid meal. They will be asked to consume the entire breakfast within 15 minutes. At hourly intervals for 11 hours after breakfast, forced end-expiratory samples of alveolar air will be collected. During the whole test, all subjects will refrain from smoking, sleeping, exercising and eating foods or meals other than the ones provided by the staff. Five hours after starting the test, volunteers will eat a fermentable fiber-free nutritionally-balanced standardized lunch provided by the study staff.
Subsequently, on three distinct occasions and with one-week wash-out between different treatments, each participant will randomly consume a dose of flavan-3-ol rich extracts. Each test day, participants, after fasting baseline urine collection, will receive the dose of one of the food extract rich in flavan-3-ols (1 mmol of PVL precursors) dissolved into 200 mL of water. Then, the same standardized breakfast (pre-packaged (poly)phenol-free snack) will be provided to subjects. After breakfast, volunteers will be allowed to leave and to perform the successive urine collections on their own. Urine samples will be collected at selected intervals of time along the 24 h following the extract ingestion. In addition, urine sampling will continue in a subgroup of volunteers for the successive 24 h to evaluate the evolution of metabotypes from 24 to 48h. This subgroup will be composed of the first 30 participants enrolled in the study.
Subjects will be asked to follow a (poly)phenol-poor diet 48-h before each test day and while sampling (to facilitate adherence to the dietary restrictions, a list of permitted and forbidden foods will be supplied; to check dietary compliance, a 3/4-days dietary record of the 2 days prior to each sampling day and of the sampling day(s), depending on the subgroup the subject belongs to, will be used.
At the end of all treatments, and on the basis of the results of gas samples analysis, one subgroup of methane producer volunteers (number=5) and one of non-methane producers (numnber=5) will be asked to provide one further faecal sample, taken from the first daily defecation for In Vitro analysis of short-chain fatty acids and gas production after incubation with different mixes of Inulin and Polyphenols used during the In Vivo part of the study . Volunteers will be asked to follow a diet poor in (poly)phenols and fermentable fiber for 2 days before fecal donation.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 4
- Model description
- single-dose, partially randomized, cross over design with 4 consecutive treatments
| Arm | Type | Receives |
|---|---|---|
| Inulin | Experimental | Dietary Supplement: InulinInulin_ extract of chicory fermentable fiber |
| green tea extract | Experimental | Dietary Supplement: green tea extractgreen tea extract_rich in tri-hydroxylated flavan-3-ol monomers (1 mmol of PVL precursor) |
| grape seed | Experimental | Dietary Supplement: grape seedgrape seed extract - rich in di-hydroxylated flavan-3-ol monomers (1 mmol of PVL precursors) |
| grape seed exctract | Experimental | Dietary Supplement: grape seed extractgrape seed extract - rich in di-hydroxylated flavan-3-ol oligomers (1 mmol of PVL precursors) |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Adult
- Both genders
- Healthy
- BMI > 18.5
- BMI < 30
Key exclusion criteria (9 listed)
- Metabolic disorder or surgeries of liver, kidney or gastrointestinal tract
- Immunodeficiency
- Food intolerance or allergies
- Regular consumption of medication
- Antibiotic therapy within the last 3 months
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InulinPowder of inulin fractions dissolved into 250 ml of water | Dietary supplement | Inulin |
| green tea extractPowder of green tea extract dissolved into 200 ml of water | Dietary supplement | green tea extract |
| grape seedPowder of grape seed extract (rich in di-hydroxylated flavan-3-ol monomers) dissolved into 200 ml of water | Dietary supplement | grape seed |
| grape seed extractPowder of grape seed extract (rich in di-hydroxylated flavan-3-ol oligomers) dissolved into 200 ml of water | Dietary supplement | grape seed exctract |
Primary outcome
Assessing the formation of urinary metabotypes of flavan-3-ol colonic metabolites
Time frame: AUC for 24 hours (sum of 0-180; 180-360; 360-540; 540-720; 720-1440 minutes)
Assessing the variability of the area under the curve of the urinary concentration of some phenolic metabolites ( tri- and di-hydroxyphenyl-γ-valerolactones and 3-hydroxyphenylpropionic acids (umol)) after consumption of 3 different sources of flavan-3-ols by using data-driven clustering.
7 secondary outcomes
Evolution over the time of the metabolites of flavan-3-ols in urine samples
Time frame: AUC for 48 hours (sum of 0-180; 180-360; 360-540; 540-720; 720-1440; 1440-2160; 2160-2880; 2880 minutes)
Identification of Firmicutes, bacteroidetes and Archea in faecal samples of participants
Time frame: Baseline
Evaluation of inter-individual differences on breath-gases production (hydrogen and methane) on alveolar air samples
Time frame: AUC for 12 hours; (sum of 60; 120; 180; 240; 300; 360; 420; 480; 540; 600; 660; 720 minutes)
Correlations between colonic fermentation, gas production and microbiota composition and metabotypes
Time frame: 24 hours
In vitro variation of gases production by fermentable dietary fibre in presence of polyphenols using faecal starters
Time frame: Baseline
In vitro variation of short chain fatty acids production of fermentable dietary fibre in presence of polyphenols using faecal starters
Time frame: Baseline
Untargeted metabolomics on urine samples
Time frame: 24 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2021.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Furio FB Brighenti, Professor principal investigator
University of Parma
Daniele DR Del Rio, Professor study director
University of Parma
Pedro Miguel PM Mena Parreño, Ph.D. study director
University of Parma
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Inulin, green tea extract and grape seed in people with Diet Modification, run by University of Parma at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 30 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Assessing the formation of urinary metabotypes of flavan-3-ol colonic metabolites (time frame: AUC for 24 hours (sum of 0-180; 180-360; 360-540; 540-720; 720-1440 minutes)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2021.