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Trial record 65 of 401 for:    PYY

Investigating Optimal Propionate Delivery to the Colon Using Stable Isotope Labeling

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ClinicalTrials.gov Identifier: NCT02229500
Recruitment Status : Completed
First Posted : September 1, 2014
Last Update Posted : April 28, 2016
Sponsor:
Collaborators:
Biotechnology and Biological Sciences Research Council
University of Glasgow
Information provided by (Responsible Party):
Scottish Universities Environmental Research Centre

Brief Summary:

Obesity, with its associated co-morbidities, is a major public health challenge. It is estimated that by 2050, 60% of men and 50% of women will be clinically obese. Obesity is associated with increased risk of developing diabetes, cardiovascular disease, and certain cancers. The increasing epidemic of obesity has necessitated the study of the complex mechanisms underlying energy homeostasis. Food intake, energy balance and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY), have been shown to play an important role in regulating short-term food intake. Peripheral administration of PYY or GLP-1 enhances satiety and reduces food intake in animals and man. PYY, GLP-1 along with a host of other hormones are produced by the gut in response to nutrient availability in different regions of the gut and provide an exquisite mechanism of nutrient sensing in response to dietary intake. These hormones therefore represent potential targets in the development of novel anti-obesity treatments. A novel and attractive strategy to induce appetite regulation is the enrichment of foods with components that stimulate the release of GLP-1 and PYY. The short chain fatty acids (SCFA) produced by microbial fermentation of dietary fibre in the colon have been shown to stimulate the release of PYY and GLP-1 from rodent enteroendocrine L cells, via stimulation of the G-protein coupled free fatty acid receptors (FFAR) on colonic L cells. Of the SCFAs produced by colonic fermentation of dietary fibre, propionate has the highest affinity for FFAR 2. Furthermore, propionate is an end product of bacterial metabolism, and thus, unlike acetate, does not undergo conversion to other SCFAs. Increasing colonic propionate is therefore an attractive target for appetite modulation.

We have developed a novel delivery system for delivering propionate to the right site in the colon and we now wish to optimise the delivery of propionate to the colon in man using stable isotope labelling methods.


Condition or disease Intervention/treatment Phase
Optimum Propionate Delivery to the Large Intestine Dietary Supplement: Inulin Dietary Supplement: 2.5 g of propionate Dietary Supplement: 5 g of propionate Not Applicable

Detailed Description:

The role of SCFA in appetite regulation: SCFA have been shown to stimulate PYY and GLP-1 production in animal models and dietary fibre, of which SCFA are the major end products, induce appetite regulation in humans. However the evidence underpinning which dietary fibres induce appetite regulation in humans is very weak because of the difficulty in controlling studies with very high fibre intake. In a recent project funded under the BBSRC DRINC initiative (BB/H004815/1), we have the first direct evidence that SCFA can directly regulate appetite in humans. Prior to this study, in order to achieve production of SCFA to a level, which is high enough to induce appetite-regulating effects, very large amounts of dietary fibre (>25 g/d and up to 40 g/d) are required, and compliance with high fibre diets is poor due to gastrointestinal side effects. Furthermore, supplementing diets with mixed high fibre does not predictably or reliably increase colonic SCFA production or circulating levels of SCFA in all human populations because of the variability in gut microbial activity. Finally, orally administered SCFAs are not palatable and are rapidly absorbed in the small intestine where L cells are sparse. In our studies to date we have focussed on the SCFA propionate because it has the highest affinity for the receptors and is an end product of metabolism in the microbiota and therefore seems the obvious target to manipulate to investigate the effects of SCFA on appetite regulation. To overcome the unpalatably high levels of fermentable dietary fibre needed to significantly increase colonic propionate levels, and the unpredictability in the production of the resulting SCFAs, we have developed and tested a novel delivery system targeting the release of gram quantities of propionate in the proximal colon. We estimate that our delivery system may lead to a 2-8 fold increase in colonic propionate, a level very difficult to achieve through feeding a mixed fermentable fibre diet. This level of propionate production might have been observed in ancestral diets and in parts of rural Africa where dietary fibre intake is very high. We have also demonstrated that delivery system increases plasma propionate levels, reduces food intake in acute studies of appetite, and in a longer term study (24 weeks), positive effects on food intake, body composition, glucose homeostasis, circulating lipids, cholesterol and liver function, liver and visceral fat and weight management were observed. However, in these studies we pragmatically chose an preparation that could be produced at scale. The amount of propionate released can be varied which in itself may affect the rate and amount of propionate released. For an ingredient, with the potential to be incorporated into a wide variety of foodstuffs, we now wish to investigate the optimum delivery system preparation that delivers the maximal propionate dose in the least amount of material.

We plan to use non-invasive, stable isotope labelling methodologies to determine propionate bioavailability from a range of delivery system preparations, in order to determine the optimum preparation for delivering maximal propionate to the proximal colon.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: Regulating Appetite by Targeting Nutrient Delivery in the Gut
Study Start Date : August 2014
Actual Primary Completion Date : August 2015
Actual Study Completion Date : December 2015

Arm Intervention/treatment
Active Comparator: Control
Inulin control, 10g/d for 7 days. Isotope and appetite measurements on day 7
Dietary Supplement: Inulin
Other Name: Beneo-Orafti HP

Experimental: Delivery system 1
Delivery system, 28.5% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.
Dietary Supplement: 2.5 g of propionate
This system delivers approximately 2.5 g of propionate to the colon in a 10g dose.

Experimental: Delivery system 2
Delivery system, 54% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.
Dietary Supplement: 5 g of propionate
This delivers approximately 5g of propionate to the colon per 10g dose




Primary Outcome Measures :
  1. Time to maximal 13C appearance in breath [ Time Frame: over 24 hrs ]
    The time to peak maximal excretion in breath 13C (measured in breath 13CO2) will be the primary outcome criterion


Secondary Outcome Measures :
  1. Area under curve of breath 13C excretion [ Time Frame: over 24hrs ]
    The area under the curve of breath 13C excretion (measured in 13CO2) will be determined to assess amount of propionate released.


Other Outcome Measures:
  1. Effect of preparations on appetite [ Time Frame: 0ver 8 hrs ]
    The effect of different delivery system preparations on appetite will be determined by visual analog scale measurements and ad libitum food intake



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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • overweight males (BMI 25-35 kg/m2) aged between 21 - 65

Exclusion Criteria:

  • Weight change of > 3kg in the preceding 2 months
  • Current smokers
  • Substance abuse
  • Excess alcohol intake
  • Pregnancy
  • Diabetes
  • Cardiovascular disease
  • Cancer
  • Gastrointestinal disease
  • Kidney disease
  • Liver disease
  • Pancreatitis
  • Use of any medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02229500


Locations
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United Kingdom
Glasgow Clinical Research Facility
Glasgow, Lanarkshire, United Kingdom, G4 0SF
Sponsors and Collaborators
Scottish Universities Environmental Research Centre
Biotechnology and Biological Sciences Research Council
University of Glasgow
Investigators
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Principal Investigator: Douglas Morrison, PhD University of Glasgow

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Responsible Party: Scottish Universities Environmental Research Centre
ClinicalTrials.gov Identifier: NCT02229500     History of Changes
Other Study ID Numbers: BB/L004259/1_SUERC_1
First Posted: September 1, 2014    Key Record Dates
Last Update Posted: April 28, 2016
Last Verified: April 2016

Keywords provided by Scottish Universities Environmental Research Centre:
Propionate
Microbiome
Dietary Fibre
Short chain fatty acids