RCT to Describe the Effects of Colon Delivered Acetate, Propionate and Butyrate on Satiety and Glucose Homeostasis

Obesity Clinical Trial

— PRO-ESTER  

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02451189
• Other study ID #: PRO-ESTER STUDY
• Status: Completed
• Phase: N/A
• First received: May 19, 2015
• Last updated: April 27, 2016
• Start date: January 2015
• Est. completion date: April 2016

Study information

• Verified date: April 2016
• Source: Scottish Universities Environmental Research Centre
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial 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. However, it is not known whether the three SCFA, acetate, butyrate and propionate, differentially affect appetite and glucose control. The aim of this study is to compare the effects of increased colonic delivery of acetate, butyrate and propionate on appetite and glucose control in overweight men in a randomised crossover study.

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), the investigators 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, the investigators have developed and tested a novel delivery system targeting the release of gram quantities of propionate in the proximal colon. It is estimated that the 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. Previous work, conducted by the investigators, has 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, at present it is not known if acetate, propionate and butyrate exert similar effects on appetite and glucose metabolism. Therefore in this study we wish to compare the the effects of targeted delivery of acetate, propionate and butyrate to the proximal colon on appetite and glucose homeostasis in overweight men.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: April 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 21 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male and Female

• Healthy

• Overweight (BMI 25-40 kg/m2)

Exclusion Criteria:

• Weight change of > 3kg in the preceding 2 months

• Current smokers

• Substance abuse

• Excess alcohol intake

• Diabetes

• Cardiovascular disease

• Cancer

• Gastrointestinal disease

• Kidney disease

• Liver disease

• Pancreatitis

• Use of any medication except contraceptive pill

• Peri-menopausal

• Pregnancy

• Breastfeeding

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Obesity
• Overweight

Intervention

Dietary Supplement:
• Inulin acetate ester
Inulin acetate ester supplementation (10g/d) for 30 days. Appetite measurements on day 15 and oral glucose tolerance test (OGTT) on day 30.
• Inulin propionate ester
Inulin propionate ester supplementation (10g/d) for 30 days. Appetite measurements on day 15 and OGTT on day 30.
• Inulin butyrate ester
Inulin butyrate ester supplementation (10g/d) for 30 days. Appetite measurements on day 15 and OGTT on day 30.

Locations

Country	Name	City	State
United Kingdom	Glasgow Clinical Research Facility	Glasgow	Lanarkshire

Sponsors (3)

Lead Sponsor	Collaborator
Scottish Universities Environmental Research Centre	NHS Greater Clyde and Glasgow, University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Intestinal bacteria composition	Faecal samples will be collected to assess the impact of the NDC esters on gut bacteria composition	24 hours	No
Other	Lipids	Serum triglycerides and cholesterol concentrations will be determined	8 hours	No
Other	Appetite regulating gut hormones	Fasting and postprandial gut hormone concentrations will be measured	8 hours	No
Other	Liver function test		1hour	No
Primary	Energy intake at ad libitum meal	Energy intake is measured at an ad libitum meal	8 hours	No
Secondary	Subjective appetite sensations	Appetite is rated on 100 mm visual analogue scales	8 hours	No
Secondary	Plasma glucose and insulin	Oral glucose tolerance test: Fasting and 2h glucose and insulin concentrations following consumption of solution providing 75g glucose	2 hours	No