RCT to Describe the Effects of Colon Delivered Acetate, Propionate and Butyrate on Satiety and Glucose Homeostasis
Condition: Obesity; Overweight
MeSH terms: Overweight
Study type: Interventional

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.
    

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), 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.
    

Intervention name(s): Inulin acetate ester; Inulin propionate ester; Inulin butyrate ester
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): 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 supplementation (10g/d) for 30 days. Appetite measurements on day 15 and OGTT on day 30.; Inulin butyrate ester supplementation (10g/d) for 30 days. Appetite measurements on day 15 and OGTT on day 30.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Obesity; Weight maintenance; Appetite; Energy intake; Dietary fibre; Short-chain fatty acids; Fermentation; Overweight