Investigating Optimal Propionate Delivery to the Colon Using Stable Isotope Labeling
Condition: Optimum Propionate Delivery to the Large Intestine
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. 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.
    

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.
    

Intervention name(s): Inulin; 2.5 g of propionate; 5 g of propionate
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): This system delivers approximately 2.5 g of propionate to the colon in a 10g dose.; This delivers approximately 5g of propionate to the colon per 10g dose
Other intervention name(s): Beneo-Orafti HP
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Propionate; Microbiome; Dietary Fibre; Short chain fatty acids