Optimum Propionate Delivery to the Large Intestine Clinical Trial
Official title:
Regulating Appetite by Targeting Nutrient Delivery in the Gut
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.
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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Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science