ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.

SummaryBackgroundShort‐chain fatty acids (SCFA) produced through fermentation of nondigestible carbohydrates by the gut microbiota are associated with positive metabolic effects. However, well‐controlled trials are limited in humans.AimsTo develop a methodology to deliver SCFA directly to the colon, and to optimise colonic propionate delivery in humans, to determine its role in appetite regulation and food intake.MethodsInulin SCFA esters were developed and tested as site‐specific delivery vehicles for SCFA to the proximal colon. Inulin propionate esters containing 0–61 wt% (IPE‐0–IPE‐61) propionate were assessed in vitro using batch faecal fermentations. In a randomised, controlled, crossover study, with inulin as control, ad libitum food intake (kcal) was compared after 7 days on IPE‐27 or IPE‐54 (10 g/day all treatments). Propionate release was determined using 13C‐labelled IPE variants.Results In vitro, IPE‐27–IPE‐54 wt% propionate resulted in a sevenfold increase in propionate production compared with inulin (P < 0.05). In vivo, IPE‐27 led to greater 13C recovery in breath CO 2 than IPE‐54 (64.9 vs. 24.9%, P = 0.001). IPE‐27 also led to a reduction in energy intake during the ad libitum test meal compared with both inulin (439.5 vs. 703.9 kcal, P = 0.025) and IPE‐54 (439.5 vs. 659.3 kcal, P = 0.025), whereas IPE‐54 was not significantly different from inulin control.Conclusions IPE‐27 significantly reduced food intake suggesting colonic propionate plays a role in appetite regulation. Inulin short‐chain fatty acid esters provide a novel tool for probing the diet–gut microbiome–host metabolism axis in humans.

Recent evidence suggests that short chain fatty acids (SCFA) trigger the release of the anorectic gut hormones peptide YY (PYY) and glucagon like peptide-1 (GLP-1) by stimulating the free fatty acid receptors (FFAR) 2 and 3 on enteroendocrine L cells (1) . Of the SCFA produced by colonic fermentation of available carbohydrates, propionate has been shown to have the highest affinity for FFAR2 (2) . We hypothesised that increasing colonic propionate would stimulate gut hormone secretion and reduce energy intake. To elevate colonic propionate levels we have developed a novel propionate ester molecule whereby propionate is chemically bound by an ester bond to inulin. The majority of the bound propionate should only be released when the inulin polymer is fermented by the colonic microbiota, thus providing targeted colonic delivery.To assess the site and extent of propionate release, 9 volunteers consumed a standardised breakfast containing 100 mg of 13 C labelled propionate ester and 10 g of unlabelled ester. Breath H 2 and 13 CO 2 enrichment were collected over 24 h to investigate gut transit times. Breath H 2 started to increase at 180 min and peaked at 240 min. More than 80% of the 13 C recovered in breath appeared co-incident with and after breath H 2 onset, suggesting delivery of the majority of the bound propionate to the colon.Plasma PYY levels after ingestion of propionate ester vs. control. Dotted lines signify the time point after which >80% propionate ester enters the colon. Data are presented as means ± SEM, *P < 0.05. This propionate ester (10 g/d) and an inulin control (10 g/d) were then administered to 20 volunteers in a randomised crossover study to determine its effect on food intake and gut hormone concentrations. Ingestion of 10 g propionate ester significantly increased plasma PYY and GLP-1 (P < 0.05) and reduced ad libitum food intake (1175 ± 103 kcal control vs. 1013 ± 94 kcal propionate ester; p < 0.01).In conclusion, these data suggest that an acute increase in colonic propionate can elevate plasma PYY and GLP-1 levels and reduce food intake in humans. Elevating propionate levels in the colon may therefore offer a potential strategy to protect against weight gain and the metabolic consequences of obesity.

It is estimated that 20-30% of adults in developed countries have non-alcoholic fatty liver disease (NAFLD), a condition characterized by the accumulation of fat within the liver (1) . NAFLD is commonly associated with an increased risk of developing Type 2 diabetes. Positive physiological effects have been linked with the production of short chain fatty acids (SCFA) by colonic fermentation of non-digestible carbohydrate (NDC), including reductions in hepatic fat content (2) . We have developed a novel inulin-propionate ester, whereby the SCFA propionate is bound to the NDC inulin. The bound propionate is only released from the inulin carrier molecule through bacterial fermentation in the colon allowing the targeted delivery of gram quantities of propionate. In humans, ∼90% of propionate produced in the colon is extracted from portal blood by the liver. Propionate is a known gluconeogenic substrate, and the energy to drive this anabolic pathway may derive from increased hepatic fat oxidation (3) . We hypothesised that long-term elevations in colonic propionate production would reduce liver fat in adults with NAFLD.Sixteen participants aged 40-65 years, with a BMI of 25-40 kg/m2 were recruited and intrahepatocellular lipid (IHCL) was determined using 1 H magnetic resonance spectroscopy (MRS) (4) . Participants were identified as having NAFLD on the basis of a liver fat content >5·5% (5) . Participants were provided with either 10 g/day propionate ester (n = 11) or 10 g/day inulin control (n = 5) to add to their normal diet for a 24 week intervention period. After 24 weeks of dietary supplementation, measurements taken at baseline were repeated. In the propionate ester group a significant reduction in IHCL content post-intervention was observed (22·1% to 15·9%; P = 0·038). This effect was not found in the control group (19·1% to 18·7%; P = 0·576). An improvement in liver function tests (alanine amino transferase and aspartate aminotransferase) was also observed within the propionate ester group, whilst these liver function tests were unchanged in the control group. There was no significant change in body weight following the intervention period in either group.Our data provides the first direct evidence in humans that gut-derived propionate can reduce liver fat in adults with NAFLD. Targeting increased colonic propionate levels, delivered via enriched food products, may offer a public health solution to the increased prevalence of NAFLD at the population level and warrants further investigation.

The colonic microbiota ferment available carbohydrates, producing short chain fatty acids (SCFAs), which trigger the release of the anorectic gut hormones peptide YY (PYY) and glucagon like peptide-1 (GLP-1) by stimulating the free fatty acid receptors (FFAR) 2 and 3 on the enteroendocrine L cells (1) . We have developed a novel inulin propionate ester that targets delivery of gram quantities of the SCFA propionate to the human colon and which significantly increases PYY and GLP-1 secretion and reduces food intake following acute ingestion at a dose of 10 g (unpublished observation). We hypothesised that long-term supplementation with propionate ester would prevent weight gain in overweight adults.Forty nine men and women aged 40-65 years, with a body mass index (BMI) of 25-40 kg/m 2 were recruited and randomly assigned to receive either 10 g/day inulin control (n = 24) or 10 g/day propionate ester (n = 25) for 24-weeks. Body composition data, assessed using magnetic resonance imaging, was collected from 17 subjects in the propionate ester group and 15 subjects in the control group.Significantly fewer subjects gained 53% (P = 0.036) and >5% (P = 0.033) of their baseline body weight following propionate ester supplementation. Weight loss after 24 weeks was greater in the propionate ester group, but this effect was not significantly different between groups (−1.02 kg [95% CI, −2.10 to 0.04] propionate ester vs. 0.38 kg [95% CI, −0.95 to 1.72] control; P = 0.099). The change in the distribution of intra-abdominal adipose tissue (AT) was significantly lower in the propionate ester group compared with control supplementation (P = 0.027). Furthermore, internal AT (P = 0.002) was significantly increased within the control group, but not in the propionate ester group.In conclusion, this investigation provides the first direct evidence that colonic propionate can prevent body weight and intra-abdominal AT gain in humans. Dietary strategies that promote colonic propionate production may play a role in weight management over the life-course.