Randomised clinical study: inulin short-chain fatty acid esters for targeted delivery of short-chain fatty acids to the human colon.

BACKGROUND: Short-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. AIMS: To 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. METHODS: Inulin 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 (13) C-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 (13) C recovery in breath CO2 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.

The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents.

BACKGROUND AND OBJECTIVES: The gut hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) acutely suppress appetite. The short chain fatty acid (SCFA) receptor, free fatty acid receptor 2 (FFA2) is present on colonic enteroendocrine L cells, and a role has been suggested for SCFAs in appetite regulation. Here, we characterise the in vitro and in vivo effects of colonic propionate on PYY and GLP-1 release in rodents, and investigate the role of FFA2 in mediating these effects using FFA2 knockout mice. METHODS: We used Wistar rats, C57BL6 mice and free fatty acid receptor 2 knockout (FFA(-/-)) mice on a C57BL6 background to explore the impact of the SCFA propionate on PYY and GLP-1 release. Isolated colonic crypt cultures were used to assess the effects of propionate on gut hormone release in vitro. We subsequently developed an in vivo technique to assess gut hormone release into the portal vein following colonic infusion of propionate. RESULTS: Propionate stimulated the secretion of both PYY and GLP-1 from wild-type primary murine colonic crypt cultures. This effect was significantly attenuated in cultures from FFA2(-/-) mice. Intra-colonic infusion of propionate elevated PYY and GLP-1 levels in jugular vein plasma in rats and in portal vein plasma in both rats and mice. However, propionate did not significantly stimulate gut hormone release in FFA2(-/-) mice. CONCLUSIONS: Intra-colonic administration of propionate stimulates the concurrent release of both GLP-1 and PYY in rats and mice. These data demonstrate that FFA2 deficiency impairs SCFA-induced gut hormone secretion both in vitro and in vivo.

Colestyramine slows gastric emptying of liquids and reduces appetite in healthy subjects.

BACKGROUND: There is evidence to suggest that the particulate resin colestyramine, a bile acid sequestrant formerly used as a cholesterol-lowering agent, enhances secretion of the gut hormone cholecystokinin (CCK). Established physiological actions of CCK include inhibition of gastric emptying and induction of satiation. This study evaluated the hypothesis that colestyramine, which is luminally retained, would slow gastric emptying of liquids and suppress appetite in humans. METHODS: Nine healthy volunteers consumed 500 mL liquid test meals containing 4 g colestyramine, 12 g colestyramine, or control (water alone), on three occasions, in a randomized order. The effect of colestyramine on gastric emptying was determined non-invasively using the (13) C-acetate breath test, and appetite and other gut-centered sensations were rated using visual analog scale questionnaires. KEY RESULTS: Colestyramine dose dependently slowed liquid gastric emptying compared with control (water) (4 g vs control, ∼20% reduction, P < 0.05; 12 g vs control, ∼35% reduction, P < 0.01). Colestyramine also significantly reduced hunger (4 g vs control, ∼20% reduction, P < 0.01), and the amount of food participants felt able to eat (12 g vs control, ∼32% reduction, P < 0.001), but increased bloating (both doses, P < 0.05), with no effect on ratings of nausea. CONCLUSIONS & INFERENCES: This study provides the first evidence that colestyramine significantly slows liquid gastric emptying and reduces appetite in healthy humans. Colestyramine therefore presents an attractive gut-brain signaling research tool in that it is not absorbed and thus lacks potentially confounding postabsorptive effects. Furthermore, with clear effects on gastric emptying and appetite, colestyramine now merits consideration as a trial therapeutic strategy for appetite suppression and weight loss.