Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

Abstract

Objective: The 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.

Design: To 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.

Results: Propionate 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.

Conclusions: These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.

Trial registration number: NCT00750438.

Keywords: APPETITE; COLONIC FERMENTATION; GUT HORMONES; NUTRITIONAL SUPPLEMENTATION; OBESITY.

Figure 1

Propionate increases peptide YY (PYY) and glucagon like peptide-1 (GLP-1) release from primary human colonic cells and inulin-propionate ester supplementation delivers propionate to the colon in vivo. Cells isolated from human colonic tissue were incubated with increasing concentrations of propionate. (A) PYY and (B) GLP-1 levels were measured in the supernatants and lysed cells by radioimmunoassay. Percentage gut hormone release per well is expressed relative to the basal release measured (n=4–6). (C) The increase in breath H₂ at 240 min suggests that >80% of the labelled propionate entered the colon. (D) Plasma acetate and propionate ¹³C enrichment (δ¹³C per mil) at baseline and 360 min. Plasma propionate was significantly more enriched at 360 min whereas no difference was seen in acetate enrichment. Total plasma propionate (E) and acetate (F) concentrations (µmol/L) at baseline and 360 min. Data are presented as mean±SEM, *p<0.05, ***p<0.001.

Figure 2

Acute inulin-propionate ester supplementation increases plasma peptide YY (PYY) and glucagon like peptide-1 (GLP-1) levels and reduces energy intake in humans. (A) The mean reduction in energy intake following inulin-control versus inulin-propionate ester. (B) A reduction in energy intake occurred in 16 of the 20 volunteers. (C–F) Plasma gut hormone levels following acute supplementation of inulin-control versus inulin-propionate ester. Arrows indicate standardised meals. Dotted lines signify the time point after which >80% inulin-propionate ester enters the colon as determined by the enrichment of ¹³C in expired air and breath H₂ methodology (figure 1C). Data are presented as mean±SEM, *p<0.05, **p<0.01. AUC, area under the curve.

Figure 3

The effect of 24 weeks inulin-control and inulin-propionate ester supplementation on weight gain, liver fat content and gut hormone response. (A) The proportion of subjects who gained 3% or more and 5% or more of their baseline weight at 24 weeks. (B) Intrahepatocellular lipid (IHCL) content at baseline and following 24 weeks of inulin-control and inulin-propionate ester supplementation in subjects with non-alcoholic fatty liver disease (NAFLD). Subjects were identified as having NAFLD on the basis of an IHCL content >5.5% at baseline. Postprandial plasma (C) peptide YY (PYY) and (D) GLP-1 release at baseline and following 24 weeks of inulin-control and inulin-propionate ester supplementation. Data are presented as mean±SEM, *p<0.05.

Figure 4

The effect of inulin-propionate ester on the gut microbiota. Bacterial concentrations expressed in Log₁₀ cells/mL culture fluid enumerated using fluorescent in situ hybridisation (FISH) targeting (A) Bifidobacterium spp (Bif164), (B) Bacteroides/Prevotella (Bac303), (C) Atopobium cluster (Ato291), (D) Lactobacillus/Enterococcus (Lab158), (E) Clostridium histolyticum (Chis150) and (F) Eubacterium rectale/Clostridium coccoides (Erec482) at 0 h, 10 h, 24 h, 34 h and 48 h anaerobic, pH controlled faecal batch culture fermentation with control (no substrate), inulin-control and inulin-propionate ester. Data are presented as mean±SEM (n=3), *<0.05, †<0.001, ‡<0.0001 with respect to the 0 h sample.