Fiber mixture-specific effect on distal colonic fermentation and metabolic health in lean but not in prediabetic men

Emanuel E Canfora, Gerben D A Hermes, Mattea Müller, Jacco Bastings, Elaine E Vaughan, Marco A van Den Berg, Jens J Holst, Koen Venema, Erwin G Zoetendal, Ellen E Blaak, Emanuel E Canfora, Gerben D A Hermes, Mattea Müller, Jacco Bastings, Elaine E Vaughan, Marco A van Den Berg, Jens J Holst, Koen Venema, Erwin G Zoetendal, Ellen E Blaak

Abstract

Infusions of the short-chain fatty acid (SCFA) acetate in the distal colon improved metabolic parameters in men. Here, we hypothesized that combining rapidly and slowly fermentable fibers will enhance distal colonic acetate production and improve metabolic health. In vitro cultivation studies in a validated model of the colon were used to identify fiber mixtures that yielded high distal colonic acetate production. Subsequently, in two randomized crossover studies, lean and prediabetic overweight/obese men were included. In one study, participants received supplements of either long-chain inulin+resistant starch (INU+RS), INU or maltodextrin (PLA) the day prior to a clinical investigation day (CID). The second trial studied beta glucan+RS (BG+RS) versus BG and PLA. During each CID, breath hydrogen, indirect calorimetry, plasma metabolites/hormones were assessed during fasting and postprandial conditions. Additionally, fecal microbiota composition and SCFA were determined. In prediabetic men, INU+RS increased plasma acetate compared to INU or PLA (P < .05), but did not affect metabolic parameters. In lean men, INU+RS increased breath hydrogen and fasting plasma butyrate, which was accompanied by increased energy expenditure, carbohydrate oxidation and PYY and decreased postprandial glucose concentrations (all P < .05) compared to PLA. BG+RS increased plasma butyrate compared to PLA (P < .05) in prediabetic individuals, but did not affect other fermentation/metabolic markers in both phenotypes. Fiber-induced shifts in fecal microbiota were individual-specific and more pronounced with INU+RS versus BG+RS. Administration of INU+RS (not BG+RS) the day prior to investigation improved metabolic parameters in lean but not in prediabetic individuals, demonstrating that effects were phenotype- and fiber-specific. Further research should study whether longer-term supplementation periods are required to elicit beneficial metabolic health in prediabetic individuals. Trial registration numbers: Clinical trial No. NCT03711383 (Inulin study) and Clinical trial No. NCT03714646 (Beta glucan study).

Keywords: Short-chain fatty acids; dietary fibers; gut microbiota; substrate metabolism.

Conflict of interest statement

The authors greatly thank all volunteers participating in the studies. The authors thank Prokopis Konstanti for help with 16S rRNA gene analyses. The authors thank all the consortium partners involved for the critical feedback during the development of this project. EEV is an employee of Sensus. MAvdB is an employee of DSM.

Figures

Figure 1.
Figure 1.
Plasma short-chain fatty acids and breath hydrogen before and after a high fat mixed meal after INU, INU+RS and PLA in lean (n = 12) and prediabetic (n = 11) men as well as BG, BG+RS and PLA supplementation in lean (n = 11) and prediabetic (n = 11) men. Plasma acetate of lean (a) and prediabetic (b), plasma butyrate of lean (c) and prediabetic (d), and breath H2 excretion of lean (e) and prediabetic (f) men in the inulin study. Plasma acetate of lean (g) and prediabetic (h), plasma butyrate of lean (i) and prediabetic (j), and breath H2 excretion of lean (k) and prediabetic (l) men in the beta glucan study. Values are means ± S.E.M. Differences in fasting (t0) and postprandial AUC between the three interventions (PLA, INU, and INU+RS or PLA, BG and BG+RS) were analyzed using a linear mixed model for repeated measures and the indicated P-values represents post-hoc testing
Figure 2.
Figure 2.
Energy Expenditure and Substrate Oxidation before and after a high fat mixed meal after INU, INU+RS and PLA supplementation in lean (n = 12) and prediabetic (n = 11) men. Energy expenditure of lean (a) and prediabetic (b), carbohydrate oxidation of lean (c) and prediabetic (d), fat oxidization of lean (e) and prediabetic (f) and respiratory quotient of lean (g) and prediabetic (h) men. Values are means ± S.E.M. Differences in fasting (t0) and postprandial AUC between the three interventions (PLA, INU, and INU+RS) were analyzed using a linear mixed model for repeated measures and the indicated P-values represents post-hoc testing
Figure 3.
Figure 3.
Plasma metabolite and insulin concentrations before and after a high fat mixed meal after INU, INU+RS and PLA supplementation in lean (n = 12) and prediabetic (n = 11). Plasma glucose concentrations of lean (a) and prediabetic (b), FFA concentrations of lean (c) and prediabetic (d), insulin concentrations of lean (e) and prediabetic (f), PYY concentrations of lean (g) and prediabetic (h) individuals. Values are means ± S.E.M. Differences in fasting (t0) and postprandial AUC between the three interventions (PLA, INU, and INU+RS) were analyzed using a linear mixed model for repeated measures and the indicated P-values represents post-hoc testing
Figure 4.
Figure 4.
Changes in fecal microbiota composition (weighted and unweighed UniFrac) after INU, INU+RS and PLA in lean (n = 8, four individuals were not able to sample feces on all 3 days) and prediabetic (n = 10, one individual was not able to sample feces on all day) men as well as after BG, BG+RS and PLA supplementation in lean (n = 10, one individual was not able to sample feces on all day) and prediabetic (n = 11) men. A & B: PCoA plots of weighted (a) and unweighted UniFrac (b): the longer the arrow, the larger the change. The start point for each arrow is the composition after PLA intervention while lighter gray depicts the change due to INU, darker gray to INU+RS, lighter gray BG and darker gray BG+RS. The random direction of the arrows after each intervention shows the individual effects. C & D: Intra-individual microbiota changes compared to placebo after fiber intervention in lean (c) and prediabetic (d) men
Figure 5.
Figure 5.
Impact of (a) INU, INU+RS and placebo (b) BG, BG+RS and placebo supplementation on microbiota alpha diversity (ASV richness and Shannon) of lean (light gray) and prediabetic (dark gray) individuals. The fecal microbiota of 8 lean (four individuals were not able to sample feces on all 3 days) and 10 prediabetic (one individual was not able to sample feces on all day) men in the inulin study and 10 lean (one individual was not able to sample feces on all day) and 11 prediabetic men in the beta glucan study was used

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