Mechanisms linking low-calorie sweeteners to impaired glycaemic control

D Kreuch, K Ivey, F M Mobegi, L Leong, N J Isaacs, N Pezos, M Horowitz, C K Rayner, G B Rogers, R L Young

Research output: Contribution to journalArticlepeer-review


Background: High consumption of beverages sweetened with low‐calorie sweeteners (LCS) is linked to an increased risk of type 2 diabetes (T2D) in humans, but the mechanisms are unknown. LCS activate intestinal sweet taste receptors to trigger gut hormone release, increase intestinal glucose absorption and trigger gut dysbiosis in animals. It unknown whether LCS exerts these effects in humans, and if so, whether postprandial glycaemia is adversely affected. Methods: 36 healthy subjects (aged 29 ± 2 years, 16 female) were randomised in double‐blind manner to supplementation with capsules containing LCS (92 mg sucralose + 52 mg acesulfame‐K, N = 19) or placebo (N = 17), taken three times daily over 2 weeks. Subjects underwent non‐sedated endoscopy incorporating a 30 minutes intraduodenal glucose infusion (3 kcal/min, including 3 g of the glucose analogue 3‐O‐ methyl glucose, 3‐OMG) with biopsy and stool collection, before and after intervention. Glucose absorption (serum 3‐OMG), plasma glucose and gut peptides were measured, and incremental areas under the curve (iAUC, over 120 min) compared by ANCOVA. Microbiome changes were assessed by shotgun sequencing; taxonomic and functional characteristics were determined using MetaPhlAn2 and HUMAnN2 abundance. Results: LCS augmented glucose absorption (15% P ≤ 0.05) and glycaemic responses to enteral glucose (26% P ≤ 0.01) and showed a trend to attenuate release of glucagon‐like peptide‐1 (GLP‐1, 32% P ≤ 0.1). LCS reduced commensal bacteria from the Ruminococcaceae family and increased opportunistic pathogens from Streptococcaceae and Odoribacteraceae families. Changes in microbiome composition and genetics due to LCS correlated with host changes in blood glucose, 3‐OMG and GLP‐1, while Eubacterium rectale and Bacteriodetes uniformis were identified as moderators and mediators of LCS effects, respectively. Conclusions: Our findings support the concept that dietary LCS supplementation impairs control of postprandial glycaemia in healthy humans by dysregulating glucose uptake and disposal, and secondary to dysbiosis of gut bacteria.
Original languageEnglish
JournalNeurogastroenterology and Motility
Publication statusPublished or Issued - 31 Aug 2020


  • *area under the curve
  • *calorie
  • *glycemic control
  • Adult
  • Analysis of covariance
  • Clinical article
  • Commensal
  • Conference abstract
  • Controlled study
  • Diet
  • Drug combination
  • Drug therapy
  • Endoscopy
  • Eubacterium rectale
  • Feces
  • Female
  • Glucose absorption
  • Glucose blood level
  • Glucose infusion
  • Glucose transport
  • Human
  • Human experiment
  • Human tissue
  • Infectious agent
  • Intestine flora
  • Male
  • Microcapsule
  • Nonhuman
  • Randomized controlled trial
  • Ruminococcaceae
  • Shotgun sequencing
  • Streptococcaceae

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