The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Mechanisms linking artificial sweeteners to impaired glycaemic control in healthy subjects (#163)

Richard Young 1 2 3
  1. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  2. Nutrition & Metabolism , South Australian Health & Medical Research Institute, Adelaide, SA, Australia
  3. Centre of Research Excellence in Translating Nutritional Science to Good Health , University of Adelaide, Adelaide, SA, Australia

Background and aims: Epidemiological studies indicate that regular high intake of beverages sweetened with low-calorie sweeteners (LCS) increase the risk of developing type 2 diabetes mellitus (T2DM), but the underlying mechanisms are unknown. We recently showed that LCS supplementation in healthy non-diabetic subjects over 2 weeks led to clinically relevant increases in glycaemic response to enteral glucose. Increased glucose absorption (serum 3-O-methyl glucose, 3‑OMG) and attenuated release of glucagon-like peptide-1 (GLP-1) contribute to this dysglycaemia, however it is unclear whether gut dysbiosis due to LCS also contributes to dysglycaemia, as occurs in rodents.


Materials and methods: 29 non-diabetic subjects (age 30 ± 2 years, body mass index 24 ± 3 kg/m2, HbA1c 32 ± 1 mmol/mol (5.2%), 16 male) were randomised, in double-blind fashion, to diet supplementation with  LCS containing capsules (92 mg sucralose + 52 mg acesulfame-K, N=14) or placebo capsules (N=15); capsules were taken three times daily over 2 weeks (equivalent to ~1.5L of diet beverage consumption/day). The gut microbiome was assessed by shotgun metagenomic sequencing in stool collected before and after treatment. Differences in taxonomic and functional microbiome characteristics were determined using MetaPhlAn2 and HUMAnN2 abundance, respectively.


Results: LCS-treated subjects exhibited a greater variation in faecal microbiota composition, along with a significant reduction in the health-associated bacterium Eubacterium cylindroides (-11 log2 fold change, FC) and an increased abundance of 11 opportunistic gut pathogens, including Klebsiella (17 FC), Porphyromonas (15 FC) and Finegoldia (12 FC; all P ≤ 0.001). A decrease in beneficial and fermentative Bifidobacterium, Lactobacillus and Bacteroides populations correlated with augmented glucose absorption (3-OMG), while a decrease in Butyrivibrio populations correlated with attenuated GLP‑1 release (Spearman correlation: ρ ≥ ±0.37; P ≤ 0.05). Finally, shifts in the abundance of microbial genes involved in sucrose degradation and pyruvate metabolism correlated with a deterioration in glucose regulation in LCS-treated subjects.


Conclusion: In healthy non-diabetic subjects 2 weeks of LCS supplementation (i) causes gut dysbiosis and (ii) increases the abundance of gut pathogens normally absent in health. Moreover, a decrease in fermentative microbial populations and shifts in bacterial energy harvesting pathways due to LCS predict a deterioration in glucose regulation. Our findings support the concept that LCS disrupt glycaemic responses in healthy humans via dysregulation of glucose uptake and disposal, and secondary to dysbiosis of gut commensal bacteria. This highlights the clinical relevance of dietary LCS patterns in overall glycaemic control.