Background: Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host.
Results: We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance.
Conclusions: Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice.
The present publication presents two studies, one randomised controlled trial (RCT) in healthy humans and a mice experiment, with both indicating that saccharin consumption at maximum acceptable levels does not alter gut microbiota nor causes glucose intolerance neither in humans nor in mice. This is the first randomised controlled trial that examines the effects of saccharin on the human gut microbiota.
The current RCT is a double-blind, placebo-controlled, parallel arm study in 46 healthy participants who were randomized to four groups: (a) placebo, (b) capsules that contained saccharin at the maximum acceptable daily intake (ADI), (c) lactisole (a human-specific inhibitor of human sweet taste receptors (STRs)), or (d) saccharin with lactisole administered twice daily for 2 weeks. Results showed that two weeks of continuous administration of pure saccharin at a dose equal to ADI did not alter microbial diversity or composition in humans and neither affected glucose or hormonal responses (insulin, glucagon, C-peptide, GLP-1) to an oral glucose tolerance test (OGTT). No treatment effects were also noted in fecal metabolites or short-chain fatty acids (SCFA).
To explore potential long-term effects that may require higher saccharin doses and time of exposure, the researchers also performed a 10-week study in mice, administering pure saccharin in the drinking water for 10 weeks to achieve daily consumption equal to 4 times the human ADI. Similar to humans, no impact of saccharin administration was observed on glucose absorption or glucose tolerance in mice. Despite the larger dose and longer duration of treatment in mice, pure saccharin did not alter microbial alpha or beta diversity indices or microbiome composition between treatments.
The authors concluded that the results of their study clearly showed that daily consumption of pure saccharin for 2 weeks at maximum ADI is inadequate to alter gut microbiota and metabolites or affect glucose tolerance in healthy humans. They also found identical results in their mice study, which involved saccharin administration for 10 weeks equal to 4-times the human ADI. The findings of these carefully designed studies by Serrano et al are in total contrast with the results of the studies by Suez et al (2014), which claimed that low/no calorie sweeteners induce glucose intolerance by altering the gut microbiota.