Abstract
BackgroundNon-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.ResultsWe 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.ConclusionsShort-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice.Trial registrationTrial registration number NCT03032640, registered on January 26, 2017.3ThJTRkvKM2w8o53nrbAgaVideo abstract
Highlights
Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia
Fecal metabolome before the treatment was similar between groups (Supp. figure 8B), but when mice were clustered according to genotype, we found a significant effect on the Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) (Supp. figure 8C) which was further evaluated by analysis of the OPLS-DA loadings S-plot to identify nuclear magnetic resonance (NMR) features that account for these differences
We identified a handful of significant NMR peaks in T1R2-KO samples which corresponded to the short-chain fatty acids (SCFA), acetate and butyrate (Supp. figure 8D), but once all spectral features assigned to these metabolites were accounted to calculate relative abundances, no statistically significant differences between genotypes were noted (Supp. table 11)
Summary
Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Many epidemiological studies do not find any effect of NCAS consumption on the risk of type 2 diabetes mellitus (T2DM) or metabolic syndrome [5,6,7,8,9,10,11], several other studies have noted positive associations between NCAS intake and these conditions [12,13,14,15,16,17,18,19,20,21] These findings have raised concerns among consumers and health professionals alike that NCAS may not be physiologically inert, as originally thought, and their general use may lead to adverse metabolic outcomes [22]. Sucralose supplementation in ileitis-prone SAMP mice caused some changes in gut microbiota, but glucose tolerance was not affected [52]
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