Abstract
Background : Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, saccharin and other NCAS have been reported to induce glucose intolerance in mice fed a high-fat diet and in a subset of humans by directly inducing unfavorable changes in gut microbiota. These findings have raised concerns about NCAS and called into question their broad use. Whether these results can be generalized to healthy populations consuming conventional diets is unknown. It is also unclear how different NCAS, that do not share a common chemical structure, can produce identical direct effects on gut microbiota. A common feature of all NCAS is their strong affinity for sweet taste receptors (STRs) which are expressed in the intestine. However, their role in mediating NCAS-induced effects has not been addressed.
Results : We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of saccharin 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 two weeks. In parallel, we performed a ten-week study administering high-dose saccharin 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 alike, none of the interventions affected glucose or hormonal responses to a glucose tolerance test, nor ex vivo glucose absorption in mice. Similarly, saccharin supplementation did not alter microbial diversity or abundance at any taxonomic level in humans or mice. 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.
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