Joan Serrano1, Kathleen R Smith1, Audra L Crouch2, Vandana Sharma3, Fanchao Yi4, Veronika Vargova4, Traci E LaMoia1, Lydia M Dupont1, Vanida Serna1, Fenfen Tang5, Laisa Gomes-Dias6, Joshua J Blakeslee6, Emmanuel Hatzakis5, Scott N Peterson3, Matthew Anderson2, Richard E Pratley4, George A Kyriazis7. 1. Department of Biological Chemistry & Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA. 2. Department of Microbiology, College of Arts & Sciences, The Ohio State University, Columbus, OH, USA. 3. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. 4. Translational Research Institute for Metabolism and Diabetes, Advent-Health, Orlando, FL, USA. 5. Department of Food Science and Technology, College of Food, Agricultural & Environmental Sciences, The Ohio State University, Columbus, OH, USA. 6. Department of Horticulture and Crop Science, College of Food, Agricultural & Environmental Sciences, The Ohio State University, Columbus, OH, USA. 7. Department of Biological Chemistry & Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA. Georgios.Kyriazis@osumc.edu.
Abstract
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. TRIAL REGISTRATION: Trial registration number NCT03032640 , registered on January 26, 2017. Video abstract.
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. TRIAL REGISTRATION: Trial registration number NCT03032640 , registered on January 26, 2017. Video abstract.
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