High-dose saccharin supplementation does not induce gut microbiota changes or glucose intolerance in healthy humans and mice

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.

The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans

“…Sex-dependent differences in glucose absorption rates can also affect OGTT responses [ 20 ], but in our study the magnitude of the genotype effect on glucose responses was similar between male and female participants (p = 0.633), so no significant interaction between genotype and sex (p = 0.752) was noted. Finally, we assessed fecal microbiota composition because of known interactions with glucose regulation [ 21 ], but found similar microbial alpha and beta diversity between genotypes ( Supp.Table.2 ), confirming findings in mice [ 15 ].…”

“…The clinical studies were performed in accordance with the requirements of Good Clinical Practice and the Revised Declaration of Helsinki. Recruitment, enrollment, and all study-related visits, including specimen collection and point-of-care laboratory testing, took place at Advent-Health Translational Research Institute (TRI) Clinical Research Unit (CRU) as previously described (NCT02835859) [ 15 ]. The study was approved by the Institutional Review Board at Advent-Health and all participants signed an informed consent.…”

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis

“…However, some AS may not be physiologically inert as originally thought. For instance, the consumption of saccharin in mice and healthy humans was shown to induce glucose intolerance through changes in gut microbiota [ 2 ], but these findings could not be subsequently replicated [ 3 ]. Moreover, saccharin supplementation did not induce glucose intolerance in healthy overweight or obese individuals [ 4 ], nor did it change fasting glucose and insulin in patients with type 2 diabetes [ 5 ].…”

Antidiabetic Function of Lactobacillus fermentum MF423-Fermented Rice Bran and Its Effect on Gut Microbiota Structure in Type 2 Diabetic Mice

“…SCFAs are the main microbial fermentation products of undigested carbohydrates in the intestine ( Serrano et al, 2021 ). Our data showed that SCFA-producing bacteria were enriched in FLRB-treated mice compared to HFD-fed mice ( Figure 5B ).…”