Low intake of digestible carbohydrates ameliorates duodenal absorption of carbohydrates in mice with glucose metabolism disorders induced by artificial sweeteners

Shi, Qing; Cai, Lei; Jia, Hongzhe; Zhu, Xuemei; Chen, Lei; Deng, Shaoping

doi:10.1002/jsfa.9727

Cited by 10 publications

(8 citation statements)

References 54 publications

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“…In contrast to our findings, mice fed chow diet and supplemented with 10% solution of commercial saccharin, which contained 95% glucose by mass, or mice fed high-fat and supplemented with pure saccharin, developed glucose intolerance mediated by unfavorable changes in gut microbiota [8]. Similarly, 12 weeks of saccharin supplementation in chow-fed ICR/HaJ mice caused marginal glucose intolerance, but responsive mice also showed increased food intake and weight gain [27]. Our saccharin-fed mice consumed similar amount of chow and experienced the same age-related increases in body weight compared to water control littermates.…”

Section: Discussioncontrasting

confidence: 99%

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

Serrano

Smith

Crouch

et al. 2020

Preprint

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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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Section: Discussioncontrasting

confidence: 99%

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

Serrano

Smith

Crouch

et al. 2020

Preprint

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“…However, it is noticeable that, among these numerous studies, there is no reproducible microbiota signature even for commonly studied NCAS, such as sucralose [49,51,52,87]. The consequences of these microbiota alterations on glucose tolerance were not assessed in these reports, except for one that found no effect on glucose tolerance (OGTT) after 6 weeks of sucralose supplementation in ileitis-prone SAMP mice [52] that is consistent with other independent reports which showed that consumption of NCAS, such as sucralose or aceK, has either a minor [82], or no effect [81] on glucose tolerance.…”

Section: Discussionsupporting

confidence: 59%

“…Similar to our findings, a thorough study in C57Bl\6J mice demonstrated that, among other NCAS, saccharin administration alone for 4 weeks did not affect body weight, OGTT responses, or insulin sensitivity (insulin tolerance test) [81]. In contrast, after 12 weeks of saccharin supplementation, chow-fed ICR/HaJ mice showed a marginal increase (15%) in the AUC of glucose during an OGTT, which may be linked to the concomitant increase in food intake and weight gain in the same mice [82]. Our saccharin-fed mice consumed similar amount of chow and experienced the same age-related increases in body weight compared to water control.…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2021

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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.

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“…A second study found that saccharin, sucralose, and aspartame impaired glucose tolerance but not insulin sensitivity (39). A third study reported that Ace K did not impair glucose tolerance (7), whereas a fourth study reported that it did (35). A fifth study found that stevioside actually improved glucose tolerance (26).…”

Section: Introductionmentioning

confidence: 99%

Low-calorie sweeteners cause only limited metabolic effects in mice

Glendinning

Hart

Lee

et al. 2020

American Journal of Physiology-Regulatory, Integrative and Comp

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There are widespread concerns that low-calorie sweeteners (LCSs) cause metabolic derangement. These concerns stem in part from prior studies linking LCS consumption to impaired glucose tolerance in humans and rodents. Here, we examined this linkage in mice. In experiment 1, we provided mice with chow, water, and an LCS-sweetened solution (saccharin, sucralose, or acesulfame K) for 28 days and measured glucose tolerance and body weight across the exposure period. Exposure to the LCS solutions did not impair glucose tolerance or alter weight gain. In experiment 2, we provided mice with chow, water, and a solution containing saccharin, glucose, or a mixture of both for 28 days, and tested for metabolic changes. Exposure to the saccharin solution increased the insulinemic response of mice to the glucose challenge, and exposure to the saccharin + glucose solution increased the rate of glucose uptake during the glucose challenge. However, neither of these test solutions altered glucose tolerance, insulin sensitivity, plasma triglycerides, or percent body fat. In contrast, exposure to the glucose solution increased glucose tolerance, early insulin response, insulin sensitivity, and percent body fat. We conclude that whereas the LCS-containing solutions induced a few metabolic changes, they were modest compared with those induced by the glucose solution.

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Low intake of digestible carbohydrates ameliorates duodenal absorption of carbohydrates in mice with glucose metabolism disorders induced by artificial sweeteners

Cited by 10 publications

References 54 publications

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

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

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

Low-calorie sweeteners cause only limited metabolic effects in mice

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