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Artificial sweeteners induce glucose intolerance by altering the gut microbiota
Abstract
Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.
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In the citing paper
“NNS consumption induced glucose intolerance in a microbiota-dependent manner (56).”
From The gut microbiota at the intersection of diet and human health (2018) · cites this paper as [56]
In the citing paper
“Emulsifiers and artificial sweeteners have been shown to be involved in the development of metabolic syndrome features through their modulation of the microbiota in mice46,47.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [47]
In the citing paper
“In a study in seven people, artificial sweeteners given at high doses resulted in insulin resistance after only 7 days47”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [47]
In the citing paper
“Chronic NAS consumption in mice was shown to impact gut microbial community structure133, resulting in an increase in abundance of bacteria belonging to the Bacteroides genus and some members of the Clostridiales order.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [133]
In the citing paper
“germ-free mice colonized with gut microorganisms from NAS-treated mice or stool microorganisms exposed to NAS ex vivo develop glucose intolerance.”
From The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism (2016) · cites this paper as [133]
In the citing paper
“Consumption of artificial sweeteners in mice and humans has been shown to lead to deregulation of the intestinal microbiota, with altered glycan degradation capacity promoting decreased glucose tolerance, a pre-diabetic condition [58].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [58]
In the citing paper
“Other dietary compounds known to alter the composition of the gut microbiome include noncaloric artificial sweeteners such as saccharin, sucralose, and aspartame (Suez et al., 2015), a feature with functional implications associated with the induction of glucose intolerance in mice (Suez et al., 2014).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Suez et al., 2014
In the citing paper
“Although earlier human studies indicated detrimental effects on microbial diversity and composition (99, 100) and a more recent study linked consumption of nonnutritive sweeteners to a “dysbiosis” [an increasingly redundant term in microbiome research (171)] and a decrease in butyrate concentration (172), some reports have concluded that no clear effects of sweeteners on the microbiota can be”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [100]
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“Rats fed saccharin showed a decreased relative abundance of Lactobacillus reuteri and increased relative abundance of Bacteroides [54].”
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Shum, B. J., & Georgia, S. K. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.625415 · Cited by 40
Inhibitory Effects of Artificial Sweeteners on Bacterial Quorum Sensing
Markus, V., Share, O., Shagan, M., Halpern, B., Bar, T., Kramarsky‐Winter, E., Teralı, K., Özer, N., Marks, R. S., Kushmaro, A., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189863 · Cited by 39
“In humans, even though randomized controlled trials (RCT) suggest bodyweight benefits from the consumption of artificial sweeteners, there is still only limited data on other metabolic alterations [19], including altering gut microbiota in a manner that could enhance the metabolic diseases that they were intended to r…”
BackgroundThe immune‐supportive diet in allergy management: A narrative review and proposal
Vlieg‐Boerstra, B., Groetch, M., Vassilopoulou, Ε., Meyer, R. W., Laitinen, K., Swain, A., Durban, R., Aalst, O. B., Bottse, R., Grimshaw, K. E. C., et al. (2023) · Allergy · doi:10.1111/all.15687 · Cited by 42
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“Recent safety concerns about them came from a large epidemiological study as well as small physiological studies in human.(3,4) In a physiological studies of artificial sweetener both aspartame and sucralose were associated with significant postprandial hyperglycemia in comparison to Stevia.”
BackgroundSweet Taste Signaling: The Core Pathways and Regulatory Mechanisms
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“In addition, they have been implicated in metabolic dysregulation, likely due to their post-ingestive signaling and adverse effects on intestinal microbiota [14,15].”
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“Differences in individual responses to the oral intake of food and drugs have been observed, with studies showing a link with gut microbiota (18, 19).”
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“Suez and colleagues discovered that NAS, in particular through diminishing the frequency of A. muciniphila in the healthy human digestive tract, can drive dysbiosis and glucose intolerance by altering the microbial diversity of the gut [95].”
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Food Additives: Emerging Detrimental Roles on Gut Health
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“Recent attention has focused on the metabolic interaction between high doses of high-intensity sweeteners and changes in both gut microbiota and glucose tolerance (2).”
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Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway
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“Changes in the microbiota patterns trigger glucose intolerance—one of the stimuli causing type 2 diabetes [29].”
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“…including those from our own laboratories indicate that diet and dietary supplements can modulate the gut microbiome resulting in both beneficial (De Vadder et al. 2016; Gurley et al. 2019) and deleterious (Suez et al. 2014; Miousse et al. 2017; Kumagai et al. 2018; Miousse et al. 2020) effects.”
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A Bitter Aftertaste: Unintended Effects of Artificial Sweeteners on the Gut Microbiome
Bokulich, N. A., & Blaser, M. J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.012 · Cited by 40
“Suez and colleagues found that germ-free mice inoculated with microbiota from NAS-fed mice became more glucose intolerant than mice conventionalized with control microbiota, demonstrating a causal role of the affected gut microbial communities (Suez et al., 2014) (Figure 1C).”
BackgroundResultInfluentialHeider, E. C., Valenti, D. J., Long, R. L., Garbou, A. M., Rex, M. M., & Harper, J. K. (2018) · Journal of Chemical Education · doi:10.1021/acs.jchemed.7b00490 · Cited by 37
Guercio, B. J., Zhang, S., Niedzwiecki, D., Li, Y., Babić, A., Morales‐Oyarvide, V., Saltz, L. B., Mayer, R. J., Mowat, R. B., Whittom, R., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0199244 · Cited by 35
Metabolic networks of the human gut microbiota
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“It has been suggested that the potential adverse effects of ASB may be caused by a detrimental effect on gut microbiota that, in turn, may have a negative effect on glucose tolerance [48].”
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“It remains to be determined whether this has clinical relevance, in regard to either medications with narrow therapeutic indexes or potentially life-threatening toxicities, or to food contaminants found to perturb the composition of the gut microbiota and its metabolism, with toxicological consequences for the host [7…”
BackgroundBjørnland, T., Langaas, M., Grill, V., & Mostad, I. L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175071 · Cited by 35
“In support of this notion several recent studies report increasing appetite [42, 43] and obesity-favouring microbiotic effects [44] by artificially sweetened beverages.”
ResultLo, W.-C., Ou, S.-H., Chou, C.-L., Chen, J.-S., Wu, M.-Y., & Wu, M.-S. (2021) · Journal of Nephrology · doi:10.1007/s40620-020-00957-0 · Cited by 34
Bhuia, M. S., Siam, M. S. H., Ahamed, M. R., Roy, U. K., Hossain, M. I., Rokonuzzman, M., Islam, T., Sharafat, R., Bappi, M. H., Mia, M. N., et al. (2023) · Biology · doi:10.3390/biology12050637 · Cited by 34
“A recent investigation demonstrated that long-time utilization of SCN enhances glucose intolerance by affecting gut microorganisms, resulting in prediabetic consequences, such as insulin resistance, heart disease, stroke, obesity, and mortality risk [15,16].”
BackgroundShu, L., Zhang, X., Zhou, J., Zhu, Q., & Si, C. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1211797 · Cited by 34
Metadata
- Authors
- Suez, J., Korem, T., Zeevi, D., Zilberman-Schapira, G., Thaiss, C. A., Maza, O., Israeli, D., Zmora, N., Gilad, S., Weinberger, A., Kuperman, Y., Harmelin, A., Kolodkin-Gal, I., Shapiro, H., Halpern, Z., Segal, E., & Elinav, E.
- Affiliations
- Weizmann Institute of Science (IL)
- Jerusalem Mental Health Center (IL)
- Tel Aviv University (IL)
- Corresponding author
- Segal, Eran
- Elinav, Eran
- ORCID
- Venue
- Nature
- Published
- 2014-09-17
- Volume
- 514
- Issue
- 7521
- Pages
- 181-186
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1989947363
- Cited by
- 2,067
- References
- 41
- Citations by year
- 2026: 145 · 2025: 182 · 2024: 175 · 2023: 166 · 2022: 218 · 2021: 190 · 2020: 189 · 2019: 182 · 2018: 159 · 2017: 159 · 2016: 153 · 2015: 123 · 2014: 24
- FWCI
- 62.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- impaired glucose tolerance, gut microbiota, dysbiosis, saccharin, sucralose, aspartame, obesity, fecal microbiota transplantation, germ-free mice, antibiotic therapy, type 2 diabetes, microbial metabolic pathways, food additives
- MeSH terms
- Animals, Anti-Bacterial Agents, Aspartame, Body Weight, Dietary Fats, Feces, Female, Germ-Free Life, Glucose, Humans, Male, Mice, Inbred C57BL, Saccharin, Sucrose, Sweetening Agents, Glucose Intolerance, Metabolic Syndrome, Gastrointestinal Tract, Waist-Hip Ratio, Mice, Diet, High-Fat, Microbiota
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