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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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“In vitro studies (62) have demonstrated that NNSs, including aspartame, saccharin, and sucralose, have antimicrobial activity against common periodontal pathogens.”
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“Furthermore, according to previous findings from animal studies, altered gut microbiota was found in mice by using artificial sweetener intervention, which was associated with the increased insulin resistance, and a similar phenomenon was also observed in humans [78].”
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“higher glucose excursions after a glucose load; the elimination of this effect by antibiotic treatment suggested that changes in the metabolic phenotype of the mice was caused by alterations in the gut microbiota.(90)”
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“While transcriptional changes were not measured, these gene content changes suggest that regulatory events like catabolite repression may be occurring (70).”
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BackgroundResultThe Influence of Dietary Factors on the Gut Microbiota
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“Prior research also found an association of artificial sweeteners with both metabolic dysfunction (26, 27) and weight gain (28–30), but these studies were based on consumption and the conclusions are likely to be affected by both confounding and reverse causality (persons already gaining weight choose to consume artif…”
BackgroundJiang, Z., Zhao, M., Zhang, H., Yang, L., Liu, M., & Feng, F. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700547 · Cited by 126
“As already demonstrated in previous studies [11, 23], dietary supplementation with non-caloric artificial sweetener (saccharin) and emulsifiers (CMC and P80), significantly promoted the metabolic syndrome by altering the diversity, composition and function of gut microbiota in mice.”
ResultExploring the gut microbiota: lifestyle choices, disease associations, and personal genomics
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“Artificial sweeteners such as aspartame, acesulfame, saccharine, sucralose, and cyclamate showed the capability to induce changes in the gut microbiota, reducing the bacterial diversity and impairing the glucose metabolism (96, 97).”
BackgroundEffects of the Artificial Sweetener Neotame on the Gut Microbiome and Fecal Metabolites in Mice
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Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome
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“, such that the microbiota composition resembles that of obese individuals [63].”
BackgroundInfluentialSucralose Promotes Food Intake through NPY and a Neuronal Fasting Response
Wang, Q., Lin, Y. Q., Zhang, L., Wilson, Y. A., Oyston, L. J., Cotterell, J., Qi, Y., Khuong, T. M., Bakhshi, N., Planchenault, Y., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.06.010 · Cited by 121
“Previous work has suggested that synthetic sweeteners act through themicrobiome (Suez et al., 2014) or by reducing the validity of ‘‘sweetness’’ to predict caloric content (Swithers et al.”
BackgroundInfluentialHughes, R. L., Kable, M. E., Marco, M., & Keim, N. L. (2019) · Advances in Nutrition · doi:10.1093/advances/nmz049 · Cited by 117
“(86) Association R: compositional change with NAS consumption; developed significantly poorer glycemic responses with NAS consumption.”
BackgroundFowler, S. P. (2016) · Physiology & Behavior · doi:10.1016/j.physbeh.2016.04.047 · Cited by 117
“Preliminary data [29] suggest that high intake of the LCS saccharin, at a level corresponding to the FDA's acceptable daily limit, may increase glucose intolerance in both humans and animals, and Fowler Page 9”
BackgroundResultInfluentialArtificial Sweeteners: History and New Concepts on Inflammation
Basson, A. R., Rodriguez‐Palacios, A., & Cominelli, F. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.746247 · Cited by 124
“Increases in LPS and bacterial pathways of LPS biosynthesis have been reported for most AS, such as stevia (2, 92), sucralose (2, 5, 92), saccharin (3, 4), and Ace-K (48).”
BackgroundInfluentialThomson, P., Santibañez, R., Aguirre, C., Galgani, J. E., & Garrido, D. (2019) · British Journal Of Nutrition · doi:10.1017/s0007114519001570 · Cited by 117
Dietary prophage inducers and antimicrobials: toward landscaping the human gut microbiome
Boling, L., Cuevas, D., Grasis, J. A., Kang, H. S., Knowles, B., Levi, K., Maughan, H., McNair, K. A., Rojas, M. I., Sanchez, S. E., et al. (2020) · Gut Microbes · doi:10.1080/19490976.2019.1701353 · Cited by 112
“Suez et al.(41) showed that saccharin supplementation triggered gut dysbiosis and increased Bacteroides spp.”
BackgroundOrtega, M. A., Fraile‐Μartinez, O., Naya, I., García‐Honduvilla, N., Álvarez‐Mon, M., Buján, J., Asúnsolo, Á., & de la Torre, B. (2020) · Nutrients · doi:10.3390/nu12092749 · Cited by 122
Research gaps and opportunities in precision nutrition: an NIH workshop report
Lee, B. Y., Ordovás, J. M., Parks, E. J., Anderson, C. A. M., Barabási, A.-Ĺ., Clinton, S. K., de la Haye, K., Duffy, V. B., Franks, P. W., Ginexi, E. M., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac237 · Cited by 132
“Others have shown the composition and function of gut microbiota to be associated with glucose intolerance (61, 62), insulin”
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Rethinking Diet to Aid Human–Microbe Symbiosis
Derrien, M., & Veiga, P. (2016) · Trends in Microbiology · doi:10.1016/j.tim.2016.09.011 · Cited by 118
“Healthy subjects (N = 7) Low-calorie artificial sweeteners 1 week Glycaemic response Subjects with a stronger glycaemic response [27_TD$DIFF]had a microbiota different from that of other subjects [98]”
InfluentialMessina, M. J., Sievenpiper, J. L., Williamson, P., Kiel, J., & Erdman, J. W. (2022) · Advances in Nutrition · doi:10.1093/advances/nmac026 · Cited by 116
Fan, Y., Qin, Y., Chen, M., Li, X., Wang, R., Huang, Z., Xu, Q., Yu, M., Zhang, Y., Han, X., et al. (2019) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2019.121534 · Cited by 109
Nettleton, J. E., Cho, N. A., Klančič, T., Nicolucci, A. C., Shearer, J., Borgland, S. L., Johnston, L., Ramay, H. R., Tuplin, E. W. N., Chleilat, F., et al. (2020) · Gut · doi:10.1136/gutjnl-2018-317505 · Cited by 115
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“microbiota with the consumption of saccharin [17] was carried out by administering the full ADI of saccharin, which does not correspond to what happens with habitual human consumption.”
BackgroundResultThe Gut Microbiome and Individual-Specific Responses to Diet
Leshem, A., Segal, E., & Elinav, E. (2020) · mSystems · doi:10.1128/msystems.00665-20 · Cited by 109
“One example of person-specific microbiome impact on dietary physiological responses to consumed food focused on artificial sweeteners, mainly saccharin, and demonstrated that glycemic responses to these seemingly inert food supplements were driven by variations in the human microbiome (95).”
BackgroundInfluentialEarly-Life Sugar Consumption Affects the Rat Microbiome Independently of Obesity
Noble, E. E., Hsu, T. M., Jones, R. B., Fodor, A. A., Goran, M. I., & Kanoski, S. E. (2016) · Journal of Nutrition · doi:10.3945/jn.116.238816 · Cited by 112
“metabolic pathologies such as insulin resistance (9) and obesity”
Immunity, microbiota and kidney disease
Knauf, F., Brewer, J. R., & Flavell, R. A. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0118-7 · Cited by 112
Zhang, Z., Cao, H., Song, N., Zhang, L., Cao, Y., & Tai, J. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111237 · Cited by 107
Maternal Exposure to Non-nutritive Sweeteners Impacts Progeny’s Metabolism and Microbiome
Stichelen, S. O.-V., Rother, K. I., & Hanover, J. A. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01360 · Cited by 110
“…2013; Palmnäs et al., 2014; Suez et al., 2014; Bian et al., 2017b) and metabolism (Brown and Rother, 2012; Cowan et al., 2013; Simon et al., 2013; Swithers, 2013; Palmnäs et al., 2014; Suez et al., 2014; Bian et al., 2017b), it is important to investigate the relationship between NNS consumption…”
BackgroundInfluentialBlood Microbiota and Circulating Microbial Metabolites in Diabetes and Cardiovascular Disease
Velmurugan, G., Dinakaran, V., Rajendhran, J., & Swaminathan, K. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.01.013 · Cited by 108
Host genetic control of gut microbiome composition
Bubier, J. A., Chesler, E. J., & Weinstock, G. M. (2021) · Mammalian Genome · doi:10.1007/s00335-021-09884-2 · Cited by 111
“The C57BL/6 J and Lepob microbiomes have been characterized by two groups (Liu et al. 2020; Suez et al. 2014), producing reference WGS or 16S data as well as creating a biobank of 126 species, represented by 244 bacterial strains.”
BackgroundMethodThe Effect of Artificial Sweeteners Use on Sweet Taste Perception and Weight Loss Efficacy: A Review
Wilk, K., Korytek, W., Pelczyńska, M., Moszak, M., & Bogdański, P. (2022) · Nutrients · doi:10.3390/nu14061261 · Cited by 114
Assessing the in vivo data on low/no-calorie sweeteners and the gut microbiota
Lobach, A. R., Roberts, A., & Rowland, I. R. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.12.005 · Cited by 104
Artificially Sweetened Beverages and the Response to the Global Obesity Crisis
Borges, M. C., Louzada, M. L., de Sá, T. H., Laverty, A. A., Parra, D. C., Garzillo, J. M. F., Monteiro, C. A., & Millett, C. (2017) · PLOS Medicine · doi:10.1371/journal.pmed.1002195 · Cited by 103
“More recently published data suggest that artificial sweeteners may contribute to the development of glucose intolerance by altering the composition and functions of gut microbiota [53].”
BackgroundArtificial sweeteners as a sugar substitute: Are they really safe?
Sharma, A. K., Amarnath, S., Thulasimani, M., & Ramaswamy, S. (2016) · Indian Journal of Pharmacology · doi:10.4103/0253-7613.182888 · Cited by 109
“Recent articles published in nature (2014) reported that NNS ingestion in mice for 11 weeks led to the development of glucose intolerance by altering the gut microbiome.[13,14] 10‐week old mice were fed with varying diet patterns (normal diet/high‐fat diet), and their drinking water was laced with either glucose or gl…”
BackgroundShil, A., Olusanya, O., Ghufoor, Z., Forson, B., Marks, J., & Chichger, H. (2020) · Nutrients · doi:10.3390/nu12061862 · Cited by 116
“Studies in humans and mice have demonstrated that the consumption of artificial sweeteners in the diet is linked with the dysbiosis of gut microbiota and an associated increase in levels of endotoxins secreted from these bacteria, such as lipopolysaccharide (LPS) [27,28].”
BackgroundJama, H. A., Beale, A. L., Shihata, W., & Marques, F. Z. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz091 · Cited by 105
Mendes‐Soares, H., Raveh-Sadka, T., Azulay, S., Ben‐Shlomo, Y., Cohen, Y., Ofek, T., Stevens, J., Bachrach, D., Kashyap, P., Segal, L., et al. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz028 · Cited by 104
“Illumina compatible libraries were prepared as described (17), and sequenced on an Illumina Nextera 500 (75 base pair, single end).”
MethodBarba, C., Beno, N., Guichard, E., & Thomas-Danguin, T. (2018) · Food Chemistry · doi:10.1016/j.foodchem.2018.02.152 · Cited by 99
Zhu, Y., Olsen, S. F., Mendola, P., Halldorsson, T. I., Rawal, S., Hinkle, S. N., Yeung, E. H., Chavarro, J. E., Grunnet, L. G., Granström, C., et al. (2017) · International Journal of Epidemiology · doi:10.1093/ije/dyx095 · Cited by 110
“In addition, the metabolic perturbations among male offspring might be partially attributable to sexspecific alterations in the gut microbiome,(33) which has been implicated in the artificial sweeteners-induced glucose tolerance.(11) On the other hand, no significant associations were observed for SSB consumption duri…”
BackgroundRoles of the gut microbiome in weight management
Carmody, R. N., & Bisanz, J. E. (2023) · Nature Reviews Microbiology · doi:10.1038/s41579-023-00888-0 · Cited by 113
Mikó, É., Csaszar, A., Bódis, J., & Kovács, K. A. (2022) · Life · doi:10.3390/life12030424 · Cited by 103
Beverage consumption and mortality among adults with type 2 diabetes: prospective cohort study
Ma, L., Hu, Y., Alperet, D. J., Liu, G., Malik, V., Manson, J. E., Rimm, E. B., Hu, F. B., & Sun, Q. (2023) · BMJ · doi:10.1136/bmj-2022-073406 · Cited by 104
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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