ArticlePDF Available

Artificial Sweeteners Induce Glucose Intolerance by Altering the Gut Microbiota

Authors:

Abstract and Figures

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.
Content may be subject to copyright.
A preview of the PDF is not available
... Replacing sugar with ASs while maintaining these functional properties is challenging. It involves assessing how well ASs can be integrated into various products without negatively affecting taste, texture, stability, and other sensory attributes (Suez et al. 2014). By isolating these interactions, the unique challenges and opportunities that arise when incorporating ASs into complex food systems are elucidated. ...
... Some studies have recently reported that the regular consumption of some ASs could worsen glucose release and cause glucose intolerance in humans and mice (Iizuka 2022). According to previous studies, aspartame, saccharin, and sucralose consumption for only 1 week led to glucose intolerance in mice (Suez et al. 2014). Moreover, saccharin promoted high-fat diet-induced glucose intolerance. ...
... Moreover, glucose intolerance was developed in mice receiving a saccharin-related gut microbiome. These findings indicate a decrease in glucose release capacity due to gut microbiome changes after the consumption of saccharin (Suez et al. 2014;Iizuka 2022). According to the results of previous studies, intestinal microbiota has an important effect on glucose intolerance caused by saccharin consumption. ...
Article
Full-text available
The application of artificial sweeteners (ASs) in food science represents a pivotal response to the global challenge of reducing sugar consumption. Although ASs offer innovative solutions to address nutritional concerns related to excessive calorie intake and sugar‐related health issues, their integration into food products creates a complex interplay of nutritional and technological challenges. The potential effects on health, including interactions with the gut microbiota, necessitate careful examination. Additionally, the successful incorporation of ASs into food formulations requires an in‐depth understanding of their physicochemical properties, sensory characteristics, microbial interactions, and cost considerations. The primary challenge for food scientists is meeting sugar‐reduction goals without compromising texture and stability. This review presents a detailed analysis of the nutritional and technological complexities of ASs, emphasizing how multidisciplinary research advances food science.
... Artificial sweeteners such as saccharin, sucralose, and aspartame can cause gut dysbiosis, resulting in glucose intolerance. Previous studies emphasize that non-nutritive sweeteners can change microbial diversity, impacting metabolic pathways J o u r n a l P r e -p r o o f and neurobehavioral outcomes [57]. Non-caloric artificial sweeteners, such as saccharin, sucralose, aspartame, and acesulfame potassium, can up-level reactive oxygen species (ROS) production and promote plasmid-mediated conjugative transfer to the gut microbiome. ...
... This might have also contributed to the altered levels of serotonin and AChE in different exposure groups. NNS can be used as a carbon source by some gut bacteria, causing changes in metabolic activity and altering shortchain fatty acid (SCFA) synthesis [57]. SCFAs are produced from the gut microbes, i.e., ...
Article
The use of non-nutritive sweeteners as calorie-free substitutes for sugar has gained popularity. The rising prevalence of metabolic disorders and neurological dysfunctions potentially associated with non-nutritive sweeteners has prompted increased scrutiny of these sugar substitutes. This study investigated the neuroendocrine and metabolic effects of chronic exposure to sucralose and stevia, both individually and in combination, using Danio rerio as a model organism. Adult zebrafish were subjected to environmentally relevant concentrations of these sweeteners, followed by a comprehensive battery of neurobehavioral assays, including scototaxis, agonistic behavior assessment, social interaction tests, and novel object recognition paradigms. Biochemical analyses encompassed acetylcholinesterase activity, serotonergic modulation, and hypothalamic-pituitary-interrenal axis function via cortisol quantification. Metabolic perturbations were evaluated through glucose tolerance tests, body mass index calculations, and metabolic enzyme activity assays. Additionally, gut microbiome alterations were assessed, with a particular focus on Lactobacillus and Bifidobacterium populations. Results demonstrated significant anxiogenic and depressogenic effects, cognitive impairment, and heightened aggression in exposed specimens. These behavioral anomalies correlated with decreased AChE activity, serotonin depletion, and elevated cortisol levels, indicative of neurotoxicity and HPI axis dysregulation. Metabolic disruptions manifested as hyperglycemia, increased adiposity, and altered enzymatic profiles, suggesting a predisposition to obesity and glucose intolerance. Notably, shifts in gut microbiota composition, particularly affecting serotonin and short-chain fatty acid production, potentially exacerbated the observed neurotoxic effects. The study revealed that combined exposure to sucralose and stevia elicited synergistic adverse outcomes, surpassing the effects observed in individual exposure groups. These findings underscore the potential risks associated with such sweetener consumption and highlight the need for further investigation into their long-term health implications.
... In the case of saccharin, it was found in amniotic fluid, fetal bladder and maternal blood in similar quantities [10]. This exposure to sweeteners during the intrauterine period has been described to have a large impact on the programming of offspring's risk of developing diseases, such as metabolic syndrome, throughout life [3,8,11,12]. ...
Article
Full-text available
Background Certain events that occur in early life, such as changes in nutrition, can promote structural and functional modifications in brain development, projecting to either short, medium, and/or long terms, resulting in metabolic programming. These effects depend on the timing, intensity, and duration of exposure, and are proposed to be the cause or contribute to chronic adult disorders. Recent studies have proposed that artificial non-nutritive sweeteners (NNS), such as saccharin, can be included as one of these developmental disruptors. Saccharin consumption during pregnancy is strongly discouraged, as it can cross through the placenta and accumulate in the fetus, potentially impacting metabolic control for life. However, the mechanisms underlying the metabolic syndrome induced by maternal NNS consumption during pregnancy are not well understood. Some studies suggest that NNS may affect sweet taste receptors in the adult’s guts, leading to changes in the release of glucagon-like peptide-1 (GLP-1) and insulin. The objective of the study is to investigate whether maternal saccharin consumption during pregnancy affects the gut-brain connection, leading to alterations in insulin/GLP-1 signaling during neurodevelopment until adolescence. Methods Pregnant rats were administered 0.1% saccharin in drinking water throughout gestation, and the main components of the insulin/GLP-1 signaling pathway were analyzed in the plasma, small intestine and hypothalamus of the offspring after weaning. Perinatal exposure to saccharin was linked to disrupted glucose homeostasis and insulin sensitivity in both male and female offspring. Results We identified sex-dependent mechanisms that affected GLP-1 signaling in the intestine, associated with the expression of taste receptors and glucose transporters. These alterations affected the gut-brain axis and disrupted hypothalamic signaling associated with glucose regulation and food intake, primarily involving the GLP-1, leptin, and insulin signaling pathways. Conclusions These results suggest that developmental NNS exposure might contribute to the growing alteration in energy metabolism.
... For instance, some studies have suggested that habitual intake of ASBs is associated with increased adipose tissue accumulation and weight gain, even in the absence of excess caloric intake [40]. This paradox may be explained by the alteration of gut microbiota composition and function, which is increasingly recognized as a key player in metabolic health [41]. In addition to potential changes in gut microbiota, ASBs may influence appetite regulation and satiety. ...
Article
Full-text available
Purpose Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with rising prevalence globally. Emerging evidence suggests that dietary factors, including the intake of sweetened beverages, may influence the risk of GERD. Uncertainty surrounds the relationship between various sweetened beverage kinds and GERD incidents, though. The purpose of this study was to investigate the relationships between the risk of GERD and the intake of natural juices (NJs), sugar-sweetened drinks (SSBs), and artificially sweetened beverages (ASBs). Methods In this prospective cohort study, 167,574 participants from the UK Biobank, free of GERD at baseline, were included. Beverage intake data were collected through repeated 24-hour dietary recalls between 2009 and 2012. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between beverage consumption and the risk of GERD. Substitution analyses were also performed to evaluate the effects of replacing SSBs and ASBs with NJs. Results During a median follow-up of 12.8 years, 10,454 incident GERD cases were recorded. Participants who consumed more than 1 serving/day of SSBs had a higher risk of GERD compared to non-consumers (HR 1.07, 95% CI 1.01–1.14). Similarly, any consumption of ASBs was associated with an increased risk of GERD (HR 1.12, 95% CI 1.05–1.21 for > 1 serving/day). In contrast, moderate consumption of NJs (> 1 serving/day) was linked to a lower risk of GERD (HR 0.91, 95% CI 0.85–0.97). Subgroup and sensitivity analyses confirmed the robustness of these findings. Substitution of 1 serving/day of SSBs (HR 0.92, 95% CI 0.88–0.95) or ASBs (HR 0.89, 95% CI 0.86–0.93) with an equivalent amount of NJs reduced the risk of GERD. Conclusion Moderate intake of NJs was linked to a lower risk of GERD, but higher consumption of SSBs and ASBs was linked to an increased risk. These results highlight the potential role of sweetened beverages in GERD prevention strategies and call for further research to understand the underlying mechanisms.
Article
Telomere attrition is a hallmark of cellular aging, influenced by oxidative stress, chronic inflammation, and metabolic dysregulation. Emerging evidence suggests that dietary patterns rich in plant-based, minimally processed foods may influence telomere dynamics, potentially extending healthspan. This narrative review synthesizes current literature on the molecular mechanisms by which specific nutrients—such as antioxidants, polyphenols, omega-3 fatty acids, and methyl donors—affect telomere length and telomerase activity. Conversely, high consumption of ultra-processed foods (UPFs) has been associated with accelerated telomere shortening and dysfunction, likely due to increased oxidative stress, inflammation, and nutrient deficiencies. We propose a tiered dietary intervention model including preventive, therapeutic, and regenerative phases, tailored to individual aging trajectories and physiological statuses. This model emphasizes the consumption of whole plant foods, functional bioactives, and the reduction of UPFs to preserve telomere integrity. Implementing such dietary strategies may offer a viable approach to mitigate age-related cellular decline and promote healthy aging.
Chapter
Our bodies are colonized with trillions of microorganisms, comprising bacteria, fungi, micro-eukaryotes, and viruses, which are collectively named “microbiome” [1–3]. Several human body sites are colonized by different and distinct microbiomes, for example, the skin [4], the oral cavity [5], the gastrointestinal tract [6], and the urogenital tract [7]. Microbiomes have been shown to play crucial roles linked with our health and disease states [3, 4, 8, 9]. For example, it has been shown to train the immune systems in newborns [10], to digest important nutrients that otherwise we would not be able to process, and to produce health-promoting metabolites [11]. More in detail, it has been shown that gut bacteria help to break down complex carbohydrates [12] as well as absorb important vitamins and minerals present in the food [13]. For instance, they produce short-chain fatty acids (SCFAs) like butyrate, propionate, and acetate, by fermenting dietary fibers that reach the colon [14–17]. Additionally, commensal bacteria stimulate the production of mucus by the gut lining and compete for nutrients with pathogens and other harmful bacteria by occupying specific ecological niches in our digestive tract, thus preventing or limiting colonization [18, 19]. Certain bacteria can moreover produce antimicrobial compounds that can directly kill or inhibit the growth of pathogenic bacteria [20].
Article
Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by insulin resistance and pancreatic β-cell dysfunction. Emerging evidence indicates that gut microbiota dysbiosis may contribute to the development of T2DM. Individuals with T2DM exhibit notable changes in gut microbiota composition, including shifts in the balance between Firmicutes and Bacteroidetes, a reduction in butyrate-producing bacteria, and an increase in opportunistic pathogens. Gut microbiota-derived metabolites—such as short-chain fatty acids, bile acids, and amino acids—have been implicated in the pathogenesis of T2DM, highlighting the critical role of host-microbe interactions. In this overview, we discuss the gut microbiota dysbiosis associated with T2DM and explore the molecular links between microbiota-derived metabolites and the pathogenesis of diseases. Additionally, we explore potential therapeutic strategies, including probiotics and dietary interventions, to modulate the gut microbiota and its metabolites, providing insights for future clinical research and the development of novel treatments for T2DM.
Article
Full-text available
Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
Article
Full-text available
Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
Article
Full-text available
Emerging next-generation sequencing technologies have revolutionized the collection of genomic data for applications in bioforensics, biosurveillance, and for use in clinical settings. However, to make the most of these new data, new methodology needs to be developed that can accommodate large volumes of genetic data in a computationally efficient manner. We present a statistical framework to analyze raw next-generation sequence reads from purified or mixed environmental or targeted infected tissue samples for rapid species identification and strain attribution against a robust database of known biological agents. Our method, Pathoscope, capitalizes on a Bayesian statistical framework that accommodates information on sequence quality, mapping quality and provides posterior probabilities of matches to a known database of target genomes. Importantly, our approach also incorporates the possibility that multiple species can be present in the sample and considers cases when the sample species/strain is not in the reference database. Furthermore, our approach can accurately discriminate between very closely related strains of the same species with very little coverage of the genome and without the need for multiple alignment steps, extensive homology searches, or genome assembly- which are time consuming and labor intensive steps. We demonstrate the utility of our approach on genomic data from purified and in silico 'environmental' samples from known bacterial agents impacting human health for accuracy assessment and comparison with other approaches.
Article
Full-text available
A 16S rRNA gene database (http://greengenes.lbl.gov) addresses limitations of public repositories by providing chimera screening, standard alignment, and taxonomic classification using multiple published taxonomies. It was found that there is incongruent taxonomic nomenclature among curators even at the phylum level. Putative chimeras were identified in 3% of environmental sequences and in 0.2% of records derived from isolates. Environmental sequences were classified into 100 phylum-level lineages in the Archaea and Bacteria.
Article
Full-text available
Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.
Article
Full-text available
Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
Article
Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose and pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this Review, we describe how glycans shape the composition of the gut microbiota over various periods of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition.
Article
To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.
Article
Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.
Article
Dynamic protein binding to DNA elements regulates genome function and cell fate. Although methods for mapping in vivo protein-DNA interactions are becoming crucial for every aspect of genomic research, they are laborious and costly, thereby limiting progress. Here we present a protocol for mapping in vivo protein-DNA interactions using a high-throughput chromatin immunoprecipitation (HT-ChIP) approach. By using paramagnetic beads, we streamline the entire ChIP and indexed library construction process: sample transfer and loss is minimized and the need for manually labor-intensive procedures such as washes, gel extraction and DNA precipitation is eliminated. All of this allows for fully automated, cost effective and highly sensitive 96-well ChIP sequencing (ChIP-seq). Sample preparation takes 3 d from cultured cells to pooled libraries. Compared with previous methods, HT-ChIP is more suitable for large-scale in vivo studies, specifically those measuring the dynamics of a large number of different chromatin modifications/transcription factors or multiple perturbations.