From Sweeteners to Sleeplessness: The Hidden Effects of Sucralose and Saccharin on the Gut–Brain Axis ^†

Abstract

Sweetener consumption has increased considerably in recent decades, driven by the growing demand from consumers of low-calorie products for weight control and, especially, from diabetic patients who require safe sweetener alternatives without affecting their glucose levels. However, the latest scientific evidence seems to indicate that the continued consumption of various sweeteners could significantly alter the gut microbiota, triggering consequences that go beyond metabolic health and could affect sleep quality. Among the most used non-caloric sweeteners in the food industry are sucralose and saccharin. Several studies have shown that prolonged consumption of these sweeteners can significantly alter the composition of the gut microbiota. In particular, its consumption might lead to a decrease in beneficial bacteria such as Lactobacillus and Bifidobacterium, along with an increase in potentially pathogenic microorganisms such as Clostridium difficile and Escherichia coli. This dysbiosis creates a chronic low-grade inflammatory environment and contributes to the deterioration of glucose metabolism, factors that negatively impact the regulation of the gut–brain axis. Consequently, these alterations could interfere with the neuroendocrine mechanisms involved in sleep, promoting the development of disorders such as insomnia, sleep fragmentation, and decreased subjective sleep quality. The aim of this narrative review is to synthesize the current scientific evidence on the impact of artificial sweeteners on the gut microbiota and their potential involvement in sleep disorders. The underlying biological mechanisms will be analyzed and the clinical relevance of these interactions discussed, laying the groundwork for future research that will contribute to the development of dietary recommendations and therapeutic strategies aimed at modulating the microbiota to improve sleep health.

1. Introduction

In recent decades, there has been an increase in the prevalence of diseases such as obesity, diabetes, and various cardiovascular diseases, which are connected with excessive sugar consumption [1]. This excessive sugar consumption has led to the substitution of simple sugars with non-caloric sweeteners (NNS) in many food products currently available on the market in order to comply with health organizations’ recommendations and the rising demand for low-calorie foods from consumers and governments [2,3].

NNS present several advantages including providing sweetness without significant metabolic energy, making them attractive for the diets of people with diabetes or those trying to lose weight [4]. Among the various NNS available on the market, saccharin and sucralose are the most commonly used [5], with an estimated market value of $2.2 million in 2020 and an annual increase of 5.1%. This increase is caused by both a decrease in the concentration of other sweeteners (like aspartame) due to their potential negative health effects and an increase in the consumption of products containing non-sweetened artificial sweeteners (NSAIDs) [6]. These emergent NNS, were considered metabolically inert. However, in recent years, various scientific studies seem to indicate that these NNS are not completely inert, since it has been observed that both saccharin and sucralose can interact with gut microbiota (Figure 1), altering its composition and function, with a consequent impact on host physiology [7].

Simultaneously, gut microbiota has been established as a fundamental regulator of diverse biological functions, including effects on the neuroendocrine, immune, and metabolic systems, as a part of the gut–brain axis (GBA) [10]. The microbiota influences these processes via several pathways, including the production of microbial metabolites (e.g., short-chain fatty acids), the regulation of intestinal permeability, the release of cytokines, and the modulation of intestinal receptors sensitive to nutrients [11,12,13]. These interactions can affect the synthesis of neurotransmitters and hormones, as well as the immune response, contributing to the maintenance of overall homeostasis and participating in neuroimmunological balance, sleep regulation, and circadian rhythms [14,15,16].

On the other hand, sleep and circadian rhythms are essential for maintaining good physical and mental health, as they influence vital processes such as metabolism, cellular repair, immune function, and memory consolidation [17]. It has been observed that inadequate sleep can cause impaired restoration of the central nervous system, disrupted hormonal regulation, and a reduced capacity to eliminate toxic metabolites accumulated during wakefulness [18]. Circadian rhythms, responsible for synchronizing sleep–wake cycles with ambient light and other temporal signals, coordinate physiological activity throughout the day, optimizing metabolic, cardiovascular, and cognitive functions [19,20]. Disruption of these two factors has been associated with an increased risk of developing conditions such as obesity, diabetes, cardiovascular disease, neuropsychiatric disorders, and cognitive decline, highlighting the importance of their regulation for overall health and long-term well-being [17,21,22]. In addition, some of these diseases have been associated with the consumption of NNS, which could constitute an aggravating factor over time.

Therefore, given the growing importance of sleep quality for physical and mental health, and the relevance of the gut microbiota as a modulator of multiple physiological axes, it is reasonable to propose that modifications induced by NNS in the microbiota could ultimately have repercussions on the processes that regulate sleep. Despite this, the current literature appears fragmented, with numerous studies on the impact of sucralose and saccharin on the microbiota, but almost no articles directly exploring the relationship between the consumption of these molecules and sleep disturbances. Given this gap in knowledge, this study aims to: (1) synthesize the current evidence on the effects of sucralose and saccharin on the gut microbiota; (2) analyze the potential biological mechanisms by which these alterations could influence the gut–brain axis; (3) assess the feasibility of extending this hypothesis to the field of sleep disorders; and (4) identify knowledge gaps and propose future research directions. This interdisciplinary approach could provide the theoretical basis for experimental or clinical–epidemiological studies, leading to dietary recommendations or therapeutic strategies targeting the microbiota to improve sleep health.

2. Search Strategy and Data Collection

Due to the exploratory nature of this proceeding, a critical narrative synthesis was carried out rather than a quantitative meta-analysis. To carry it out, the main databases of the biomedical literature (PubMed, Medline, and Google Scholar) were consulted. The keywords employed in the literature search include “sucralose,” “saccharin,” “non-nutritive sweeteners (NNS),” “artificial sweeteners,” “gut microbiota,” “intestinal microbiota,” “microbiome,” “human,” “animal model,” “in vitro,” “sleep,” and “gut–brain axis.” Only peer-reviewed articles in English presenting experimental or analytical information on CBA were retained. Publications focused exclusively on other sweeteners, non-English sources, non-peer-reviewed materials, opinion articles, letters to the editor, and non-peer-reviewed articles were excluded. The scarcity of information made it unfeasible to establish the exclusion criterion of studying only recent literature. Following PRISMA recommendations, duplicates were removed, and the remaining records were screened through titles, abstracts, and full texts to ensure the inclusion of studies providing reliable and relevant evidence. The results were grouped by type of evidence (preclinical vs. clinical) and by type of effect (composition, function, implications for the gut–brain axis), which allowed for the identification of consistencies, contradictions, and knowledge gaps.

3. Discussion

Natural sweeteners (e.g., sucrose, glucose, thaumatin, steviol glucosides, monellin, polyols) are digestible carbohydrates that are either absorbed in the small intestine or, when reaching the colon, can serve as fermentable substrates for commensal bacteria. Several studies have shown that these sugars can support the growth of beneficial microbial taxa, particularly lactic acid bacteria such as Lactobacillus spp. and Bifidobacterium spp., through enhanced carbohydrate availability and increased production of short-chain fatty acids [23,24]. In particular, trehalose has been reported to promote the growth of probiotic strains and improve microbial metabolic activity, contributing to gut homeostasis [25].

In contrast, artificial sweeteners such as sucralose and saccharin are non-nutritive compounds that are poorly metabolized by host enzymes and often reach the colon largely intact. Their presence in the gut has been associated with significant changes in the gut microbiota, with the degree and duration of these changes varying depending on the experimental models studied [7,23]. The strongest evidence has been obtained in in vitro models and laboratory animals, in which a significant reduction in gut microbiota diversity has been observed [26,27]. Furthermore, some studies have shown that continued consumption of these sweeteners promotes the growth of opportunistic and/or harmful bacteria (e.g., Proteobacteria such as Escherichia coli) and a decrease in the number of bacteria associated with the production of short-chain fatty acids (e.g., Lactobacillus acidophilus) [28,29]. For instance, saccharin consumption has been associated with an increased abundance of Bacteroides spp. and members of the phylum Proteobacteria, alongside a reduction in beneficial Firmicutes, including Clostridiales involved in short-chain fatty acid production. These microbial shifts have been linked to altered glucose metabolism and inflammatory responses [30]. Conversely, sucralose exposure has been shown to reduce populations of Lactobacillus and Bifidobacterium while increasing Enterobacteriaceae, suggesting a selective inhibitory effect on beneficial fermentative bacteria [31]. In a similar study, it was observed that continued consumption of acceptable daily intake of sucralose in rats generated a reduction of probiotics abundance (Lachnoclostridium, Lachnospiraceae, and Akkermansiaceae) in cecum and rectum, and an increase in Acidaminoccaceae (genus Phascolarctobacteriam), Allobaculum (which was reported positively correlated with diabetes), and the potential pathogens Tenacibaculum, Ruegeria, Staphylococcus in jejunum, ileum and colon [32,33]. According to available scientific evidence, the mechanism of action of sucralose consists of its persistence within the intestinal lumen, where it directly interacts with the gut microbiota. This interaction disrupts intestinal barrier function and mucosal immune homeostasis, thereby altering host–microbe signaling. As a consequence, selective ecological pressures emerge that reshape microbial composition and promote dysbiosis [32]. Additional studies have reported decreased levels of Clostridiumcluster cluster XIVa in feces following chronic sucralose intake, potentially affecting gut barrier integrity and host–microbiota interactions [34]. This could be associated with a loss of various metabolic functions considered protective for the integrity of the intestinal mucosa, including reduced short-chain fatty acid production, changes in microbial gene expression, and impaired microbial network stability. Such alterations in the gut microbiota can actively influence host physiology by modulating immune responses, intestinal barrier function, and metabolic homeostasis, thereby highlighting the microbiome as a key upstream regulator of downstream physiological processes [28,29]. Together, these findings indicate that some artificial sweeteners can selectively inhibit or promote specific microbial taxa through metabolic and ecological mechanisms, thereby influencing gut–brain axis signaling pathways.

At a functional level, available studies demonstrate that the effects of prolonged consumption of these artificial sweeteners are not limited to a change in the composition of the gut microbiota but that this change also has a significant impact on the consumer’s metabolism [35], as well as greater probability of other diseases, coupled with an unexpected increase in body weight, adverse gestational outcomes, and possible risks for individuals prone to seizures [28,29]. For example, the consumption of these sweeteners is associated with a lower production of metabolites such as butyrate and propionate, compounds essential for maintaining epithelial homeostasis and regulating local immune processes [36]. Some studies also describe changes in intestinal permeability and in the expression of molecules involved in the inflammatory response, which raises the possibility that repeated consumption of sucralose and saccharin may have broader repercussions on host physiology [7,37]. The main impacts can be seen in Figure 2.

However, it should be noted that all these studies were carried out with controlled models, so the results obtained may vary significantly when analyzing real cases since these models fully reproduce the complexity of the human diet, although they are considered a good approximation to processes that could also occur, while more attenuated, in real consumption situations. Nevertheless, although these changes are more subtle in humans, the latest scientific evidence seems to indicate that these moderate alterations can cause significant alterations in various physiological functions. For example, a reduction in short-chain fatty acids or a slight increase in local inflammatory markers could affect communication between the gut and the central nervous system, since the microbiota plays an active role in regulating the immune response, producing neurotransmitters, and modulating hormones linked to energy metabolism and stress [37,38]. In all cases, the studies conducted in humans are characterized by more heterogeneous findings and several limitations. The first of these is that the available clinical trials are of short duration. Furthermore, these studies analyze doses of sweeteners within the recommended limits, which may underestimate the average amounts ingested by a population [39,40]. These reasons could explain why studies conducted in humans did not detect significant changes in microbial diversity or the relative abundance of the main bacterial genera, while others described discrete variations affecting specific microbial subpopulations. Furthermore, in these in vivo studies, it is necessary to consider individual variability since subjects exhibit intrinsic variability in their gut microbiota, which will also generate variability in the results obtained [41]. This suggests that susceptibility to sweeteners could depend on both the pre-existing microbial composition as well as dietary and lifestyle factors. In all cases, the changes observed in humans tend to be more subtle than in experimental models.

Regarding the impact of sucralose and saccharin consumption on sleep parameters in humans, some authors suggest that a sustained modification of the gut ecosystem could influence the stability of circadian rhythms and processes linked to nighttime rest, especially in individuals with a vulnerable gut microbiota or unbalanced dietary patterns [7]. These effects have already been demonstrated in in vivo studies in rats, in which prolonged consumption of saccharin (0.1% w/v) disrupted the circadian sleep–wake cycle and caused behavioral inactivity [42]. A similar study concluded that doses of sweeteners considered safe (equivalent to 7–28% of the FDA-recommended human DIV) caused changes on memory, rhythm behaviors, and modifications at the molecular level in the brains in mice [43]. In another study, it was observed that sucralose induced hyperactivity, insomnia, and reduced sleep quality (patterns that align with a mild starvation- or fasting-like state) with comparable sleep-related effects previously observed in human research [44]. For instance, the consumption of beverages with artificial sweeteners has shown an interaction between their consumption and the modification of sleep patterns [45]. In guinea pigs, it was observed that saccharin consumption increased the abundance of Firmicutes and Lactobacillasceae in the ileum, and subsequently increased levels of lactic acid and short-chain fatty acids, regulating the microbiota–hypothalamus–gut axis, via activating sweet receptor signaling in the gut and growth-hormone-releasing peptide hormone secretion [46].

Regarding the mechanism by which these artificial sweeteners alter the gut microbiota and consequently the gut–brain axis, changes in microbial composition and metabolite production, such as short-chain fatty acids and bile acids, can affect signaling to the central nervous system through the bloodstream and the vagus nerve [37]. These microbial signals also modulate systemic immune and inflammatory responses, influencing gene expression in hypothalamic centers involved in circadian and sleep regulation. In animal models, alterations in microbial metabolites have been associated with changes in neural activity and neuroinflammation that affect sleep architecture, providing a mechanistic framework in which sweetener-induced dysbiosis can modulate gut–brain axis physiology and sleep patterns [29,47]. Another study suggested that exposure to saccharin during the perinatal period was linked to alterations in glucose regulation and reduced insulin sensitivity in both male and female progeny. These metabolic disturbances were accompanied by modifications in gut–brain communication and by dysregulation of hypothalamic pathways involved in glucose control and appetite regulation, predominantly affecting GLP-1, leptin, and insulin signaling mechanisms [48]. Together, these observations suggest potential effects of sucralose and saccharin on the gut–brain axis, indicating that even commonly consumed artificial sweeteners may influence sleep and other physiological processes, although further studies are needed to confirm these findings.

4. Conclusions

Taken together, the findings indicate that exposure to sucralose and saccharin could modify, to varying degrees, both the composition and functional activity of the gut microbiota. These alterations are more significant in experimental models, making it necessary to analyze individual variability as well as the dietary context in humans. However, the similarity in some patterns (e.g., decrease in bacteria that produce beneficial metabolites, variations in the metabolic capacity of microorganisms) suggests that these sweeteners are not entirely inert to the gut ecosystem. Although it is still too early to determine their effect on complex functions such as sleep regulation, current evidence seems to indicate a link between variations in the microbiota, metabolites, inflammatory markers, and circadian parameters, which will help us better understand the systemic implications of their regular intake.