The nonnutritive sweeteners (NNS), artificial (AS) and natural (NS) are commonly used worldwide dietary supplements. The high consume of these is the result of changes in lifestyle, specifically in countries with occidental diet. The NNS are used in the industrial formulation of food and beverages, especially for the low caloric intake, the low costs and the greater sweetness sensation compared with sucrose (regular sugar) and other caloric sweeteners [1]; On the other hand, due to the incomplete absorption of the NNS, the gastrointestinal tract suffers a series of alterations, especially in colonic microbiota. These variations in bacterial population could cause changes in the intestinal habit and motility, generating symptoms in patients with predisposition such as Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) [2]. Since 1980, studies assessing bacterial cultures have reported associations between the use of sweeteners and the presence of intestinal symptoms. However, more recent literature shows contradictory results, causing discussion on the matter [3].

The objective of this review is to describe the association between NNS and the respective gastrointestinal alterations related to intestinal habit.

The PubMed, Scopus, and Embase databases were searched for studies published in English and Spanish between January 1980 and December 2017. The key search words used were gastrointestinal disease AND non-caloric sweeteners, microbiota OR microbiome AND non-caloric sweeteners. Once both authors of the study agreed with the research statement, articles with two associations of the principal related variables in the tittle or summary were included in the analysis. Observational, experimental and review studies were included, this approach was because it was provided more information and the expert’s opinion in the analysis.

In this narrative review NNS were defined as sweeteners that provide sweetness without energy or with negligible values, we used the terms high-intensity sweeteners, low-calorie sweeteners and non-caloric sweeteners as synonyms (Table 1 and Figure 1).

Table 1: All articles PubMed, Scopus, and Embase databases searched with key words used (gastrointestinal disease AND non-caloric sweeteners, microbiota OR microbiome AND non-caloric sweeteners).

Figure 1: Effect of sweeteners on microbiota and production of abdominal pain, discomfort, abdominal distension, diarrhea and flatulence, through of an increase of hydrogen (H₂), methane (CH₄) and water (H₂O) levels; Furthermore, the relationship between gastrointestinal motility and enteroendocrine secretion with sweeteners. The cyclic secretion of motilin, and perhaps of ghrelin, regulates interdigestive gastrointestinal motility. Cholecystokinin, (CCK), gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and pancreatic polypeptide Y (PPY) are released after meals; where motilin and ghrelin are suppressed. This represents the change of an interdigestive gastrointestinal motor pattern to a postprandial one.

More than a century ago, NNS were introduced in the food industry trying to give food the sweet taste without the usual high caloric and sugar intake. NNS consume got popular because of the low costs, the low caloric intake and the good perception of health benefits in weight loss and normalization of blood glucose [4]. Today with all these advantages, their use in food and beverages is more common. A study from the United States of America (USA) from 2005 to 2009 showed that 15% of the volume of food and beverages contains NNS and that this percentage has been gradually increasing [5].

There have been identified several NNS in the Food Industry, however, the Food and Drug Administration (FDA) has approved only six high intensity sweeteners such as saccharine, aspartame, neotame, acesulfame K, sucralose and advantame; and two Generally Recognized as Safe (GRAS), stevia and luo han guo [1]. Each one of them has different intensities of sweetness, origin and characteristics related to gastrointestinal processes, as shown on Table 2 [6,7].

Table 2: Principal NNS in the market, sweetness intensities, sources and characteristics of interest in the gastrointestinal processes [6,7].

Due to the lack of absorption of NNS by the intestinal microvilli, especially of sucralose, it has been suggested that a possible consequence of this could be intestinal dysbiosis. Recent studies have described that intestinal microbiota is importantly involved in the guest’s metabolism and that has a key role in the food digestion, energetic homeostasis, the immune system’s development, the enteric nerves regulation and the prevention of pathogenic invasion [8]. Abou-Donia et al. showed in animal models that the absorption of sucralose is only of 11 to 27%, the rest remaining in the gastrointestinal tract until its excretion in the feces; and suggest that this significantly modifies the growth of intestinal bacteria (Table 3) [6,9]. Also, recent studies have reported that the NNS such as saccharine affect glucose tolerance by means of the modulation of intestinal bacterial concentrations and that the latter could produce several proinflammatory intermediaries, causing an inflammatory process in the guest [4,8].

Table 3: Changes in the gastrointestinal tract associated to NNS consume.

In patients with gastrointestinal predisposition, such as IBD or IBS, these changes in the microbiota and in intestinal motility could be of great importance during the disease follow-up, as shown in Table 3.

Changes in gastrointestinal motility secondary to NNS consume

Gastrointestinal tract motility is a process modulated by a neural and hormonal complex. The latter includes intestinal peptides secreted by neuroendocrine cells during interdigestive and postprandial periods. This process is an important determinant of the hormonal secretion of the bowel and the luminal transit, which affects the amount of absorption of the nutrients by the enteroendocrine cells in different parts of the bowel [10].

Also, enteroendocrine cells release more than 30 peptides, such as motilin and ghrelin, during the inter-digestive period; and cholecystokinin (CCK) and gastric inhibitory polypeptide (GIP), during the postprandial period. These hormones are the main mediators during the change of the gastrointestinal motor pattern from the inter-digestive period to the postprandial, and during the emptying of the lumen; detected by the enteroendocrine cells dependent of the gastrointestinal motor activity [11,12]. On the other hand, some studies suggest that the effects of the glucagon-like peptide-1 (GLP- 1) in the gastrointestinal motility are upon the interaction of certain brain centers or afferent nerve pathways [13,14]. An increase of GLP- 1 reduces the motility in the antrum-jejunal segment and inhibits the migratory motor complex in healthy subjects and in patients with IBS. Particularly the CCK has strong effects over the bowel’s smooth muscle contractility; and several other studies suggest that the CCK, GIP and the pancreatic polypeptide Y (PPY) could slow the gastric emptying and the intestinal transit too [15-19].

Nevertheless, there is evidence that NNS consume modifies the expression of hormones such as GLP-1, GIP, PYY and CCK; which consequently could affect gastrointestinal motility. It has been demonstrated in studies of animal and human models that NNS (especially assessed in sucralose) can affect the secretion of peptides and serotonin and that this could indirectly affect the gastrointestinal motility [7,20-22].

However, another study in animal models did not show differences in CCK and GLP-1 concentrations in duodenal samples between the group receiving placebo and the one with sucralose. Despite, there was a significant increase in both hormones in the latter when sucralose was mixed with vegetal protein; which suggests that together this macronutrient and sucralose could have a synergic action in the secretion of CCK and GLP-1 [23].

Contrary to these findings, in animal models with sucralose, saccharine and acesulfame showed that there was no increase of GLP-1 or GIP, despite the concentrations of NNS were 1.000-fold greater than the concentrations used in diet sodas [24].

On the other hand, in clinical trial seven healthy patients were given intragastric infusions of 50 g of sucrose diluted in water, 80 mg of sucralose in 500 mL of normal saline solution (NSS), 800 mg of sucralose in 500 mL of NSS and 500 mL of NSS, found that sucralose did not stimulate the secretion of GLP-1 or GIP, and that gastric emptying had not stopped, according to exhaled carbon dioxide tests assessment [25]. In another randomized controlled clinical trial, healthy patients received 50 mL of water with sucralose 0,083% or maltodextrin and sucralose, showed that the administration of sucralose did not raise the concentrations of GLP-1 or PYY in blood [26]. Steinert et al. assessed twelve healthy volunteers in a randomized double blind clinical trial; the patients were given intragastric infusions of aspartame, acesulfame, sucralose, fructose, glucose and water. It was found that the equivalent sweetness of NNS did not affect the GLP-1, ghrelin and PYY secretion [27].

Nevertheless, in a crossover clinical trial with twenty-two healthy patients who received 240 mL of diet cola or mineral water ten minutes after an oral glucose load of 75 g, the concentrations of GLP-1 were significantly higher in the individuals receiving diet cola than in the ones receiving mineral water. This suggests that sucralose combined with glucose could increase the secretion of GLP-1, but not the sucralose alone [28].

Current literature available based on in vivo studies show that the GLP-1, GIP, PYY and CCK secretion could result indirectly in gastrointestinal motility changes; however, in humans these effects have only been demonstrated when sucralose is combined with glucose.

Therefore, NNS affect gastrointestinal motility secondary to an increase of GLP in the presence of glucose or any other macronutrient (Table 3).

Effects over intestinal microbiota

The microbiota and their interactions with the host or surrounding environment has been extensively investigated for the last 50 years and results show that 90% of intestinal microbiota is represented by phylum such as Firmicutes, Bacteroidetes and Actinobacteria, and in lower concentration Verrucomicrobia and Proteobacteria [7,29]. Intestinal microbiota has several functions like the synthesis of certain vitamins (K and B12), sensitivity modulation, digestive motility, permeability, regulation of the intestinal barrier, and it has recently been described that it is also involved with some metabolic pathways, food allergies and food intolerance [30]. Changes in the microbiota could contribute to a chronic low inflammatory process, facilitating the progression of chronic diseases or the exacerbation of their symptoms. In several studies it has been demonstrated that certain macronutrients consume could modulate and affect composition of the microbiota such as NNS [31,32]. Aderson et al. have shown that saccharine significantly affects the balance of aerobic and anaerobic bacteria [33], and Uebanso et al. monstrated results that suggest that daily intake of maximum acceptable daily intake (ADI) levels of sucralose, but not acesulfame-K, affected the relative amount of the Clostridium cluster XIVa in fecal microbiome and cholesterol bile acid metabolism in mice [34]. On the other hand, in vitro and in vivo studies it has been noted that sucralose consume is associated with greater presence of subpopulations of commensal strains in the microbiota such as Bacteroides, Lactobacillus and Bifidobacterium. Nonetheless, aspartame consume has been associated with a lower number of Lactobacillus and greater of Enterobacteriaceae, Clostridials y Roseburia [33]. Other studies of animal models show that the combination of ethanol and saccharine significantly decreases the number of intestinal Eubacteria [35].

Studies assessing the association between the changes in the intestinal microbiota and gastrointestinal diseases such as IBS and IBD, are becoming increasingly numerous and NNS could cause significant changes in the microbiota that affect the symptoms of these diseases.

NNS and irritable bowel syndrome

The IBS is characterized by recurrent episodes of abdominal pain, distension and changes in the intestinal habit, which could be diarrhea predominant (IBS-D), constipation predominant subtype (IBS-C), or IBS with mixed bowel habits (IBS-M). It is a prevalent disease accounting for 10 to 20% of the general population [2], and 4.4 to 35% of the Mexican population, depending on the specific region [36,37].

IBS is considered a multifactorial disease in which different environmental, genetic, physiologic and psychosocial factors contribute to its development through direct or indirect influence over the brain-bowel axis. However, a bacterial infection, changes in the intestinal microbiota homeostasis, an inadequate immune response and low-grade inflammation are additional contributing factors, which role is calling the attention for the comprehension of the pathophysiology of IBS [29,38].

More than 50% of the patients with IBS worsen their symptoms with the consume of food rich in fermentable carbohydrates (fermentable, oligo-, di-, mono-saccharides and polyols or FODMAPs) such as, sugar alcohols also called polyols xylitol, sorbitol and mannitol commonly used as sweeteners and they have a negative effect on the gut microbiota. Other NNS like aspartame, neotame, sucralose, saccharine, cyclamate, stevia and acesulfame K, through different pathways, could cause imbalance in the intestinal microbiota; which in turn contributes to alterations in the immune system, greater intestinal permeability and sensitivity, microinflammation, as well as changes in motility, especially in patients with IBS-C [4,31,39,40].

In a meta-analysis Mayer et al. reported that lower number of Bifidobacterium and Lactobacillus, and changes in the balance of Firmicutes-Bacteroides in fecal samples are a consequence of stress and diet changes; which all together triggers symptoms in patients with IBS [41]. On and other hand, some studies suggest that commercial saccharine greatly affects the microbiota function due to its composition of 95% of glucose. In animal models, there have been reported changes of the microbiota secondary to saccharine metabolism, since it increases the glycan degradation pathways to produce short-chain fatty acids (SCFAs); which rises the amount of energy in the bowel and consequently promotes obesity. Therefore, saccharine could indirectly unleash a mechanism of dysbiosis in the host and exacerbate the symptoms in predisposed patients [4,41,42].

Polyols are a group of versatile, reduced-calorie carbohydrates that provide sweet taste with about half the calories, such as sorbitol, mannitol, maltitol and xylitol. These have poor digestibility and absorption in colon, generating osmotic effects in the intestinal lumen, increasing the water volume, which together with the rapid fermentation by bacteria, easily produces gas. This is the basis of gastrointestinal symptoms after the ingestion of NNS in patients with visceral hypersensitivity. Free-fructose diets have based on the latter; however, there are only observational studies in patients with functional motility disorders that support this hypothesis, unfortunately indirectly assessed through the effect in gastric emptying and the gastric and intestinal hormonal profile [25,42,43].

Mugajic et al. showed that the lack of absorption of different sugars and NNS could be an indicator of greater intestinal permeability. This study concluded that the sucralose and erythritol absorption, was significantly associated with greater intestinal permeability during IBS-C and IBS-D episodes [44].

Furthermore, a study where it was evaluated the sucralose effect in animal models in doses of 100, 300, 500 mg/kg of weight for 12 weeks; reported lower concentrations of fecal aerobic bacteria, which persisted during the whole follow-up. Other studies showed that the combination of saccharine and neohesperidin dihydrochalcone in volunteers was associated with the growth of Lactobacillus relative population. In general, both in animal models and in interventional studies with patients conclude that the refined sugar and NNS consume changes the composition of intestinal microbiota and its functions [45,46]. Therefore, there is a great research field on the matter of the changes in the microbiota as an attempt to have a better understanding of digestive disorders [47].

The etiology of IBS remains unknown, however change of the intestinal microbiota secondary to dietary factors like the consumption of sweeteners could have a significant effect on the symptoms.

NNS and inflammatory bowel disease

IBD is a group of inflammatory conditions, represented by Crohn’s disease (CD) and Ulcerative Colitis (UC), both of unknown etiology. At present, it is understood that a combination of environmental risk factors such as stress, appendectomy, smoking, socioeconomic conditions, nonsteroidal anti-inflammatory drugs, oral contraceptives, infections, hygiene conditions and diet modulate the immune response in front of intestinal bacteria that produce chronic inflammation in genetically predisposed patients [48,49].

Epidemiologic studies have demonstrated that different types of diets can affect the microbiota composition and in consequence, could increase the risk of IBD. The disease has been associated with a diminution in the number of Firmicutes and growth of Proteobacteria [50].

Prebiotics have the function of maintaining the balance in the microbiota composition in colon, some of which could be directly related to the progress of IBD [10]. A series of observational studies and clinical trials have shown that a diet restricted in FODMAPs (sorbitol, xylitol and mannitol), could diminish the symptoms in more than 50% of the patients with IBD. As carbohydrates are slowly absorbed and fermented by the microbiota, hydrogen and methane concentrations in colon increase, leading to worsening of intestinal gas and other typical IBD symptoms such as abdominal pain, distension, diarrhea and flatulence. This can easily explain why these restrictive diets cause an important improvement of the symptoms [51,52].

On the other hand, colonic microbiota has a key role in the immune response of patients with IBD. There is an association between the polymorphisms of the nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15) gene and CD, and this is thought to be regulated by microbiota. In patients with IBD the changes in NOD2 reduce the enteric tolerance to bacteria, and consequently produce inflammation. The latter together with a diet rich in polyols has shown an increase of intestinal dysbiosis as well as mucosa inflammation and deterioration of intestinal permeability [50-53]. Sorbitol, mannitol and xylitol are susceptible to fermentation with secondary production of hydrogen, methane, carbon dioxide and SCFAs; recognized as potential regulators of the inflammatory process and of intestinal permeability in patients with IBD [54].

Qin XF in a paper suggest that a decade ago, several discoveries made hypothesized that saccharin (the first and more ancient AS since the late 1880s), could have importance in the IBD through the inhibition of intestinal bacteria and affection to the digestive proteases, as well as excessive damage to the mucin layer and the underlying intestinal tissue [52]. In other paper suggested that in Canada the incidence of IBD is directly associated with the use of NNS in cereals, beverages, desserts, chewing gum, candy and other products; also, these products are used indiscriminately by the food industry in pediatric population from 1983 to 2005 [55,56].

Recently, studies in animal models have demonstrated that saccharine and sucralose could contribute to the onset of CD and UC because of the inhibition of the beta-glucuronidase activity and bacteria overgrowth during the homeostatic inactivation of digestive proteases. NNS like stevia are a source of sweet glucosides of sativoside that substantially increase the lymphocytes B and T proliferation and that induce the tumor necrosis factor α (TNF-α) secretion partially regulated by the Toll-like receptor 4 (TLR4), which are involved factors in the IBD activity (Table 3) [53,57-61].

The etiology of IBD is unknown, but consumption of sweeteners could influence the incidence and symptoms of the patients.

The specific effects of NNS on the microbiome have been conflicting and the available studies have been heterogeneous in terms of the population studied and both the NNS and doses evaluated. Nevertheless, scientific evidence suggests that the increase of the NNS consume, could be one of the dietetic factors causing a rise in the symptoms of IBS and IBD, secondary to changes caused in intestinal microbiota composition and gastrointestinal motility. Therefore, it is of great importance that further studies continue to evaluate the role of NNS over the gastrointestinal tract alterations.

The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported. The reporting of this work is compliant with PRISMA guidelines. The lead author affirms that no important aspects of the study have been omitted and that any discrepancies from the study as planned (please add in the details of any organisation that the trial or protocol has been registered with and the registration identifiers) have been explained.

The study was funded by the National Council on Science and Technology (CONACYT) with the number 261575.

We thank all experts who participated in this review with different ideas, Gabriela Alejandra Sanchez-Medina, Ernesto Roldan Valadez and Sergio A. Islas Andrade.