Clinical trials gasoline additives

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In some people, the excessive consumption of polyols may cause gastrointestinal symptoms such as gas or laxative effects, similar to the gastrointestinal reaction to beans and certain high-fiber foods.

Such symptoms depend on an individual's sensitivity and the other foods eaten at the same time Intestinal microbial communities play a significant role in human health and disease; indeed, the intestinal microbiome is involved in metabolism, immunity, growth, and the fermentation of undigested carbohydrates More importantly, the gut microbiota cooperates with the immune system, providing signals to promote the maturation of immune cells and the induction of susceptibility to many pathophysiologic conditions The composition and function of the microbiome are modulated and can be rapidly altered by diet However, there are many gaps in the evidence related to the health effects of NNSs and LCSs in both healthy and nonhealthy populations.

Intensive sweeteners have negligible caloric content and high-power sweetening and are used in low quantities in foods. All of them have been classified in synthetic and natural sweeteners 5. Their structures and ADI, as well as their main biological effects, are summarized in Table 1.

Structure, ADI, and biological effects of natural and synthetic sweeteners 1. Acesulfame is an acidic cyclic sulfonamide and acesulfame K E is the potassium salt of acesulfame.

Acesulfame K decreases glucose fermentation by the cecal microbiota in Cara rats, suggesting that sweeteners might affect glucose transport systems The effects of acesulfame K were not associated with gut microbial functional capability In contrast, Bian et al. Bacteroides were highly increased in acesulfame K—treated male mice and significant changes in Anaerostipes and Sutterella populations occurred as well.

Conversely, in female mice, acesulfame K treatment decreased the relative abundance of Lactobacillus and Clostridium.

Those changes in the populations of gut microbiota after the consumption of acesulfame K indicate sex-specific effects With regard to human consumption, the Uebanso et al. Indeed, this work might be physiologically irrelevant The metabolism and fate of aspartame are dominated by presystemic hydrolysis to the constituent parts, with little or no parent compound entering the general circulation.

According to EU regulation no. A mg dose of aspartame did not affect the peak insulin concentrations in subjects with or without diabetes but did cause a decrease in plasma glucose concentrations Tordoff and Alleva 27 compared the consumption of aspartame and high-fructose corn syrup and concluded that aspartame reduces sugar intake. Although we have a huge quantity of information with regard to aspartame safety in humans, few of those studies focused on the effects of aspartame intake on the composition of gut microbiota.

In rats, the impact of chronic low-dose aspartame consumption on anthropometric, metabolic, and microbial variables was tested in a diet-induced obesity model. Aspartame consumption increased the fasting glucose concentrations in both the standard feed pellet diet and high-fat groups independent of body composition.

A metabolomics analysis showed that aspartame was rapidly metabolized and related to SCFA production, especially propionate production. Changes in the microbial composition were observed in animals that received aspartame; the total bacteria and abundance of Enterobacteriaceae and Clostridium leptum increased In addition, mice treated with aspartame for 11 wk developed glucose intolerance, although analyses of the microbiota did not show significant differences between the groups To our knowledge, there are no data on the potential influences of aspartame on the human gut microbiome.

It is hard to understand how aspartame influences the gut microbiota because this NNS is rapidly hydrolyzed in the small intestine.

Upon ingestion, aspartame breaks down into residual components, including aspartic acid, phenylalanine, and methanol and their components, which are readily absorbed so that they do not reach the large bowel Neotame E is an artificial sweetener that is between and 13, times sweeter than sucrose with a structure close to that of aspartame [i. The suggested ADI is 0. Neotame is moderately heat stable, extremely potent, rapidly metabolized, completely eliminated, and does not appear to accumulate in the body.

Mice and other test animals fed neotame did not show adverse physical symptoms, water consumption, or clinical pathology evaluations and there were no reports of morbidity, mortality, organ toxicity, or macroscopic or microscopic postmortem findings 31— Neither sweetener has been evaluated in animals or in humans because only trace amounts of advantame or neotame are needed to sweeten foods. The amount of methanol derived from the intestinal hydrolysis of neotame is much lower than that found in common foods; therefore, it is improbable that either neotame or advantame would have any influence on the gut microbiota.

This was because of the detection of bladder tumors in rats fed a cyclamate-saccharin mixture supplemented with cyclohexylamine, a metabolite of cyclamate that is more toxic than cyclamate alone 35 , However, these studies were severely criticized because of their designs and doses 37 and cyclamate is being reevaluated.

The first finding of microbiota changes caused by cyclamate was reported in the study by Drasar et al. The authors observed that the conversion of cyclamate to cyclohexylamine in rats does not occur after either parenteral administration of cyclamate or with incubations of cyclamate with the liver, spleen, kidney, or blood preparations.

The principal hypothesis was that cyclohexylamine formation occurred solely in the gut as the result of microorganism metabolism In , Mallett et al. They found a maximum formation of cycloheximide at 8 wk and increased levels of sulfamatase activity in the fecal content. The authors did not find any taxonomic changes in the fecal microbiota cultured in an in vitro system after the administration of cyclamate.

The presence of cyclamate decreased the fermentation of glucose by the microbiota in Cara rats Cyclamate increases the bacterial sulfatase activity in the intestine To our knowledge, there are no available data on the effects of cyclamate on gut microbiota in humans. A range of food and beverages are sweetened by saccharin E , which is considered safe despite controversial debate about its potential carcinogenicity.

However, studies indicate that the consumption of saccharin might perturb the gut microbiota. The effect of 7. The presence of saccharin did not alter the total numbers of anaerobic microbes but resulted in the elimination of a specific anaerobic group of microbes from the cecal contents Saccharin administration inhibited the growth of 6 bacterial strains 3 Lactobacillus species and 3 Escherichia coli strains isolated from the small intestinal contents in rats that received a 2.

Saccharin inhibited the fermentation of glucose by the microbiota from Cara rats Pyrosequencing studies in animals showed that the addition of saccharin plus neohesperidin dihydrochalcone increases the abundance of the Lactobacillus cecal population and increases intraluminal lactic acid concentrations The deleterious metabolic effects of saccharin in animals were abrogated by antibiotic treatment and were fully transferrable to germ-free mice upon microbiota transplantation.

In addition, the altered metabolic pathways were linked with glucose tolerance and dysbiosis in healthy human subjects. In mice fed saccharin, Akkermansia muciniphila , a commensal bacterium that exhibits probiotic properties, was underrepresented Since the study by Suez et al. Sweeteners are often used to encourage the consumption of agents such as ethanol and nicotine in laboratory studies that use rodents.

Labrecque et al. Saccharin reduced Clostridium numbers, even though the total amounts of ethanol consumed were the same for the 2 groups Inflammation is frequently associated with disruptions to the gut microbiota. Mice treated with 0. In addition, altered gut bacterial genera were associated with saccharin-induced liver inflammation.

These changes in the intestinal microbiota were observed in Ruminococcus , Adlercreutzia , Dorea , Corynebacterium , Roseburia , and Turicibacter Early studies suggest that artificial sweeteners maintain plasma glucose and peak insulin concentrations without affecting the gut microbiota. However, more recent animal and human studies showed specific changes in the intestinal microbiota related to alterations in the metabolic pathways linked to glucose tolerance and dysbiosis in human subjects, especially with the ingestion of saccharin Figure 1.

Effects of artificial sweeteners and saccharin on gut microbiota. Animal studies have reported specific shifts in the intestinal microbiota related to alterations in the metabolic pathways linked to glucose tolerance after ingestion of saccharin. The first study that evaluated sucralose on the intestinal microbiota was performed in with the use of fecal samples from Sprague-Dawley rats that received the sweetener for 12 wk.

The consumption of sucralose decreased the total number of anaerobic and aerobic bacteria, bifidobacteria, lactobacilli, Bacteroides , and Clostridium More recently, the administration of sucralose in mice produced modifications in the intestinal microbiota at 14 different taxonomic levels, including Turicibacteraceae, Lachnospiraceae, Ruminococcaceae, Verrucomicrobiaceae, Staphylococcaceae, Streptococcaceae, Dehalobacteriaceae, Dehalobacterium, Lachnospiraceae, Clostridiaceae, Christensenellaceae, Peptostreptococcaceae, Erysipelotrichaceae, and the order Bacillales, and changes in the synthesis and regulation of amino acids.

These variations were related to inflammation in the host The main reported effects of synthetic sweeteners on the gut microbiota are listed in Table 2.

Natural sweeteners are sweeter than sucrose, contribute few calories, have no carcinogenic effects, and do not affect insulin production 5. Stevia rebaudiana is a shrub belonging to the family Ateracea native to South America , whose leaves contain diterpene glycosides such as stevioside, steviolbioside, rubusoside, dulcoside A, and rebaudiosides A, B, C, D, E, F, and M.

Its extracts are used as natural noncaloric sweeteners because it is times sweeter than sucrose 51 , although only highly purified steviol glycosides are approved for use in food in the EU 7. Stevioside extracts from S. Several in vitro studies have investigated how the components of stevia extract are metabolized.

The data show that the microbiota no differences found between humans and rats are able to degrade the main components, stevioside and rebaudioside A, to steviol 55 , Therefore, neither stevioside nor rebaudioside A is absorbed in the upper gastrointestinal tract Bacteroides are the most efficient group of bacteria at hydrolyzing stevioside and rebaudioside A to steviol Other bacterial groups, such as lactobacilli, bifidobacteria, Clostridium , coliforms, and enterococci species, were tested.

None of the tested bacteria were able to hydrolyze and use steviol glycosides as a usable substrate These tested bacterial groups are the major types of bacteria found in the gastrointestinal tracts of animals and humans In addition, compared with glucose, 24 h incubation of mixed fecal bacteria from volunteers with stevioside and rebaudioside A caused a slight alteration of the human microbiota Stevioside weakly inhibits anaerobic bacteria, whereas rebaudioside A weakly inhibits aerobic bacteria, in particular over coliforms.

The roots of S. The fermentation capacity of fructans as a substrate for microbiota is strain specific. Fructans derived from S. Glycyrrhizin comes from the roots and rhizome of Glycyrrhiza glabra. Glycyrrhizin has anticancer, anti-inflammatory, antioxidant, antiviral, and hepatoprotective properties. However, it has potential hypertensive effects and an intense aftertaste In the gut, glycyrrhizin is de-glycosylated to glycyrrhetic acid the major product by Eubacterium spp.

Some data suggest that the relation between glycyrrhizin and the intestinal microbiota exerts positive effects on the host 60 , 61 , Better-designed studies are needed to determine if this is truly the case and what the implications of its metabolism and its mechanism of action and effects are on the composition of the intestinal microbiota. Neohesperidin dihydrochalcone is metabolized by intestinal microbiota to innocuous products 5 , Thaumatin is a sweet protein isolated from the fruit of Thaumatococcus daniellii Benth, a plant native to tropical West Africa.

Thaumatin is , times sweeter than sucrose 5. Monellin is a sweet protein, naturally extracted from the fruit of the serendipity berry shrub To our knowledge, there are no ongoing or past studies ascertaining the potential effects of those natural sweeteners on the intestinal microbiota. In summary, natural sweeteners have only a few studies associating their consumption with changes in the intestinal microbiota.

Stevia extracts have the most information with regard to their effects on the gut microbiota composition, although the current effects of stevia on Bacteroides need further study Figure 2.

Natural sweeteners and their effects on gut microbiota. Stevia extracts have been described as capable of changing the gut microbiota composition, although the current effects of stevia on Bacteroides need further study.

Polyols are a specific group of compounds used as food additives. They are stable at high temperatures and through pH changes and do not intervene in Maillard reactions. A number of polyols are naturally present in some fruits, vegetables, and mushrooms. Their industrial production started in the last century with the hope of solving health problems related to excessively consumed NNSs.

The FDA, Codex Alimentarius, and EFSA have approved 8 different polyols—erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol—for use as bulk sweeteners in human foods 5 , 7 , 65 , The excessive consumption of polyols causes gastrointestinal symptoms and laxative effects in healthy patients. Polyols also induce dose-dependent symptoms of flatulence, abdominal discomfort, and laxative effects when consumed by both healthy volunteers and patients with irritable bowel syndrome IBS.

In addition, moderate doses of polyols increase the number of bifidobacteria in the microbiomes of healthy individuals and may therefore be beneficial as a prebiotic, but the data are limited to patients with a number of intestinal diseases, including IBS It is important to know the impact of polyol consumption on gut microbiota both in healthy and diseased humans.

As with all food additives, the safety of polyols is being re-evaluated by the EFSA. This re-evaluation will be completed by the end Erythritol E , a four-carbon sugar alcohol, occurs widely in nature and in foods such as wine, beer, mushrooms, pears, grapes, and soy sauce The estimated daily intake of erythritol is 1.

Oral microorganisms do not metabolize erythritol and the in vitro incubation of erythritol with Streptococci species does not produce lactic acid or other organic acids 70 , Erythritol is rapidly absorbed in the small intestine by passive diffusion, it is scattered widely through tissues with minimum metabolism, and finally, it is quantitatively excreted in the urine Hence, erythritol does not affect plasma glucose or insulin concentrations or gut microbiota 72 , Despite the adjustment and consideration of all the fermentation variables e.

Although there is no evidence on the effects of erythritol on gut microbiota in humans in clinical trials, erythritol is considered a safe additive after many specific tests on its toxicity, carcinogenicity, and reproductive hazards were found to be negative 5. Hydrogenated isomaltose, isomaltitol, or isomalt E is a polyol used worldwide as a sugar replacement with technological properties comparable to those of sucrose.

Isomalt is used in bubble gums, gelatins, chocolate, coatings, baked goods, and yogurts. Isomalt is obtained through the enzymatic transformation of sucrose, is stable at high temperatures, and has a very low hygroscopic value. Moreover, it is low in energy, noncariogenic, and is as sweet as other polyols. Isomalt is considered a prebiotic carbohydrate that might contribute to a healthy luminal colonic mucosal environment. Fecal SCFAs, lactate, bile acids, neutral sterols, nitrogen, ammonia, phenol, and p-cresol were not affected by isomalt consumption.

In addition, in vitro, several bifidobacteria strains were capable of metabolizing the isomalt and generated high butyrate concentrations Moreover, at the end of each test phase, rectal biopsy samples were taken and gene expression was measured by microarray and qRT-PCR.

Dietary intervention with low digestible isomalt compared with digestible sucrose did not affect gene expression in the rectal mucosa lining Hence, isomalt is a polyol with bifidogenic properties that might contribute to a healthy colonic environment.

Lactitol E is a non—naturally occurring sugar alcohol, which is obtained by the hydrogenation of lactose.

Compared with the other polyols, its sweetening power is limited and consequently it is usually used in combination with intense sweeteners 5. However, higher lactitol intakes can produce laxative effects; studies showed that lactitol promotes the growth of bifidobacteria and lactobacilli. On the other hand, fermentation of lactitol by saccharolytic bacteria has also been shown to decrease counts of proteolytic bacteria, such as Bacteroides , coliforms, Enterobacteria , and Enterococci Ballongue et al.

Lactitol also causes a decrease in fecal pH In rats, lactitol increases the production of butyrate and IgA secretion without signs of mucosal inflammation