Is Zero Calories Really Better?

No sugar, zero calories, and a delicious drink??? It seems like a win all around right? Go zero calorie artificial sweeteners! Well, maybe not. Recent studies have show that zero calorie and sugar free food products may be affecting your gut microbiome.

Products with the advertisement of zero calories contain something called non-nutritive artificial sweeteners. These artificial sweeteners are able to make a food products really sweet without increasing the calories in the food significantly. Go grab your Diet Coke and look on the ingredients list for aspartame and acesulfame-K (or acesulfame potassium). Those are zero calorie artificial sweeteners.

The following article goes into more depth comparing research articles on different artificial sweeteners and how they affect the gut microbiome.

Artificial Sweeteners: What Are They?

What is the Gut Microbiome?

The Different Types of Artificial Sweeteners

Sucralose

Saccharin

Aspartame

Acesulfame-K

Conclusion

References

Non-nutritive artificial sweeteners (NAS), which are low or zero calorie sugar substitutes, have become a popular replacement for sugar in many food products including beverages, gum, jams, and candy among many others. These sugar substitutes are an attractive alternative to many people struggling with weight gain, diabetes, or those who are trying to cut down on sugar because they contain a low number of calories while retaining a high level of sweetness. Although NAS received approval from the Food and Drug Administration (FDA), some recent studies have indicated possible negative effects to the gut microbiome surrounding consumption of NAS, creating a controversy over the ethical use of zero calorie artificial sweeteners in food. 

The FDA has approved eight different artificial sweeteners: saccharin, aspartame, acesulfame potassium (acesulfame-K), sucralose, neotame, advantame, steviol glycosides, and luo han guo fruit extracts. This article focuses on the zero calories sweeteners saccharin, aspartame, acesulfame-K, and sucralose.

Currently, there is not a clear “yes” or “no” answer to the investigation of the question, “do artificial sweeteners affect the gut microbiome and glucose intolerance?”. Multiple studies on the consumption of saccharin, sucralose, aspartame, and acesulfame-K in relation to the gut microbiome have been done, and no consensus has been reached surrounding these NAS. Although the subjects in the research consumed different amounts of NAS for different periods of time depending on the study they participated in, no clear line was found on how much and how long a specific NAS is safe to consume without negative effects on the gut microbiome or if they have any negative effects at all.

Microorganisms including bacteria, fungi, archaea, viruses, and protozoans make up the bulk of the microbiome. (Jandhyala et al., 2015). Along with promoting digestion, these microbes are essential in overall health and immunity (Eckburg et al., 2005). Changes in the gut microbiome could lead to harmful problems in the overall health of a subject. Jandhyala et al. (2015) claims there is evidence pointing to a relationship between the gut microbiome and diseases like inflammatory bowel disease, allergies, neurodevelopment diseases, and even obesity and diabetes. A person’s diet modulates their gut microbiome, and if zero calorie artificial sweeteners causes changes to the microbiome, a significant portion of the population who consumes food products containing NAS could face negative health effects.

The four most commonly used zero calorie artificial sweeteners globally include sucralose, saccharin, aspartame, and acesulfame-K. The FDA has set maximum daily intake levels called Acceptable Daily Intake (ADI) for each of these NAS, but some studies show that these ADI’s may not be accurate while others claim they are fine. This review will go into the research done on each of the four main NAS and how they may affect the gut microbiome.

First, sucralose, often referred to as Splenda, can be found in a variety of common products at the grocery store. Over 4,500 products contain some amount of sucralose, and it accounts for 62% of the global non-nutritive artificial sweetener market (Wang, Browman, Herzog, & Neely, 2018). The FDA set the ADI for sucralose at 5 mg/kg of the body weight of the person consuming the NAS. Out of the most common sweeteners, sucralose has the most research suggesting the presence of negative effects tied to its consumption.

Six studies with subjects consuming amounts of sucralose below the ADI, at the ADI, or above the ADI for different lengths of time, found disruption of the gut microbiome, indicating that the level for the ADI may be too high (Suez et al., 2014; Uebanso et al., 2017; Bian et al., 2017; Dai et al., 2020; Abou-Donia, El-Masry, Abdel-Rahman, Mclendon, & Schiffman, 2008; and Wang et al., 2018). Both Suez et al. (2014) and Bian et al. (2017) used mice as their research subjects and had them consume 100% of the ADI of sucralose for 11 weeks and six months respectively.

Mice consuming the zero calorie artificial sweetener developed marked glucose intolerance and a significantly different microbe community in the gut microbiome compared to the control groups who just drank water. For example, the mice consuming the ADI of sucralose were found to have a higher number of pro-inflammatory genes and less overall development in their gut microbiome. 

Likewise, the studies done by Wang et al. (2018) and Dai et al. (2020), who used a higher level of sucralose than the ADI in their research, are consistent with these findings. They also found that ingestion of sucralose leads to a reduced amount of E. coli colonies and Bacteroidetes in the microbiome. Most strains of E. coli are harmless and play an essential part in the health of the digestive system. Bacteroidetes are a vital component for the creation of butyrate in the gut microbiome which goes on to influence healthy lipid profiles, insulin sensitivity, and reduce the risk of disease. A decrease in both critical bacteria caused by the overconsumption of sucralose could lead to undesirable health effects.

Interestingly, Uebanso et al. (2017) and Abou-Donia et al. (2008) used amounts of sucralose well below the ADI (30% and 22%) on their test subjects, and they still found changes to the gut microbiome, albeit the changes found were different from each other. Abou-Donia et al. (2017) who had their mice consuming only 22% of the ADI for 12 weeks found a 67.5% decrease in the number of Bacteroidetes.

On the other hand, Uebanso et al. (2017), who had their mice consume 30% of the ADI for eight weeks, saw no change in the amount of Bacteroidetes in the subjects but did find a decrease in the amount of Clostridium cluster XIVa, which acts as a regulator for intestinal homeostasis. Even though both Uebanso et al. (2017) and Abou-Donia et al. (2008) agree that intake of sucralose at levels well below the ADI causes some form of dysbiosis, they had distinct findings on what changes took place in the gut microbiome.

Despite multiple studies showing dysbiosis of the gut microbiome with consumption of sucralose at many different levels, Ahmad, Friel, & Mackay (2020) and Thomson, Santibañez, Aguirre, Galgani, & Garrido (2019) have research that says otherwise. While all the previous studies used animal models as the main research subjects, Ahmad et al. (2020) and Thomson et al. (2019) used healthy humans as the research subjects. The length they had the human subject’s intake sucralose was only two weeks and seven days, respectively, which is shorter than the studies done with animals. Intake was also below the FDA’s approved ADI. When the measurements were taken at the end of both studies, no marked difference in the bacteria in the gut microbiome appeared between the people ingesting sucralose and those in the control group. These studies indicate that no damage is done to the microbiome by short-term consumption of sucralose.

Because no studies have been done on human subjects with a long-term intake of sucralose, no definite conclusion can be made on the effect of the NAS (zero calorie sweeteners) on the human gut microbiome. Results from the different animal models suggest a possibility that intake of sucralose for about eight weeks or more could cause dysbiosis of the gut microbiome, including decreasing E. coli, Bacteroidetes, Clostridium cluster XIVa, and increasing glucose intolerance (Wang et al. 2018; Dai et al. 2020; Suez et al. 2014; Bian et al. 2017; Uebanso et al. 2017; and Abou-Donia et al. 2008). However, none of these changes were seen in the short-term human models, therefore, further research needs to be done on human models with long-term consumption of sucralose.

Similarly, no obvious assumption can be made about the impact of saccharin on the gut microbiome. Saccharin has a higher ADI approved by the FDA than sucralose at 15 mg/kg of the body weight of the person consuming the NAS. Along with being present in many low-calorie foods and drink, saccharin is commonly known as “sweet’n low”, a product found in a small pink package.

In the studies that looked at multiple artificial sweeteners at once, saccharin tended to have the most distinct effect on the gut microbiome (Suez et al. 2014; Wang et al. 2018). Similar to sucralose, in a study by Wang et al. (2018), saccharin inhibited the growth of healthy E. coli. This level of growth was tested by adding saccharin to the bacteria on a petri dish containing different strains of E. coli including E. coli HB101 and E. coli K-12. The E. coli HB101 was inhibited by saccharin by 98% and the E. coli K-12 was inhibited by saccharin by 99.5%. This substantial reduction in the E. coli colonies has potential for harmful effects on the gut microbiome and the immunity of the subject consuming saccharin.

Along with Wang et al. (2018), Suez et al. (2014) also included saccharin in their study. The researchers gave mice 100% of the ADI for saccharin for 11 weeks and noticed significant glucose intolerance, change in the abundance of different bacteria, and change in microbiota function. Remarkably, unlike sucralose, saccharin caused an increase in the Bacteroidetes microbes, but a decrease in Firmicutes microbes. Firmicutes support digestion and are vital to immune function. The exact impact of this transformation in the microbes of the gut microbiome cannot be perfectly predicted, but significant changes in the bacteria colonies from the normal amounts, generally are not beneficial in the long run. Both Wang et al. (2018) and Suez et al. (2014) agree that saccharin most likely causes some sort of dysbiosis to the gut microbiome.

Conversely, Labrecque, Malone, Caldwell, & Allen (2015) and Serrano et al. (2021) completed studies showing no change to the gut microbiome or glucose intolerance to subjects consuming saccharin. Serrano et al. (2021) used both an animal model and human model in their research on saccharin in relation to the gut microbiome. For the human model, researchers had participants take a supplement equal to 100% of the ADI of saccharin for two weeks and then observed the gut microbiome in each participant to look for variations. This short-term study showed no changes in the gut microbiome after the two weeks of supplementation. Even though both Serrano et al. (2021) and Suez et al. (2014) had their test groups ingest 100% of the ADI, the two sets of researchers saw different results.

To assess the long-term outcomes of saccharin use, Serrano et al. (2021) used mice as test subjects and had them consume 400% of the ADI of saccharin for 10 weeks. Similar to the short-term human model done by the same researchers, no effect on glucose tolerance or changes to the abundance of different bacteria in the gut microbiome was seen in the long-term animal model. Again, Suez et al. (2014) and Serrano et al. (2021) got opposite results from very similar studies, but the results from Labrecque et al. (2015) support the findings of Serrano et al. (2021).

Labrecque et al. (2015) also used an animal model for their research. Pregnant and non-pregnant mice were given saccharin (percentage of the ADI is not specified) for two weeks, and no significant change in the composition of the microbial diversity and glucose tolerance was seen. Collectively these studies indicate no adverse effects to the gut microbiome come from the intake of saccharin for both human and animal models.

Altogether, Serrano et al. (2021) and Labrecque et al. (2015) saw no changes to the gut microbiome with consumption of saccharin for a short or long period of time, but Wang et al. (2018) and Suez et al. (2014) believe changes do occur with consumption of the zero calorie artificial sweeteners. No clear conclusion to whether or not saccharin affects the gut microbiome and glucose intolerance has been made, and further research is necessary.

Often combined in food products with other NAS, Aspartame is found in over 6,000 food products globally and has an ADI of 50 mg/kg of the body weight of the person consuming the NAS (Palmnäs et al., 2014). Akin to the studies on sucralose and saccharin, no clear answer on whether aspartame affects the gut microbiome has come to light.

As found with their research on sucralose and saccharin, Suez et al. (2014) showed through an animal model that consumption of aspartame also led to gut dysbiosis and glucose intolerance. Mice in the study were given an amount of the zero calorie artificial sweetener below the ADI. These mice experienced glucose intolerance after 11 weeks of consumption unlike the mice who only consumed normal drinking water.

A paper by Palmnäs et al. (2014) supports the findings of Suez et al. (2014). Palmnäs had mice consume 14% of the ADI of aspartame for eight weeks and observed high blood glucose levels and an increase in the gut bacteria Clostridium leptum and Enterobacteriaceae. These findings show that even at low doses of aspartame, dysbiosis of the gut microbiome can happen.

On the other hand, in two papers on human models with the consumption of aspartame, no change in the bacterial communities of the gut was seen. First, Frankenfeld, Sikaroodi, Lamb, Shoemaker, & Gillevet (2015) had people consume around 2% of the ADI of aspartame for 4 days, and no modification of the microbiome was viewed in the subjects. The amount of Bacteroidetes and Firmicutes stayed consistent between the group consuming aspartame and the group not consuming aspartame. It must be taken into account that the percentage of the ADI used for this study was small and the amount of time intaking the NAS was short, so the paper cannot be directly compared to the studies by Suez et al. (2014) and Palmanäs et al. (2014) who used a higher percentage of aspartame for a longer time, but it still gives insights into the use of aspartame by humans.

A more comparable study done by Ahmad et al. (2020) used 14% of the ADI of aspartame like the study done by Palmnäs et al. (2014). After two weeks of consuming aspartame, the researchers found no change in glucose tolerance or levels of bacteria. Again, the papers who used humans as the research participants found no alterations to the bacteria in the gut after consumption of the zero calorie artificial sweetener, but in the studies done with animals, significant alterations to the gut were found.

Finally, found in many foods because of its stability at high temperatures, acesulfame-K has been studied in conjunction with the gut microbiome. With an ADI of 15 g/kg of the body weight of the person consuming the NAS, acesulfame-K also has research showing changes and no changes to the gut microbiome. Interestingly, there has been evidence of gender-specific changes to the gut microbiome with its consumption.

Bian et al. (2017) ran a study with both male and female mice consuming 250% of the ADI for four weeks and not only saw dysbiosis of the gut microbiome, but gender specific dysbiosis of the gut microbiome. The male mice consuming acesulfame-K saw an increase in Bacteroidetes, Anaerostipes, and Sutterella, whereas the female mice consuming acesulfame-K experienced decreased the abundance of Lactobacillus and Clostridium, and an increase in Mucispirillum. Because the other studies who used mice in this review only examined one gender, no other comparisons can be made with this discovery of gender specificity.

Another study that saw effects from acesulfame-K was Wang et al. (2017). Like in their previous study on saccharin, Wang et al. (2017) also saw an inhibition of bacteria when adding acesulfame-K to a petri dish with E. coli HB101 and E. coli K-12. The E. coli HB101 was inhibited by acesulfame-K by 90% and the E. coli K-12 was inhibited by saccharin by 98%. This experiment shows the possible connection between acesulfame-K and changes to the gut microbiome.

Conversely, in a study done by Uebanso et al. (2017) where mice consumed 100% of the ADI of acesulfame-K for eight weeks, no variance in the abundance of the specific gut bacteria was found. The total Firmicutes and Bacteroidetes were comparable between the test group and control group. This finding has support from Frankenfeld et al. (2015) in a cross-sectional study on humans consuming acesulfame-K. Following the trend of the other zero calorie artificial sweeteners there is evidence for both sides of the argument for and against acesulfame-K.

Overall, inadequate evidence is available, and no definite conclusion can be made surrounding the effects of zero calorie artificial sweeteners on the gut microbiome and glucose intolerance. In many animal models there seems to be significant dysbiosis of the gut microbiome, but these studies are not replicable on humans because of ethical problems and the difficulty of controlling variables in a group of humans. Giving someone a product at an amount and length of time that possibly could be harmful to them is unethical. Also, because so many factors go into the make-up of the gut microbiome, it is hard to control for every factor when testing on humans who tend to be different and somewhat unpredictable. In contrast, in the short-term studies done on human models, no change to the gut microbiome was seen. These differing conclusions indicate the need for further research.

Want more nutrition/health tips and information? Check out the other articles on my blog.

References

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