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By Elvira Rostanzo, MSc and Emeran Mayer, MD

The global rising of obesity has become a worldwide public health crisis and represents one of the main challenges for prevention policies. In 2017, it has been estimated that over 2.1 billion people, or nearly 30% of the global population, are overweight or obese. Moreover, the obesity rate among US children and adolescents has tripled in the last three decades. It is estimated that 9.6% of children aged 6–11 years and 18.1% of adolescents aged 12–19 years are obese.

Obesity is not just a cosmetic problem, but it is also associated with multiple serious comorbidities including type 2 diabetes, metabolic syndrome, cardiovascular disease, as well as an increase in the risk to develop many types of cancer (breast, ovarian, renal, pancreatic among others).

“The growing rate of obesity is related to dramatic changes in eating habits, with the widespread adoption of the so-called Western Diet in both high- and low-income countries.”

The growing rate of obesity is related to dramatic changes in eating habits, with the widespread adoption of the so-called Western Diet (the US version of this diet is the Standard American Diet or SAD) in both high- and low-income countries. The Western Diet is characterized by a regular intake of ultraprocessed foods (containing additives like emulsifiers and hidden sugars such as high fructose corn syrup), “fast food” products, unhealthy snacks, and sugary soft drinks. Not surprisingly, the consumption of sugary soft drinks and the rate of obesity and type 2 diabetes have risen in parallel.

In response to this diet-induced health crisis, the food industry has made a major effort to replace “classic” sugary sweeteners such as sucrose, dextrose, and high-fructose corn syrup with non-nutritive sweeteners (NNS) that can be classified as artificial (saccharin, sucralose, aspartame, acesulfame-K) or natural (stevia, monk fruit and xylitol).

At first glance, there are obvious advantages of making this switch, which promises to allow lovers of sweet tasting foods to “have the cake and eat it too”. The main advantages of using NNS (in addition to their low cost) are the fact that some of these substances are either non-absorbable (sucralose), or have such high sweetening power that they can produce the desired sweet taste, without the negative metabolic effects of high sugar absorption. The perception of sweet taste is mediated by so called sweet taste receptors on your tongue, but also throughout the small intestine. As a result, NNS have become popular thanks to their negligible caloric content, and NNS-sweetened products (in particular beverages) are labeled as “zero calories” or “no sugar added”. However, because of the various functions of sugar, removing sugar from food products not only influences sweetness, but can also affect the overall functionality, flavor perception, texture, and overall liking of food.

But do NNS really live up to their promises of weight loss, and prevention of glucose intolerance and type 2 diabetes mellitus? Unfortunately, there are conflicting findings reported regarding their effects on body weight control, glucose homeostasis, and underlying biological mechanism.

Trying to find an answer may be not so easy. NNS are widely-used and to find people that do not use NNS on a regular basis is challenging, leading to several studies which have been either negative (not showing any benefit) or inconclusive. A recent research study from the research team led by Eran Elinav at the prestigious Weizmann Institute in Tel Aviv published in the journal Cell explored the effect of three of these NNS on glycemic response, and on the human microbiome. The same group of investigators had published results from an earlier study showing that consumption of the three most commonly used NNS — saccharin, sucralose and aspartame — directly induces the development of obesity and glucose intolerance in mice. In this earlier study, the investigators showed that these effects were mediated by changes in the composition and function of the mice’s intestinal microbiota of the mice and that the deleterious metabolic effects could be transferred to germ-free mice by faecal transplantation and were abolished by suppressing the altered microbes in the recipient mice by antibiotic treatment. Demonstrating the translational relevance of these findings for human health, the authors were able to induce changes in the gut microbiome and glucose intolerance by the ingestion of NNS in healthy human subjects.

“Two of the tested sweeteners, saccharin and sucralose, significantly elevated the glycemic response during consumption…”

The recent study by the Weizmann Institute investigators was conducted on 120 subjects in good metabolic health and lasted 29 days. All the participants were normal weight (according to Body Mass Index, BMI) and had not been consuming any NNS. Two of the tested sweeteners, saccharin and sucralose, significantly elevated the glycemic response during consumption, while neither aspartame nor stevia had a significant effect on glucose tolerance during this time period. These results indicated that short-term consumption of sucralose and saccharin, even in doses lower than the Acceptable Daily Intake, can negatively impact glycemic responses in healthy individuals, and that not all NNS had the same negative effects.

“The results of both studies highlighted that NNS are not inert compounds, even when consumed in very small amounts…”

Similar to their findings in the 2014 study, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as well as gut microbial metabolites in circulation, impacting the gut microbial ecosystem through several direct and indirect mechanisms. NNS inhibited the growth of some bacteria, while the prevalence of other bacterial species increased in the presence of NNS. Importantly, germfree mice which received microbiomes from human subjects from each of the four NNS-supplemented groups exhibited glycemic responses largely reflecting those noted in the respective human donors. In other words, the specific gut microbial changes induced by saccharin, sucralose, aspartame, and stevia consumption were able to cause similar metabolic changes as seen in the human subjects in the recipient mice. Based on their findings, the authors concluded that human NNS consumption may induce person-specific, microbiome-dependent changes in glucose absorption.

The results of both studies highlighted that NNS are not inert compounds, even when consumed in very small amounts, and that such small amounts can produce significant metabolic changes in our body even when the NNS are consumed in doses lower than the Acceptable Daily Intake. One of the reasons for these unexpected, and largely unknown, findings is the role of the gut microbiome. Further studies are needed to better elucidate their effects on human health on long term.

NNS have long been used to restrict caloric intake and prevent or reverse obesity; the label “zero calories”, “with natural sweeteners” or “no added sugar” may suggest that these sugar alternatives are better for our health. However, there is no scientific evidence that this is indeed the case. On the contrary, it has been shown that the growing rate of overweight and obesity occurs primarily among children who are most exposed to foods and beverages rich in NNS. Thus, while people with hyperglycemia, type 2 diabetes, or metabolic syndrome have been advised to avoid or limit sugar intake, the recommended alternative to replace sugar with NNS seems to increase the risk to develop the very metabolic disorders that they are thought to prevent.

“The extract is 150-250 times sweeter than table sugar, has zero calories and carbs, and does not raise blood glucose levels.”

As the recent Suez study showed differences in negative metabolic effects between synthetic NNS and those derived from plants, one may ask if natural NNS like Stevia and monk fruit may be a better alternative to replace sugar. Stevia sweeteners are derived from the leaves of the Stevia rebaudiana plant, an herbal shrub native to South America. This plant has been used for food and medicinal purposes for hundreds of years. Monk fruit, or lo han guo, is a small green melon native to southern China and named after the monks who first cultivated it centuries ago. Monk fruit gets its sweetness from natural compounds called mogrosides, which are also thought to have anti-inflammatory effects. Monk fruit sweetener is made from extract derived from dried fruit. The extract is 150-250 times sweeter than table sugar, has zero calories and carbs, and does not raise blood glucose levels. Its health benefits have been well-known in Traditional Chinese Medicine (TCM) for decades, long before it became a popular topic in the wellness conversation. According to a 2011 study, based on its anti-inflammatory effects, monk fruit has been used in TCM for centuries to make hot drinks that relieve sore throats.

Most NNS can cause side effects like gas, bloating, or allergic reactions. Based on the assessment that there are no known side effects of monk fruit sweeteners, the Food and Drug Administration has given monk fruit the label of “generally recognized as safe” (GRAS) for everyone, including pregnant women and children, even in the absence of controlled scientific studies on the effects of long-term use.

“Unless specifically stated on the label, one should not assume that all monk fruit products are carb- and sugar-free.”

Even though the ingestion of monk fruit is generally safe for those with diabetes (as it doesn’t increase blood sugar levels), foods and drinks sweetened with monk fruit (as well as some monk fruit sweetener blends) may include added sugars and other ingredients that increase calorie counts or affect insulin sensitivity. Unless specifically stated on the label, one should not assume that all monk fruit products are carb- and sugar-free.

In conclusion, a growing number of studies have identified negative metabolic effects in response to the ingestion of certain NNS. One of the reasons for these largely unknow negative effects are related to the interaction of these molecules with the gut microbiome which plays a key role in maintaining glucose homeostasis. As shown in these studies, the microbiome can be altered by some NNS and even healthy people can be affected. Based on current evidence, plant-derived NNS like stevia and monk fruit do not have the same metabolic side effects as synthetic compounds, even though definitive clinical evidence remains to be established.

Elvira Rostanzo, MSc is a registered Biologist who graduated in Human Nutrition. She is a practicing nutritionist and is currently attending the Specialization School of Food Sciences at University of Siena in Italy.