#1 What is the difference between regular sugars and sweeteners?

Nutritive sweeteners provide energy (calories) because they can be metabolized by our bodies. You probably know them as sugarcarbohydratesglucosefructosehigh-fructose corn syrupmaltosesucrose, or agave syrup.

Non-nutritive sweeteners can’t be metabolized by our body and therefore don’t provide energy (no calories), because they won’t be metabolized. They just taste incredibly sweet. You’ve probably heard of saccharineaspartame, or cyclamate but there a dozens more. They’re also called artificial sweeteners (AS). If they’re derived from natural sources (e.g. Stevia) they’re called natural sweeteners.

AS can be found in a variety of food products and are consumed by all groups of people — lean and obese, old and young, diabetics and non-diabetics. Since AS don’t offer the same functional properties as “real sugar” (like browning, texture, acid balance, or microbial inhibition), zero-products usually need additional food additives that fulfill those functions.

#2 How does the sweet taste work?

On your tongue, there are sweetness receptors that bind molecules and transmit a chemical message through the nervous system to the brain. It doesn’t have to pass your intestines for that! “Real sugars” bind to only one subunit of the receptor, whereas AS can bind to several subunits of the sweet receptors and cause a synergy that enhances the signal. Therefore, they taste much sweeter.

#3 Are artificial sweeteners even tested if they’re safe for human consumption?

Yes, AS are food additives and therefore highly controlled and tested before they’re approved for human consumption. Those tests include experiments about absorption, tissue distribution, metabolism, and excretion. All information will be gathered to define toxicity mechanisms and set intake levels. For some food additives even further tests need to be performed, for example clinical studies with humans, especially when it can affect the metabolism (like AS do).

Three concepts are crucial:

  • Highest no-effect level (HNEL) is the intake level of AS where no harmful effects were seen. Those are usually determined by animal studies.
  • Acceptable Daily Intake (ADI) is the amount considered safe to consume every day for your whole life without negative effects. It is calculated from the HNEL, adding a safety factor to compensate for differences between species.
    For example, if the HNEL in mice was 10 mg/kg body weight, the intake level for humans would be 0.1 mg/kg body weight, after applying the safety factor of 100.
  • Estimated Daily Intake (EDI) will be calculated from the actual amount of AS in food and how much is consumed by people in real life. It is overestimated — assuming a high consumption throughout the whole population — just to be safe to include also groups at high risk.

Finally, the EDI needs to be compared to the ADI to see if the estimated intake is far below the acceptable intake, to make sure that human exposure is not even close to the risk level.


#4 Do artificial sweeteners help to regulate body weight?

  • When consuming AS the body tends to compensate for missing calories.
    Sugar has an undeniable addictive potential because of its downstream effects on dopamine. This reward phenomenon is based on two pathways: the sensory pathway (when binding sugar to the sweet taste receptors on the tongue) and the post-ingestion pathway (when the body notices that calories entered the body). Both pathways combined send signals to the brain saying “Attention! Sweet stuff and calories incoming” and therefore triggering the reward system. Since AS only activate the sensory pathway but don’t contain calories, the post-ingestion pathway is altered. But changes in the reward system can be counterproductive, since this may lead to increased food cravings and compensating caloric consumption.
  • When consuming AS you change your perception of what’s sweet.
    Manipulating your innate and individual perception of sweetness means getting used to an incredible and unnatural sweet taste from artificial substances. You will inevitably and constantly be reaching for sugary products instead of food with natural sugars as you could find in fruit or vegetables. Nothing will ever be sweet enough.
  • When consuming AS you can trigger an anticipatory insulin release. Humans have the capability to activate certain physiological responses to react to flavor or taste cues. This means that the body anticipates that sugar is going to enter the body when tasting something sweet and prepares for optimal nutrient absorption. Insulin can be released even though no glucose was ingested. Insulin regulation no longer follows the sugar load, but the taste buds. AS have even been associated with the development of insulin resistance and type-2 diabetes.
  • When consuming AS your gut microbiome can be changed negatively.
    Since AS do not contain calories and are not digested, most of them directly pass the gut and enter the colon where they are excreted or metabolized by your microbiota. But although it sounds like it’s all done now, the gut microbiome is a key step in regulating body weight and its composition is crucial (more about that in #5).
  • AS can help regulate the body weight short-term, since it can reduce total calorie intake (if you had consumed sugar instead). Still, it’s not a recommended long-term diet, and their effect on actual prevention of obesity is highly controversial.

#5 Do artificial sweeteners influence metabolic response?

Since AS are not metabolized by your body like nutrients, it is believed that they do not affect anything. This is wrong.

  • They affect your microbiome composition.
    It’s no news that the microbes in our gut highly influence your metabolism — they have the ability to extract calories and produce energy from otherwise indigestible food and therefore alter our energy homeostasis. The composition is crucial for regulating body weight (Bacteroidetes are found more often in lean subjects, Firmicutes in obese subjects). It has been shown that AS can negatively influence that composition and alter the glucose homeostasis through that pathway. Some rodents were transplanted fecal material from AS-fed mice (so with an unfavorable composition of gut microbes) that showed impaired glucose tolerance which is a sign of insulin resistance. This indicates that AS can adversely affect the metabolism even though they are not metabolized.
  • They affect the secretion of digestions hormones.
    Usually, digestion hormones (like Ghrelin or GLP-1) are released when nutrients enter the stomach or the intestines. They stimulate the pancreas to release insulin when glucose is present. In rodents, it was possible to show that AS affected that mechanism and interfered with the hormonal regulation of glucose homeostasis, even though no glucose was present.
  • They affect satiety.
    AS do not induce satiety the same way sugars do. Sugar — as a nutrient — has multiple downstream effects on the digestion, absorption, and metabolism, in contrast to a non-nutrient like AS. For example, the before mentioned hormones Ghrelin or GLP-1 cause satiety, because they delay emptying the stomach into the small intestine.

#6 Why is it so difficult to determine if artificial sweeteners are beneficial or not?

Science is never black and white and especially nutrition and the human body are complex issues that cannot always be answered with a simple yes or no. Some of the reasons why it is difficult to evaluate the benefits and disadvantages of AS are listed below:

  • The long-term effects of AS on humans are not fully uncovered.
  • The best approach for evaluation are human studies with interventions regarding only one AS, but often multiple AS are used in products. Their synergetic effects are still not fully understood.
  • AS are also found in non-edible products (toothpaste, mouthwash, gum) and are ingested without people knowing and without them reporting it in their dietary questionnaires. This can lead to biased results when evaluating. This could be avoided by using rodent models with a strictly controlled environment, but then you have limited insight into the effects on humans.
  • Humans consuming AS, are often predisposed with a metabolic disorder.
  • It is difficult to draw a conclusion regarding AS, since there are different types of AS, not all of them behave the same way, or studies used different AS in different concentration levels in different models (human or rodent). A general comparison can not be done.
  • The inconsistency of results can be due to confounding factors like increased food intake for compensation or psychological effects.
  • Short duration or false design of studies can be limiting to consider their results relevant.

#7 Do artificial sweeteners cause cancer?

If AS cause cancer is probably one of the biggest controversies of our modern nutrition and I’m not the one to solve it. I can simply lay out what’s in front of us.

Yes, there were rodent studies for cyclamate and saccharin in the 70s that showed an increased risk for urothelial tumors and bladder cancer. Why can we not trust those findings?

  • They were fed irrational doses of AS — interestingly, even Vitamin C causes bladder cancer when given doses that high.
  • Rodents are particularly susceptible to developing urothelial tumors, due to high urine osmolarity and following precipitation of calcium phosphate and sodium salts, which are toxic in high amounts and lead to tumorigenesis.
  • Other data from the same time (the 1960s to 80s) — higher quality case-control studies in humans — did not show the risk of bladder cancer when consuming AS.

But although this popular study from the 70s might have sucked big time, more current studies are still inconclusive.

  • meta-analysis for the most commonly used AS aspartame assessed 10 carcinogenic bio assays in rodents and found no carcinogenic effect.
    But: meta-analysis can be misleading, depending on chosen studies; rodents; only aspartame tested
  • Another study (retrospective observational with 100 patients) found an association between AS use and thyroid carcinoma when consuming 4g per day for an average duration of 5 years.
    But: retrospective is always quite biased, observational is not an intervention
  • An evaluation of aspartame cancer epidemiology studies, which was based on two case-control studies and five prospective studies did not support an increased risk of cancer.
    But: again just aspartame

Conclusion: Should you consume artificial sweeteners or not?

Due to efficient marketing, a bunch of claimed health benefits regarding artificial sweeteners are out there — especially regarding bodyweight — but we’re still lacking long-term and large-scale clinical studies to prove their efficacy. It has been shown that artificial sweeteners not only negatively alter our gut microbiota and our body weight regulation, but our glucose metabolism, our satiety, and our individual perception of sweetness. The enthusiasm regarding weight reduction and fighting obesity quickly vanished. and were replaced by their possible side-effects instead: nonalcoholic fatty liver disease, insulin resistance, type-2 diabetes.

Although it is not proven and unlikely that artificial sweeteners are baring a high risk for cancer when consumed in low amounts and not regularly, a diet based on artificial sweeteners is not recommended when striving for a healthy lifestyle. This doesn’t mean that sugar should be preferred to artificial sweeteners — since it has even worse effects on the body — but neither of both should be part of your regular diet. A holistic dietary environment, including food products with naturally low sugar content like fiber-rich grains, green vegetables, (fruits), and low-fat dairy products, should be preferred.

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