The impact that low-calorie sweeteners (LCS) have on human physiology has been much debated. A recent review by the 2020 Dietary Guidelines Advisory Committee concluded that low-calorie sweeteners might be an effective approach to managing body weight. However, the NOVA system, which is gaining traction in dietary guidance globally, categorizes food containing an LCS as ultra-processed and should therefore be avoided. Thus, the evidence on LCS needs to be critically reviewed to determine their role in the diet. In the presentation “Low-Calorie Sweeteners Impact on Blood Glucose, Hunger, Weight & the Microbiome,” at the 2023 Clean Label Conference, Dr. Richard Mattes, Ph.D., Distinguished Professor of Nutrition Science at Purdue University, Affiliated Scientist at the Monell Chemical Senses Center delved into this topic. He reviewed the evidence on the effects of LCS on blood glucose concentrations, appetite, food intake, body weight, and the microbiome. One crucial question is whether it is appropriate to view all LCS as a single class or to evaluate them individually.
Low-Calorie Sweeteners’ Health Impact
“Current recommendations by the WHO for added sugar consumption are that it should contribute less than 10% of energy in the diet,” stated Mattes. “Yet in the U.S., three-quarters of four to 18-year-olds and about 50% of adult men and women are exceeding the goal, at around 13% of energy,” he noted. This corresponds to about 400kcals/day and 300kcals/day for males and females, respectively.
Mattes explained that the recommendation to limit sugar intake originated from dental health and highlighted that this guideline lacks scientific evidence regarding overall energy balance and body weight. He argued that the recommended goal should be 5% instead of 10%, which increases the potential value of low-calorie sweeteners (LCSs) as alternatives to caloric sweeteners. However, the beneficial impact of LCSs continues to be questioned—without a well-founded reason to do so.
Regarding blood glucose, an analysis of 29 studies showed no overall effects following the consumption of various doses and types of LCSs (Nichol et al. 2018. https://pubmed.ncbi.nlm.nih.gov/29760482). Similarly, other meta-analyses of 55 studies found no effects on insulin responses to LCSs. (Greyling et al. 2020. https://pubmed.ncbi.nlm.nih.gov/32672338).
Low-Calorie Sweeteners & Weight
In a clinical trial with 166 individuals who consumed various LCSs over an extended period, no significant impact was reported on self-reported hunger, fullness ratings or desire to eat (Fantino et al., 2018. https://pubmed.ncbi.nlm.nih.gov/29526693/). “Hunger represents an energy-driven desire to eat,” explained Mattes, “while sensory and cognitive factors influence the desire to eat.” Mattes presented research showing that LCSs may not directly influence appetite sensations, challenging the notion that sweetness alone primes the body to desire energy.
An early meta-analysis of cohort studies revealed a small but statistically significant increase in body weight among LCS users. However, small but statistically significant benefits were observed in terms of BMI, fat mass, and waist circumference based on randomized controlled trials, a stronger methodological approach (Miller & Perez. 2014. https://pubmed.ncbi.nlm.nih.gov/24944060).
A more recent meta-analysis by the WHO examined the effects of replacing sweeteners with LCSs, which is where the most significant impact would be expected (Rios-Leyvraz & Montez. 2022. https://apps.who.int/iris/handle/10665/353064). “When a source of energy is removed by substituting an LCS, the anticipated effect would be more significant than simply adding an LCS to a diet where it replaces water,” explained Mattes. The results found that substituting LCSs for nutritive sweeteners lowered BMI and body fat mass. This was driven primarily by findings from trials less than three months in duration.
No overall effect was observed among the limited number of trials of longer duration (N=6), but two reported significant benefits—with one noting an adverse outcome, compared LCS to water. And, while both groups lost weight, the water group lost slightly more. “Overall, the claim by the WHO that LCSs lead to weight gain is considered flawed and not supported by their own scientific evidence,” stated Mattes.
Different Structures, Different Physiological Effects
Mattes explained that LCSs have diverse chemical structures, ranging from carbohydrates and proteins to small molecules. Like any other array of chemicals introduced into the body, these substances would be expected to have different physiological properties.
Different LCSs bind to the same sweet receptor but with varying strengths and locations. This binding sets off a chain of physiological reactions within taste receptor cells, ultimately releasing neurotransmitters and the perception of sweetness in the brain (Dubois. 2016. https://pubmed.ncbi.nlm.nih.gov/26992959) that are LCS-specific. (See sidebar “Sweeteners & the Microbiome: What’s the Goal?”)
Importantly, “sweet taste receptors” are found not only in the mouth but throughout the body. When a sweetener binds to these extra-oral enteroendocrine cells it stimulates the cell to perform its specific function (e.g., enteroendocrine cells release gut peptides; beta cells release insulin), suggesting a broader role for LCS in the body.
Mattes summarized that using LCSs appears not to be associated with disordered blood sugar levels, increased appetite or increased overall food intake. In fact, LCS use is associated with lower BMI. He emphasized that each LCS may have different physiological effects, including sensory, gastric, neural and metabolic effects. It may prove important to consider each sweetener individually rather than viewing them as a single class of compounds with uniform effects.
SIDEBAR: Sweeteners & the Microbiome: What’s the Goal?
The impact of LCSs on gut microbiomes is a hot topic in popular and peer-reviewed literature. Studies and general health advice point to the importance of microbial diversity (Editor’s Note: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366966).
Other research works to identify desirable and undesirable microbial strains. These two approaches are not necessarily consistent. “If the desire is to determine which sweeteners can be used to preferentially increase ‘good’ bacterial strains and decrease the ‘bad’ ones, that is antithetical to the originally stated goal of increasing overall diversity for a healthful gut microbiome,” Mattes concluded.
Mattes walked through an analysis of what could be the mechanism behind the proposed impact of artificial or LCSs on the microbiome. LCSs that reach the colon may serve as signaling molecules or substrates for the microbiota there, whereas LCSs that are fully digested or absorbed before reaching the colon would have to work by other mechanisms.
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