Artificial sweeteners may disrupt metabolism, review finds

A new review and meta-analysis suggests that artificial and other non-nutritive sweeteners — including saccharin, aspartame, and sucralose — are not inert in the human body and may be harming metabolism. In addition to randomized clinical trials, the researchers pooled findings from large observational studies, which generally found that consuming these sweeteners is linked to a higher risk of developing cardiometabolic diseases. 

Across 21 randomized clinical trials in adults, researchers observed that artificial and other low-calorie sweeteners — compared to non-caloric controls such as water or a placebo — raised fasting insulin and HbA1c, a marker of long-term blood sugar control, and reflected worsening insulin sensitivity.

Nutrition Insight speaks to first author Meng Wang, a research assistant professor at the Friedman School of Nutrition Science and Policy at Tufts University, US, about what the available evidence says about non-nutritive sweeteners affecting health.

“At this point, I would not single out one sweetener as clearly the most concerning,” she tells us. “The ingredient-specific data are still too sparse and mixed.”

On an individual level, Wang’s team observed small shifts in fasting insulin and HbA1c. “They matter scientifically because they suggest a biological signal and point to a possible mechanism, but they are not the size of change that has a clear clinical interpretation for an individual,” Wang notes.

“The strongest evidence is a randomized human trial that tested saccharin, sucralose, aspartame, and stevia,” she highlights. “The study found that some sweeteners changed the gut microbiome and that saccharin and sucralose worsened glucose responses.”

“Most importantly, when stool from human ‘responders’ (those having potent changes in glucose tolerance in response to non-nutritive sweeteners) was transferred into germ-free mice, the mice showed similar glucose-response changes. That makes the microbiome explanation more plausible.”

Altering gut microbiota

Based on the reviewed evidence, one explanation of metabolic disruption involves the gut microbiome. Non-nutritive sweeteners generally pass through the gut and come into direct contact with these microbes, explain the researchers.

The new review was completed by researchers from the Food is Medicine Institute at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University. The findings are published in Current Atherosclerosis Reports.

Non-nutritive sweeteners generally pass through the gut and disrupt gut microbes, explain the researchers.In one reviewed trial that used detailed microbiome profiling along with experiments transferring microbes from humans to mice, certain low-calorie sweeteners were shown to alter the composition and the function of the gut microbiota.

This finding builds on research published earlier this year, which found that popular sucralose and stevia sweeteners may negatively affect the gut microbiome and gene expression. This could compromise metabolic health, which the authors of that paper suggested can be transmitted between generations.

“I would be cautious about naming any alternative sweetener as clearly ‘most promising,’” says Wang. “Rare sugars such as allulose and tagatose are interesting because some controlled human studies suggest they may reduce post-meal glucose or insulin responses.”

“But the evidence is still limited, and longer-term effects remain unclear. These new sweeteners are worth further study, but I would not present them as promising healthier alternatives.”

Study limitations and considerations

The review authors stress the need for additional carefully designed randomized controlled trials of cardiometabolic risk factors and mechanistic pathways.

They acknowledge that these studies have limitations, as people already at risk for these conditions may be more likely to choose these products. Moreover, they say different sweeteners may also pose varying health effects, meaning that grouping them together can obscure the full picture.

However, when considering the clinical findings, they say that the overall body of evidence raises concern.

“The rapidly increasing use of these sweeteners has outpaced our understanding of their long-term health effects,” says study senior author Dariush Mozaffarian, a cardiologist and director of the Food is Medicine Institute. “Until we know more, caution is needed.”

“If you’re replacing large amounts of added sugar in your diet, such as in multiple servings of soda, these low-calorie sweeteners may be a better alternative. But we can’t simply assume they are safe and innocuous, and avoiding them whenever possible appears a prudent choice.” 

Finally, the researchers highlight a gap in the US labeling policy that hinders the research. They note that current regulations require manufacturers to list non-nutritive sweeteners in the ingredient list, but not the amount included. 

This has made it challenging for researchers to accurately assess non-nutritive sweetener intake and generate more definitive evidence about their health risk in large community or population studies.

“The most useful improvement would be to require labels to list the amount (weight) of each non-nutritive sweetener per serving, just as labels now list grams of added sugar,” says Wang. 

“Today, consumers and researchers can usually see that a product contains sucralose, aspartame, stevia, etc., but not the dose. Dose matters: without it, we cannot accurately compare products, estimate intake, or study health effects by specific non-nutritive sweeteners.”