Sweeteners such as aspartame, found in Equal packets, sucralose (Splenda), or sugar alcohols are often seen as healthier alternatives to food with refined sugar (glucose).
But that assumption is being challenged with new scientific research, including the recent finding that the sugar alcohol sorbitol is not as harmless a sugar substitute as once thought.
The study, published recently in Science Signaling, follows a line of research detailing the harmful effects of fructose on the liver and other systems from the lab of Gary Patti, at Washington University in St. Louis.
Patti, the Michael and Tana Powell Professor of Chemistry, in Art & Sciences, and of genetics and medicine, at WashU Medicine, previously has published research about how fructose processed in the liver can be hijacked to supercharge cancer cells. Previous research also has found that fructose is a key contributor to steatotic liver disease, affecting 30% of the adult population worldwide.
The most surprising finding from the current work is that because sorbitol is essentially "one transformation away from fructose," it can induce similar effects, Patti said.
The research involved experiments with zebrafish demonstrating that sorbitol, often used in "low-calorie" candy and gum, and commonly found in stone fruits, can naturally be made by enzymes in the gut and eventually converted into fructose in the liver.
Patti's team found there are many roads to fructose in the liver, and potential detours, depending on a person's sorbitol and glucose consumption patterns, along with the bacterial populations colonizing their gut.
For starters, although most of the research on sorbitol metabolism has focused on its production due to glucose overload in pathological settings such as diabetes, sorbitol can be naturally produced in the gut from glucose after eating, Patti said.
The enzyme that produces sorbitol has a low affinity for glucose, so glucose levels must be high for it to take effect. That is why sorbitol production has primarily been associated with diabetes, where blood glucose levels can become elevated. But, even in healthy settings, glucose levels in the gut become high enough after feeding to drive sorbitol production within the intestine, according to the team's zebrafish experiments.
"It can be produced in the body at significant levels," said Patti. "But if you have the right bacteria, turns out, it doesn't matter."
Sorbitol-degrading Aeromonas bacterial strains convert the sugar alcohol into a harmless bacterial byproduct.
"However, if you don't have the right bacteria, that's when it becomes problematic. Because in those conditions, sorbitol doesn't get degraded and as a result, it is passed on to the liver," he said.
Once in the liver, it is converted to a derivative of fructose. It's important to determine if alternative sweeteners are providing a healthy alternative to table sugar since people with diabetes and other metabolic disorders may be relying on them as "sugar free" products.
Gut bacteria do a good job of clearing sorbitol when it is present at modest levels, such as those found in fruit. But problems arise when sorbitol quantities become higher than what gut bacteria can degrade. This can occur when excessive amounts of glucose are consumed in the diet, which lead to high levels of glucose-derived sorbitol, or when dietary sorbitol itself is too high.
The more glucose and sorbitol consumed, then, even if someone has the friendly bacteria that clears it, those gut microbes may be overwhelmed with the task.
Avoiding both sugar and alternative sweeteners is increasingly complicated, as many foods are packed with multiple varieties of all the above. Patti was bemused to discover his own favorite protein bar was chock full of sorbitol.
The lab will need to do more research to understand the specific mechanisms for how bacteria clears sorbitol, but the basic idea that these sugar alcohols, called polyols, are harmlessly expelled, may not hold true.
"We do absolutely see that sorbitol given to animals ends up in tissues all over the body," he said.
Bottom line: it's becoming more apparent that "there is no free lunch" when trying to find sugar alternatives, with many roads leading to liver dysfunction.
Jackstadt MM, Fowle-Grider R, Song MG, Ward MH, Barr M, Cho K, Palacios HH, Klein S, Shriver LP, Patti GJ. Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria. Sci Signal. 2025 Oct 28. DOI
https://10.1126/scisignal.adt3549
This work was supported by the National Institutes of Health, grants R35ES028365 (G.J.P.) and P30DK056341 (S.K.).
