That “sugar-free” gum or low-calorie candy in your desk drawer might not be the harmless treat you thought. Researchers at Washington University in St. Louis have discovered that sorbitol, a common sugar alcohol found in diet foods and naturally present in stone fruits, can drive the development of fatty liver disease under certain conditions.
The findings challenge long-held assumptions about sugar substitutes and reveal a complex relationship between gut bacteria, dietary sweeteners, and liver health that could affect millions of people worldwide who rely on “sugar-free” products.
Gary Patti, the Michael and Tana Powell Professor of Chemistry at Washington University, led the research published in Science Signaling. His team’s work follows earlier discoveries about how fructose processed in the liver can fuel cancer growth and contribute to steatotic liver disease, which affects 30% of adults globally.
The new study reveals that sorbitol is essentially “one transformation away from fructose,” according to Patti, meaning it can trigger similar metabolic problems in the liver. Using zebrafish as a model organism, the researchers traced how dietary glucose gets converted to sorbitol by enzymes in the gut, then shuttled to the liver where it becomes fructose.
Gut Bacteria as Metabolic Gatekeepers
The story gets interesting when gut microbes enter the picture. Certain bacterial strains, particularly members of the Aeromonas genus, can break down sorbitol before it reaches the liver. These microorganisms essentially act as a protective buffer, degrading the sugar alcohol in the intestine and preventing it from causing metabolic havoc downstream.
But problems arise when these helpful bacteria are absent or overwhelmed. In zebrafish experiments, depleting gut bacteria with antimicrobials led to fatty liver disease within just seven days, even when the animals ate normal diets. The culprit? Sorbitol accumulating in the intestine and transferring to the liver.
“We do absolutely see that sorbitol given to animals ends up in tissues all over the body,” Patti said.
The enzyme that produces sorbitol from glucose has a relatively low affinity for glucose, so it typically only kicks into gear when glucose levels are high. That’s why sorbitol production has historically been associated with diabetes and elevated blood sugar. However, the research team discovered that even in healthy individuals, glucose concentrations in the gut after eating can climb high enough to trigger significant sorbitol production in the intestine.
When Good Bacteria Can’t Keep Up
The protective effect of gut bacteria works well when sorbitol levels stay modest, like the amounts naturally present in fruits. But the system can be overwhelmed in two scenarios: when people consume excessive amounts of glucose-rich foods that lead to high levels of glucose-derived sorbitol, or when they eat large quantities of sorbitol itself through diet products.
“If you have the right bacteria, turns out, it doesn’t matter. 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,” Patti explained.
Once sorbitol reaches the liver, it converts to a fructose derivative that activates an enzyme called glucokinase. This triggers a metabolic cascade: increased glucose metabolism, excessive glycogen storage, and ultimately, fat accumulation in liver cells. The researchers confirmed this mechanism using isotope tracing experiments that tracked labeled carbon atoms from sorbitol through various metabolic pathways.
In a striking validation of their findings, the team showed they could prevent liver disease in bacteria-depleted zebrafish by administering epalrestat, a drug that blocks sorbitol production. Conversely, giving zebrafish high concentrations of exogenous sorbitol mimicked the effects of gut bacteria depletion and induced fatty liver, even when beneficial microbes were present.
The research carries particular significance for people with diabetes and metabolic disorders who often turn to “sugar-free” products containing sorbitol. Many diet foods pack substantial amounts of the sweetener, with some products containing 30 to 95 grams of sorbitol per 100 grams of food. The assumption has been that sorbitol offers a safer alternative because it doesn’t spike blood glucose levels like regular sugar.
Patti discovered his own favorite protein bar was loaded with sorbitol, illustrating how pervasive these sugar substitutes have become in processed foods. The findings suggest that while dietary fructose has received considerable attention for its negative effects on liver health, sorbitol has flown under the radar despite being just one enzymatic step away from becoming fructose in the body.
The work points toward potential new treatment strategies, including developing probiotic therapies that enrich the gut with sorbitol-degrading bacteria. Species like Aeromonas salmonicida successfully cleared sorbitol and protected against liver disease when introduced into bacteria-depleted zebrafish intestines.
As Patti notes, the broader lesson emerging from this research is sobering: there may be no free lunch when it comes to sugar substitutes, with multiple pathways leading to potential liver dysfunction. The conventional wisdom that sugar alcohols like sorbitol pass harmlessly through the digestive system appears increasingly questionable.
Science Signaling: 10.1126/scisignal.adt3549
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