Alternative Sweeteners May Lead to Liver Disease

By Irene Yeh 

Alternative sweeteners, such as sucralose, aspartame, and sugar alcohols, are usually viewed as healthier substitutions for refined sugar (glucose). However, new research has found that sorbitol, a sugar alcohol, may not be a healthier alternative. A study by Washington University at St. Louis found that sorbitol can be converted into fructose by gut bacteria, which can be harmful to the liver when consumed in large quantities (Science Signaling, DOI: https://10.1126/scisignal.adt3549). Fructose activates the liver’s sugar-processing mechanism, resulting in excess storage of sugars and fats. 

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease and affects about 30% of the world’s adult population. It is often associated with overweightness or obesity and cardiometabolic conditions, such as prediabetes, type 2 diabetes, high blood pressure, and dyslipidemia. Certain gut microbes can protect the liver by depleting or modifying dietary substances before it is absorbed and delivered to the liver.  . However, when the right gut microbes are not present, after sorbitol is carried to the liver, it can convert into fructose, thus damaging the liver.  

Testing Zebrafish’s Gut Microbiome 

The team used adult zebrafish to assess changes in the gut microbiome that can lead to liver disease. The zebrafish were split into two groups: those with a depleted gut microbiome and the control group that did not have their microbiome altered. It was hypothesized that those with depleted gut bacteria would accumulate diet-derived chemicals in the intestines, liver, and serum. The treated fish were kept in a tank with sterilized facility water with penicillin/streptomycin, ampicillin, kanamycin, and amphotericin B. The control group was kept in normal sterilized facility water. The fish were fed once daily and were treated for seven days. At the end of the seven days, their blood was collected after euthanasia.  

Using metabolomics and isotope tracing, the team was able to identify sorbitol as a key metabolite produced from dietary glucose within the gastrointestinal tract in the zebrafish without gut bacteria. Even though sorbitol is conventionally believed to be poorly absorbed in the intestines, the results of this study showed that sorbitol accumulated in the fish with microbiome depletion and was transferred to the liver, where it rewired liver metabolism and caused lipid biosynthesis.  

The researchers also sought to determine if high levels of exogenous sorbitol mimicked glucose-derived sorbitol in the intestine. Sorbitol was dissolved in tank water, and fish from both the control group and with depleted microbiomes were transferred to tanks containing the sorbitol supplementation. Through isotope tracing, it was found that the presence of gut microbes decreased a fraction of exogenous sorbitol that reached the liver, but not enough to prevent the sorbitol from being converted into fructose in the liver. The fish that had their microbes depleted had fifteen times more sorbitol-derived fructose in their livers. This indicates that sorbitol from external sources, such as candy and gum, can still be detrimental to liver health if consumed in high amounts. 

The research team also tested to see if antimicrobials affected sorbitol production. By examining the tissues, they discovered that there was no difference in how much the liver absorbed sorbitol or how much it converted to fructose. This suggests that antimicrobials do not influence sorbitol metabolism in the liver, regardless of gut microbiome or lack thereof.  

To see if glucose-derived sorbitol could be prevented from developing in the gut, the team also conducted an experiment with epalrestat, an inhibitor for diabetic neuropathy and a drug that blocks the enzyme responsible for converting glucose into sorbitol, on the zebrafish. They found that epalrestat reduced sorbitol levels by about 50% in microbiome-depleted fish compared to those treated only with antimicrobials. Fish treated with both antimicrobials and epalrestat even demonstrated no development of liver steatosis compared to fish without a microbiome that did not receive the drug. Additionally, liver glycogen levels were significantly reduced by epalrestat treatment. This demonstrates that reducing sorbitol production in the intestine is sufficient enough to prevent liver fat accumulation in zebrafish lacking a gut microbiome and highlights that sorbitol synthesis in the intestine is the key driver behind liver steatosis. 

Alternative Sweeteners Are Not Necessarily Healthier 

More studies need to be conducted to fully understand the specific mechanisms for how bacteria degrade sorbitol. Nonetheless, the study supports the idea that sugar replacements may not be healthier. While sorbitol may be lower in calories and have less influence on blood glucose levels, it can still lead to liver disease. Patients with diabetes or obesity that consume high levels of sorbitol are at risk of developing MASLD.