Josh Rabinowitz

Mouse study reveals gut effects of too much fructose

Joshua Rabinowitz, a professor of chemistry and the Lewis-Sigler Institute for Integrative Genomics, led a research team that found that fruit sugars are processed mainly in the small intestine in mice, but sugary drinks and high-sugar foods overwhelm the small intestine and spill into the liver for processing.

Princeton University researchers report that in mice, fructose, a sugar found in fruit, is processed mainly in the small intestine, not in the liver as had previously been suspected. Sugary drinks and processed high-sugar foods overwhelm the small intestine and spill into the liver for processing. Additionally, the authors learned that the ability of the small intestine to process fructose is higher after a meal. The work appeared Feb. 6 in the journal Cell Metabolism.

“There is a fundamental physiological difference in how smaller and larger amounts of sugar are processed in the body,” said Joshua Rabinowitz, a professor of chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University, whose laboratory led the study.

The prior view was that the liver processes all ingested sugar, but this study showed that more than 90 percent of the fructose is cleared by the small intestine in mice.

“We can offer some reassurance — at least from these animal studies — that fructose from moderate amounts of fruits will not reach the liver,” he said. However, the small intestine probably starts to get overwhelmed with sugar halfway through a can of soda or large glass of orange juice.

In the study, Rabinowitz and his colleagues studied the path of isotope-labeled fructose through the digestive systems of laboratory mice. The researchers observed that excess fructose that is not absorbed by the small intestine continues through the intestine into the colon. As a consequence, it also comes into contact with the natural microbiotic flora of the large intestine and colon, known as the microbiome.

“The microbiome is designed to never see sugar,” Rabinowitz said. “One can eat an infinite amount of carbohydrates, and there will be nary a molecule of glucose that enters the microbiome. But as soon as you drink the soda or juice, the microbiome is seeing an extremely powerful nutrient that it was designed to never see.”

While the study did not show that fructose influences the microbiome, the authors suggest an effect is likely and should be studied further to learn more about the biological consequences of high sugar intake. 

The investigators also found that the small intestine clears fructose more efficiently after a meal. “We saw that feeding of the mice prior to the sugar exposure enhanced the small intestine’s ability to process fructose,” said Rabinowitz. “And that protected the liver and the microbiome from sugar exposure.” The researchers theorize that in a fasting state, such as upon awakening or in the mid-afternoon, one is extra vulnerable to fructose due to a lessened ability to process it in the small intestine.

Although the study was conducted in mice, Rabinowitz encourages “the most old-fashioned advice in the world” for humans: limit sweets to moderate quantities after meals, and do not have sweet drinks away from mealtime.


The Small Intestine Converts Dietary Fructose into glucose and organic acids,” by Cholsoon Jang, Sheng Hui, Wenyun Lu, Alexis Cowan, Raphael Morscher, Gina Lee, Wei Liu, Gregory Tesz, Morris Birnbaum, and Joshua Rabinowitz, was published Feb. 6 in the journal Cell Metabolism.  

This research was supported by National Institutes of Health Pioneer Award 1DP1DK113643 and Diabetes Research Center Grant P30 DK019525. Jang is a postdoctoral fellow of the American Diabetes Association. Hui is a Merck Fellow of the Life Sciences Research Foundation. Lee is a postdoctoral fellow of the LAM Foundation (LAM00100F01-14) and the Tuberous Sclerosis Alliance (TSA-01-14).