New light shed on fructose metabolism: Mouse data

By Tim Cutcliffe contact

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This graphical abstract depicts the findings of Jang et al., which show that it is actually the small intestine that clears most dietary fructose, and this is enhanced by feeding. High fructose doses spill over to the liver and to the colonic microbiota for metabolism.  Picture credit: Jang et al./Cell Metabolism 2018
This graphical abstract depicts the findings of Jang et al., which show that it is actually the small intestine that clears most dietary fructose, and this is enhanced by feeding. High fructose doses spill over to the liver and to the colonic microbiota for metabolism. Picture credit: Jang et al./Cell Metabolism 2018
Big differences between how the body processes small and large quantities of fructose are revealed in a new study in Cell Metabolism.

In mice, fructose is processed predominantly in the small intestine, rather than in the liver, as had previously been thought, found researchers from Princetown University.

Sources of fructose include fruit, table sugar and beverages sweetened with high-fructose corn syrup.

By following the path of isotope-labelled fructose through the digestive system of mice, the researchers discovered that the capacity of the small intestine to process fructose is limited.

Although this part of the gut can cope with small amounts of fructose, the small intestine is overwhelmed by large intakes, which spill over into the liver for processing. Under these conditions, free fructose reaches the liver rather than just glucose and other metabolites of fructose.

"There is a fundamental physiological difference in how smaller and larger amounts of sugar are processed in the body,"​ commented lead researcher Professor Joshua Rabinowitz.  

“Low doses of fructose are ∼90% cleared by the intestine.” ​he added. “In this manner, the small intestine shields the liver from fructose exposure​.”

However, high doses of fructose overwhelm this shielding capacity.

“High doses of fructose (≥1 gram/kilogram (1g/kg)) overwhelm intestinal fructose absorption and clearance, resulting in fructose reaching both the liver and colonic microbiota,”​ Rabinowitz explained.

Fructose link with metabolic disease

Previous animal and human studies have linked fructose consumption with non-alcoholic fatty liver disease (NAFLD), insulin resistance and type-2 diabetes.

Fat accumulation within the liver and the development of metabolic disease has widely been regarded as being driven by fructose metabolism in the liver itself. However, the scientists speculate on the possibility that metabolism by microbiota in the large intestine could be the driver.

The researchers observed that excess fructose that is not absorbed by the small intestine continues through the intestine into the colon. Consequently, it is exposed to the bacteria in the large intestine and colon.

"The microbiome is designed to never see sugar​," said Rabinowitz. "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."

Improved fructose clearance after meal

The scientists also discovered that the small intestine cleared 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.​"

Additionally, they found that in fasted mice, the threshold for fructose spillover into the liver was lower than the 1 g/kg intake level.

Although the corresponding dose needed to induce fructose spillover in humans has not been measured exactly, Rabinowitz suggested that "we can offer some reassurance--at least from these animal studies--that fructose from moderate amounts of fruits will not reach the liver.”

However, he speculated that the small intestine probably starts to get overwhelmed after half a can of soda or a large glass of orange juice.  

Source: Cell Metabolism
Volume 27, Issue 2, p351–361.e3, doi: 10.1016/j.cmet.2017.12.016
“The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids”
Authors: Choolson Jang, Joshua D. Rabinowitz et al

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