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According to a preclinical study by researchers at Weill Cornell Medicine and NewYork-Presbyterian, consuming fructose appears to alter cells in the digestive tract in a way that allows it to absorb more nutrients. These changes could help explain the well-known link between increased fructose consumption around the world and increased rates of obesity and certain cancers.
The research, published Aug. 18 in Nature, focused on the effect of a high-fructose diet on the villi, the fine, hair-like structures that line the inside of the small intestine. Villi expand the surface of the intestine and help the body absorb nutrients, including dietary fat, from food as it passes through the digestive tract. The study found that mice fed diets containing fructose had villi 25 to 40 percent longer than those of mice that were not fed fructose. Additionally, increased villus length was associated with increased nutrient uptake, weight gain, and fat accumulation in animals.
“Fructose is structurally different from other sugars like glucose, and it is metabolized differently,” said lead author Dr. Marcus DaSilva Goncalves, researcher Ralph L. Nachman, assistant professor of medicine in the Division of Endocrinology, diabetes and metabolism and an endocrinologist at NewYork-Presbyterian / Weill Cornell Medical Center. “Our research has shown that the major metabolite of fructose promotes villus elongation and supports the growth of intestinal tumors.”
The investigators had not planned to study the villi. Previous research from the team, published in 2019, found that dietary fructose may increase tumor size in mouse models of colorectal cancer, and that blocking fructose metabolism may prevent this from happening. Believing that fructose might also promote hyperplasia, or accelerated growth, of the small intestine, the researchers examined tissue from mice treated with fructose or a control diet under a microscope.
The observation that mice given a high fructose diet had increased villus length, which was done by first author Samuel Taylor, a tri-institutional MD-Ph.D. Student of the program in the laboratory of Dr. Gonçalves, was a total surprise. And once he made the discovery, he and Dr Gonçalves set out to learn more.
After observing that the villi were longer, the team wanted to determine if these villi functioned differently. So they divided the mice into three groups: a normal low fat diet, a high fat diet, and a high fat diet with added fructose. The mice in the third group not only developed longer villi, but they also became more obese than the mice given the high fat diet without fructose.
The researchers took a closer look at the changes in metabolism and found that a specific metabolite of fructose, called fructose-1-phosphate, accumulated to high levels. This metabolite interacted with a glucose-metabolizing enzyme called pyruvate kinase, to alter cell metabolism and promote survival and villus elongation. When the pyruvate kinase or the enzyme that produces fructose-1-phosphate was removed, the fructose had no effect on the length of the villi. Previous animal studies have suggested that this fructose metabolite also helps tumor growth.
According to Taylor, observations in mice make evolutionary sense. “In mammals, especially mammals that hibernate in temperate climates, fructose is very available during the fall months when the fruit is ripe,” he said. “Eating a lot of fructose can help these animals absorb and convert more nutrients into fat, which they need to get through the winter.”
Dr Gonçalves added that humans did not evolve to eat what they eat now. “Fructose is almost ubiquitous in modern diets, whether it comes from high fructose corn syrup, table sugar, or natural foods like fruit,” he said. “Fructose by itself is not harmful. It is a problem of overconsumption. Our bodies weren’t designed to eat as much of it as we do.
Future research will aim to confirm that the results in mice translate into humans. “There are already drugs in clinical trials for other purposes that target the enzyme responsible for the production of fructose-1-phosphate,” said Dr. Gonçalves, who is also a member of the Sandra and Edward Meyer Cancer Center. “We hope to find a way to reuse them to shrink villi, reduce fat absorption, and possibly slow tumor growth.”
Dr Marcus DaSilva Goncalves is a paid consultant and shareholder of Faeth Therapeutics which develops cancer therapies. Dr. Goncalves has received conference and / or consulting fees from Pfizer, Novartis, Petra Pharmaceuticals and TruMacro Nutrition. Dr Gonçalves’ laboratory has received financial support from Pfizer.
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