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Too much fructose disrupts intestinal barrier in mice, leading to liver damage

Nature Metabolism
Reuters Health - 03/09/2020 - A mouse study of fatty liver disease suggests that excessive fructose consumption disrupts the intestinal barrier, allowing endotoxins to leak out into the liver, thereby triggering cytokine production and conversion of fructose and glucose into fatty acid deposits. The process can set the stage for nonalcoholic fatty liver disease (NAFLD).

"As far as high-fructose corn syrup (HFCS) and other high-fructose foods consumed by humans, I think our studies suggest that only excessive, high-end (i.e., 90th percentile and above) fructose consumption is worrisome," Dr. Michael Karin of the University of California, San Diego told Reuters Health by email. "Occasional drinking of HFCS-containing soft drinks or processed food and moderate consumption of dried fruits may not lead to barrier deterioration, as observed after high-end fructose consumption."

"Therefore, clinicians need to caution their patients about excessive fructose consumption, such as a six-pack of soda a day plus pizza or other processed foods and sweets," he said. "As such, the eating habits of American children and teenagers are probably more of a concern than those of most adults".

The researchers explain in Nature Metabolism that benign hepatosteatosis progresses to non-alcoholic steatohepatitis (NASH, a severe manifestation of NAFLD) on stress and inflammation. Fructose has been proposed as a key macronutrient that increases both hepatosteatosis and NASH risk.

Working in mice, the team uncovered mechanisms by which excessive fructose may trigger these liver conditions. They found that excessive fructose intake causes intestinal-barrier deterioration (so-called "leaky gut"), resulting in endotoxemia, a chronic inflammatory condition that has been documented in both animals and pediatric NAFLD patients. When the leaked endotoxins reach the liver, they provoke increased production of inflammatory cytokines, stimulating the conversion of fructose and glucose into fatty acid deposits.

Notably, short-term high-fructose feeding did not alter intestinal barrier permeability; similarly, when fructose intake was reduced, the mice did not demonstrate any adverse effects. This suggests, as Dr. Karin noted, that only excessive, long-term fructose consumption might be a health risk. Further, antibiotic treatment reduced much of the damage to the intestinal barrier.

Dr. Kathleen Viveiros, a specialist in gastroenterology, hepatology and endoscopy at Brigham and Women's Hospital in Boston commented in an email that the findings seem feasible and "outline several mechanisms by which the pathway of hepatic steatosis and steatohepatitis could occur via fructose consumption."

That said, she told Reuters Health, "In mouse models, there was evidence that fructose induces barrier deterioration and intestinal epithelial endoplasmic reticulum stress. The (authors) showed that with administration of an antibiotic cocktail, the effect of increased permeability of the colon wall could be prevented. The gut microbiome in mouse models is different than in humans and quite complex. This finding is interesting but would require additional and continued study in humans."

"Fructose is found in sodas and many beverages - so high-yield dietary advice for clinicians counseling patients is to eliminate these items from daily consumption," she said. "However, fructose is present in many, many products - even those that are not considered 'sweet' - for example, sliced bread, cereals, etc."

"Clinicians who care for patients with NAFLD should try to counsel them on the importance of reading labels and avoiding foods with added sugars or sugars in the top of the ingredient list. Limiting these foods will help with insulin resistance, which contributes to NAFLD," she said. "In addition, clinicians should continue to encourage patients to eat whole foods whenever possible (vegetables, fruits, dairy products, eggs, meats, fish, poultry) and limit sugary, processed foods and beverages as much as they can."

By Marilynn Larkin

SOURCE: https://go.nature.com/3hXVL4W Nature Metabolism, online August 24, 2020.

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