Excess dietary fructose does not alter gut microbiota or permeability in humans: A pilot randomized controlled study.

José O Alemán,José O Alemán,Kyle Bittinger,Robert Macarthur,Wendy A Henderson,Roger Vaughan,Jan L Breslow,Drew R Jones,Kun Chen,Peter J Walter,Jeanne M Walker,Andrea Ronning,Peter R Holt,Peter J Walter,Scott G Daniel

doi:10.1017/cts.2021.801

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans. We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30-40mg/kg/m2). Each arm provided 75grams of either fructose or glucose added to subjects' individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites. Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention. In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome
NAFLD may lead to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer [3]
The present pilot study aimed to determine the effects of excess fructose compared to isocaloric glucose ingestion on the fecal microbiome, metabolome, intestinal permeability, and markers of endotoxemia in individuals with obesity in a rigorous cross-over study conducted in an inpatient metabolic unit

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. Conclusions: In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD. A fructose bolus in humans increases serum triglycerides and palmitate [7] and nine days of a diet including 25% of total calories as fructose increases hepatic fatty acid synthesis [8], which is reversed by substitution of fructose by starch [9]. Fructose undergoes first pass metabolism in the liver [13] and is a substrate for de novo lipogenesis driving triglyceride accumulation which causes cellular injury [14]

Methods

Results

Conclusion