Bibliography: Fructose causes leaks

Elsewhere on the site, I talk about Dr. Richard Johnson’s claims that fructose consumption, which elevates uric acid, makes your digestive tract “leaky” so that food molecules get into bloodstream.  Those cause an allergic reaction, leading to food allergies, most notably gluten found in wheat and other grains.  Gluten gets extracted and added to other food products, too.  Johnson isn’t alone in this line of research, although he may be further along studying the underlying mechanisms than anyone else.  Here are some citations, his among them.  I’ve included the abstracts.  Note the underlined links to the original articles on the Internet.

Astbury et al, 2014, A high fructose diet during pregnancy significantly affects markers of intestinal permeability in the offspring (816.2) The FASEB Journal 28 no.1 Supplement 816.2.   A high fructose diet during pregnancy increases intestinal permeability in pregnant offspring.

Maternal diet in pregnancy has been shown to affect offspring development but few studies have examined changes in the gut. Gut barrier dysfunction may allow components of the microbiota to pass into the circulation, which has been linked to the development of obesity and the metabolic syndrome. This study examined the effect of a maternal diet that is high in fructose on gut permeability markers in pregnant offspring. Female Wistar rats were placed on 10% fructose (F1) or water (W1) at 8 weeks of age and were mated at 10 weeks; the intervention continued throughout pregnancy. Female offspring continued on the same diet as their dams (W2, n=10 and F2, n=10) from 4 weeks of age, were mated at 10 weeks, and tissue was collected at gestational day 20. Ileum and jejunum expression of occludin (OCLN), claudin 3 (CLDN3) and zonulin 1 (ZO1) were used as markers of intestinal permeability. F2 pups had a lower birth weight but similar weights at 13 weeks of age compared with W2. F2 also had a significantly higher % fat mass and reduced gut length vs W2. Expression of ZO1 (W2=1.64±0.28; F2=0.64±0.09), OCLN (W2=1.27±0.15; F2=0.51±0.09), but not CLDN3 (W2=1.09±0.19; F2=2.15±0.45) was reduced in the jejunum (p<0.05) but not different in the ileum. A high fructose diet during pregnancy increases intestinal permeability in pregnant offspring. Further studies will examine the effect of the fructose diet on the microbiome during pregnancy.

Prof. Michael Trauner, MD, Medical University of Vienna, 2012  Impact of Fructose Consumption on Intestinal Permeability in Non-alcoholic Fatty Liver Disease (NAFLD) – a Pilot Study. http://clinicaltrials.gov/show/NCT01696487

The spectrum of NAFLD as emerging epidemic ranges from steatosis to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Disease progression is poorly understood and treatment options are limited. Fructose overconsumption has been associated with gut permeability and progression of NAFLD. To unravel the mechanisms of fructose-induced intestinal changes, volunteers will receive a 4-week fructose challenge prior to assessment of intestinal permeability/translocation using endomicroscopy, sugar probes, serum markers of intestinal damage, inflammation, iron/copper homeostasis and histological/molecular analysis of intestinal biopsies. Findings in volunteers will be compared with liver patients undergoing study procedures without fructose challenge. Translational in vitro experiments will explore cellular responses to fructose and endotoxin. This project should provide novel insights into dietary induced alterations of the gut integrity in progression of NAFLD to NASH

Thuy, et al, 2008. Nonalcoholic Fatty Liver Disease in Humans Is Associated with Increased Plasma Endotoxin and Plasminogen Activator Inhibitor 1 Concentrations and with Fructose Intake1 J. Nutr. August 2008 vol. 138 no. 8 1452-1455

Results of animal experiments suggest that consumption of refined carbohydrates (e.g. fructose) can result in small intestinal bacterial overgrowth and increased intestinal permeability, thereby contributing to the development of nonalcoholic fatty liver disease (NAFLD). Furthermore, increased plasminogen activator inhibitor (PAI)-1 has been linked to liver damage of various etiologies (e.g. alcohol, endotoxin, nonalcoholic). The aim of the present pilot study was to compare dietary factors, endotoxin, and PAI-1 concentrations between NAFLD patients and controls. We assessed the dietary intake of 12 patients with NAFLD and 6 control subjects. Plasma endotoxin and PAI-1 concentrations as well as hepatic expression of PAI-1 and toll-like receptor (TLR) 4 mRNA were determined. Despite similar total energy, fat, protein, and carbohydrate intakes, patients with NAFLD consumed significantly more fructose than controls. Endotoxin and PAI-1 plasma concentrations as well as hepatic TLR4 and PAI-1 mRNA expression of NAFLD patients were significantly higher than in controls. The plasma PAI-1 concentration was positively correlated with the plasma endotoxin concentration (Spearman r = 0.83; P < 0.005) and hepatic TLR4 mRNA expression (Spearman r = 0.54; P < 0.05). Hepatic mRNA expression of PAI-1 was positively associated with dietary intakes of carbohydrates (Spearman r = 0.67; P < 0.01), glucose (Spearman r = 0.58; P < 0.01), fructose (Spearman r = 0.58; P < 0.01), and sucrose (Spearman r = 0.70; P < 0.01). In conclusion, our results suggest that dietary fructose intake, increased intestinal translocation of bacterial endotoxin, and PAI-1 may contribute to the development of NAFLD in humans.

Johnson, et al, 2013. Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection? J Equine Vet Sci. 2013 Feb;33(2):120-126.

Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis.

Astrid Spruss & Ina Bergheim.  Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease, The Journal of Nutritional Biochemistry Volume 20, Issue 9 , Pages 657-662, September 2009

Worldwide, not only the prevalence of obesity has increased dramatically throughout the last three decades but also the incidences of co-morbid conditions such as diabetes type 2 and liver disease have increased. The ‘hepatic manifestation of the metabolic syndrome’ is called nonalcoholic fatty liver disease (NAFLD) and comprises a wide spectrum of stages of liver disease ranging from simple steatosis to liver cirrhosis. NAFLD of different stages is found in ∼30% of adults and ∼20% in the US population. Not just a general overnutrition but also an elevated intake of certain macronutrients such as fat and carbohydrates and herein particularly fructose has been claimed to be risk factors for the development for NAFLD; however, the etiology of this disease is still unknown. The present review outlines some of the potential mechanisms associated with the development of NAFLD and fructose intake with a particular focus on the role of the intestinal barrier functions.

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