Intestinal Permeability in Non-alcoholic Fatty LIVER Disease: The Gut-liver Axis

AbstractToll-like receptors (TLRs) in the liver compartment have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD). Knowledge on TLR expression in blood cells and their relation to intestinal microbiota and NAFLD development is limited. Here, we determined TLR expression patterns in peripheral blood mononuclear cells (PBMCs) of NAFLD patients and controls, their relation to intestinal microbiota and the impact of TLRs found altered in NAFLD development. Markers of intestinal permeability in blood and TLR mRNA expression in PBMCs were determined in 37 NAFLD patients and 15 age-matched healthy controls. Fecal microbiota composition was evaluated in 21 NAFLD patients and 9 controls using 16S rRNA gene amplicon sequencing. Furthermore, TLR1−/− and C57BL/6 mice (n = 5–6/group) were pair-fed a liquid control or a fat-, fructose- and cholesterol-rich diet. Intestinal microbiota composition and markers of intestinal permeability like zonulin and bacterial endotoxin differed significantly between groups with the latter markers being significantly higher in NAFLD patients. Expression of TLR1-8 and 10 mRNA was detectable in PBMCs; however, only TLR1 expression, being higher in NAFLD patients, were significantly positively correlated with the prevalence of Holdemanella genus while negative correlations were found with Gemmiger and Ruminococcus genera. TLR1−/− mice were significantly protected from the development of diet-induced NAFLD when compared to wild-type mice. While intestinal microbiota composition and permeability differed significantly between NAFLD patients and healthy subjects, in PBMCs, only TLR1 expression differed between groups. Still, targeting these alterations might be a beneficial approach in the treatment of NAFLD in some patients.

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Genetic susceptibility of increased intestinal permeability is associated with progressive liver disease and diabetes in patients with non-alcoholic fatty liver disease

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/j.numecd.2020.06.013 ◽

2020 ◽

Vol 30 (11) ◽

pp. 2103-2110

Author(s):

Luca Miele ◽

Valentina Giorgio ◽

Antonio Liguori ◽

Salvatore Petta ◽

Roberta Pastorino ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Genetic Susceptibility ◽

Intestinal Permeability ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Progressive Liver Disease ◽

Alcoholic Fatty Liver Disease

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Intestinal permeability after Mediterranean diet and low-fat diet in non-alcoholic fatty liver disease

World Journal of Gastroenterology ◽

10.3748/wjg.v25.i4.509 ◽

2019 ◽

Vol 25 (4) ◽

pp. 509-520 ◽

Cited By ~ 12

Author(s):

Marco Biolato ◽

Fiorella Manca ◽

Giuseppe Marrone ◽

Consuelo Cefalo ◽

Simona Racco ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Mediterranean Diet ◽

Intestinal Permeability ◽

Fatty Liver Disease ◽

Low Fat ◽

Alcoholic Fatty Liver ◽

Low Fat Diet ◽

Alcoholic Fatty Liver Disease

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Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity

Digestive and Liver Disease ◽

10.1016/j.dld.2014.02.010 ◽

2014 ◽

Vol 46 (6) ◽

pp. 556-560 ◽

Cited By ~ 86

Author(s):

Valentina Giorgio ◽

Luca Miele ◽

Luigi Principessa ◽

Francesca Ferretti ◽

Maria Pia Villa ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Disease Severity ◽

Intestinal Permeability ◽

Fatty Liver Disease ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics

International Journal of Molecular Sciences ◽

10.3390/ijms22158008 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8008

Author(s):

Mayumi Nagashimada ◽

Masao Honda

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Intestinal Permeability ◽

Kupffer Cells ◽

Fatty Liver Disease ◽

Low Grade ◽

Alcoholic Fatty Liver ◽

The Impact ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut–liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.

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Non-Alcoholic Fatty Liver Disease in Overweight Children: Role of Fructose Intake and Dietary Pattern

Nutrients ◽

10.3390/nu10091329 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1329 ◽

Cited By ~ 12

Author(s):

Anika Nier ◽

Annette Brandt ◽

Ina Conzelmann ◽

Yelda Özel ◽

Ina Bergheim

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Intestinal Permeability ◽

Dietary Pattern ◽

Fatty Liver Disease ◽

Overweight Children ◽

Alcoholic Fatty Liver ◽

Fructose Intake ◽

Alcoholic Fatty Liver Disease

The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In addition, in a feasibility study, we assessed the effect of a moderate dietary intervention only focusing on nutrients identified to differ between groups on markers of intestinal barrier function and health status. Anthropometric data, dietary intake, metabolic parameters, and markers of inflammation, as well as of intestinal permeability, were assessed in overweight children (n = 89, aged 5–9) and normal-weight healthy controls (n = 36, aged 5–9). Sixteen children suffered from early signs of NAFLD, e.g., steatosis grade 1 as determined by ultrasound. Twelve children showing early signs of NAFLD were enrolled in the intervention study (n = 6 intervention, n = 6 control). Body mass index (BMI), BMI standard deviation score (BMI-SDS), and waist circumference were significantly higher in NAFLD children than in overweight children without NAFLD. Levels of bacterial endotoxin, lipopolysaccharide-binding protein (LBP), and proinflammatory markers like interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were also significantly higher in overweight children with NAFLD compared to those without. Total energy and carbohydrate intake were higher in NAFLD children than in those without. The higher carbohydrate intake mainly resulted from a higher total fructose and glucose intake derived from a significantly higher consumption of sugar-sweetened beverages. When counseling children with NAFLD regarding fructose intake (four times, 30–60 min within 1 year; one one-on-one counseling and three group counselings), neither alanine aminotransferase (ALT) nor aspartate aminotransferase (AST) activity in serum changed; however, diastolic blood pressure (p < 0.05) and bacterial endotoxin levels (p = 0.06) decreased markedly in the intervention group after one year. Similar changes were not found in uncounseled children. Our results suggest that a sugar-rich diet might contribute to the development of early stages of NAFLD in overweight children, and that moderate dietary counseling might improve the metabolic status of overweight children with NAFLD.

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