Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis

Brun, Paola; Castagliuolo, Ignazio; Leo, Vincenza Di; Buda, Andrea; Pinzani, Massimo; Palù, Giorgio; Martines, Diego

doi:10.1152/ajpgi.00024.2006

Cited by 735 publications

(679 citation statements)

References 58 publications

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“…In addition, genetically obese fa/fa rats and ob/ob mice quickly develop steatohepatitis after exposure to low doses of LPS (41). This is in agreement with a two-to four-times-increased endotoxemia characterizing db/db and ob/ob mice due to an increased intestinal permeability (42). Furthermore, polymyxin B treatment, which specifically eliminates Gram-negative bacterias and further quenches LPS, diminishes hepatic steatosis (43).…”

Section: Discussionsupporting

confidence: 69%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

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Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPScontaining microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. Diabetes 56: [1761][1762][1763][1764][1765][1766][1767][1768][1769][1770][1771][1772] 2007 T he outbreak of a fat-enriched diet in Western countries is becoming a problem of the utmost importance. Obesity is the result of a complex interaction between genetic and environmental factors. Among the latter, changes in eating habits to increase fat intake are involved in the increased occurrence of metabolic diseases, such as obesity and diabetes, which are bearing features of the metabolic syndrome. The major metabolic consequence of a high-fat diet is that insulin action and the regulatory mechanisms of body weight are impaired through a well-described lipotoxic effect (1). In addition, it has been recently determined that obesity and insulin resistance are associated with lowgrade chronic systemic inflammation (2). In models of diet-induced and genetic obesity, the adipose tissue presents increased expression and content of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣ (3,4), interleukin (IL)-1 (3,4), and IL-6 (4). This cytokine production is then deleterious for muscle insulin action; for example, TNF-␣ has been shown to cause insulin resistance by increasing serine phosphorylation on insulin receptor substrate-1 (5), leading to its inactivation. The consequent insulin resistance will favor hyperinsulinemia and excessive hepatic and adipose tissue lipid storage. However, while extensive research is dedicated to the effects of an in...

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Section: Discussionsupporting

confidence: 69%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

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“…have recently demonstrated that obese and diabetic mice (ob/ob and db/db) exhibited significantly higher plasma endotoxin levels, which correlated to higher plasma inflammatory markers [30]. Multiple Pearson's correlations analysis of our data revealed that endotoxaemia positively correlated with glucose intolerance, fasted insulinaemia, inflammatory markers, adipose tissue and body weight gain, while bifidobacteria negatively correlated with these parameters.…”

Section: Discussionsupporting

confidence: 52%

“…Glucose tolerance test Oral glucose tolerance tests were performed after 13 weeks of treatment in mice that had been fasted for 6 h. Glucose was orally administered (3 g/kg body weight, 660 g/l glucose solution) and blood glucose determined through a glucose meter (Roche Diagnostics, Meylan, France) using 3.5 μl of blood collected from the tip of the tail vein before and at administration of glucose load (−30 and 0 min) and after glucose load (15,30,60, 90, 120 min). To assess plasma insulin concentration, 20 μl of blood was sampled 30 min before and 15 min following the glucose load.…”

Section: Methodsmentioning

confidence: 99%

Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia

et al. 2007

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Aims/hypothesis Recent evidence suggests that a particular gut microbial community may favour occurrence of the metabolic diseases. Recently, we reported that high-fat (HF) feeding was associated with higher endotoxaemia and lower Bifidobacterium species (spp.) caecal content in mice. We therefore tested whether restoration of the quantity of caecal Bifidobacterium spp. could modulate metabolic endotoxaemia, the inflammatory tone and the development of diabetes. Methods Since bifidobacteria have been reported to reduce intestinal endotoxin levels and improve mucosal barrier function, we specifically increased the gut bifidobacterial content of HF-diet-fed mice through the use of a prebiotic (oligofructose [OFS]). Results Compared with normal chow-fed control mice, HF feeding significantly reduced intestinal Gram-negative and Gram-positive bacteria including levels of bifidobacteria, a dominant member of the intestinal microbiota, which is seen as physiologically positive. As expected, HF-OFS-fed mice had totally restored quantities of bifidobacteria. HFfeeding significantly increased endotoxaemia, which was normalised to control levels in HF-OFS-treated mice. Multiple-correlation analyses showed that endotoxaemia significantly and negatively correlated with Bifidobacterium spp., but no relationship was seen between endotoxaemia and any other bacterial group. Finally, in HF-OFS-treated-mice, Bifidobacterium spp. significantly and positively correlated with improved glucose tolerance, glucose-induced insulin secretion and normalised inflammatory tone (decreased endotoxaemia, plasma and adipose tissue proinflammatory cytokines). Conclusions/interpretation Together, these findings suggest that the gut microbiota contribute towards the pathophysiological regulation of endotoxaemia and set the tone of inflammation for occurrence of diabetes and/or obesity. Thus, it would be useful to develop specific strategies for modifying gut microbiota in favour of bifidobacteria to prevent the deleterious effect of HF-diet-induced metabolic diseases.

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“…21,22 However, the exact mechanisms involved in sugar and particularly fructose-induced NAFLD are still poorly understood. Here, by feeding mice lacking the endotoxin receptor TLR-4 chronically with a moderate fructose-enhanced diet (e.g., 30% fructose in drinking solutions) we further tested the hypothesis that the endotoxin-induced activation of hepatic Kupffer cells resulting from intestinal bacterial overgrowth and increased intestinal permeability 13,14 is a key factor in the onset of fructose-induced NAFLD. Indeed, despite similarly elevated plasma endotoxin levels in portal plasma, hepatic steatosis in livers of TLR-4 mutant mice fed with fructose solution, and plasma ALT levels were markedly lower than in wildtype controls exposed to fructose.…”

Section: Discussionmentioning

confidence: 99%

“…10 In support of these findings, Baraona et al 12 reported that the bacterial flora of rodents can ferment carbohydrates to alcohol when intestinal stasis allows their overgrowth in the upper parts of the gastrointestinal tract. Furthermore, an increased mucosal permeability in the small intestine, which was found in genetically obese mice 13 and after high-fat feeding in mice, 14 leads to portal endotoxemia. Gut-derived bacterial endotoxin is brought to the liver in the portal circulation, thereby activating Kupffer cells, the resident hepatic macrophages by way of the Toll-like receptor 4 (TLR-4) complex on the cell surface.…”

mentioning

confidence: 98%

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

et al. 2009

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A link between dietary fructose intake, gut-derived endotoxemia, and nonalcoholic fatty liver disease (NAFLD) has been suggested by the results of human and animal studies. To further investigate the role of gut-derived endotoxin in the onset of fructose-induced NAFLD, Toll-like receptor (TLR-) 4-mutant (C3H/HeJ) mice and wildtype (C3H/HouJ) mice were either fed plain water or water enriched with 30% fructose for 8 weeks. Hepatic steatosis, plasma alanine aminotransferase (ALT), and markers of insulin resistance as well as portal endotoxin levels were determined. Hepatic levels of myeloid differentiation factor 88 (MyD88), interferon regulatory factor (IRF) 3 and 7, and tumor necrosis factor alpha (TNF␣) as well as markers of lipid peroxidation were assessed. Chronic intake of 30% fructose solution caused a significant increase in hepatic steatosis and plasma ALT levels in wildtype animals in comparison to water controls. In fructose-fed TLR-4 mutant mice, hepatic triglyceride accumulation was significantly reduced by Ϸ40% in comparison to fructose-fed wildtype mice and plasma ALT levels were at the level of water-fed controls. No difference in portal endotoxin concentration between fructose-fed wildtype and TLR-4-mutant animals was detected. In contrast, hepatic lipid peroxidation, MyD88, and TNF␣ levels were significantly decreased in fructose-fed TLR-4-mutant mice in comparison to fructose-fed wildtype mice, whereas IRF3 and IRF7 expression remained unchanged. Markers of insulin resistance (e.g., plasma TNF␣, retinol binding protein 4, and hepatic phospho-AKT) were only altered in fructose-fed wildtype animals. Conclusion: Taken together, these data further support the hypothesis that in mice the onset of fructose-induced NAFLD is associated with intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to an endotoxin-dependent activation of hepatic Kupffer cells.

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Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis

Cited by 735 publications

References 58 publications

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia

Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†

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