Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability
Top Cited Papers
Open Access
- 24 February 2009
- Vol. 58 (8), 1091-1103
- https://doi.org/10.1136/gut.2008.165886
Abstract
Background and aims: Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Methods: Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Results: Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. Conclusion: We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions during obesity and diabetes.Keywords
This publication has 86 references indexed in Scilit:
- Targeted Ablation of Glucose-dependent Insulinotropic Polypeptide-producing Cells in Transgenic Mice Reduces Obesity and Insulin Resistance Induced by a High Fat DietOnline Journal of Public Health Informatics, 2008
- Diet-Induced Obesity Is Linked to Marked but Reversible Alterations in the Mouse Distal Gut MicrobiomeCell Host & Microbe, 2008
- Lactobacillus rhamnosus Strain GG Prevents Enterohemorrhagic Escherichia coli O157:H7-Induced Changes in Epithelial Barrier FunctionInfection and Immunity, 2008
- Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signalingJCI Insight, 2007
- Mechanisms underlying the resistance to diet-induced obesity in germ-free miceProceedings of the National Academy of Sciences of the United States of America, 2007
- TLR4 links innate immunity and fatty acid–induced insulin resistanceJCI Insight, 2006
- Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytesBiochemical and Biophysical Research Communications, 2006
- Relation between colonic proglucagon expression and metabolic response to oligofructose in high fat diet-fed miceLife Sciences, 2006
- Obesity alters gut microbial ecologyProceedings of the National Academy of Sciences of the United States of America, 2005
- Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndromeAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2005