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  • Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability

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Inflammatory bowel disease
1506
Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability
  1. P D Cani1,
  2. S Possemiers2,
  3. T Van de Wiele2,
  4. Y Guiot3,
  5. A Everard1,
  6. O Rottier1,
  7. L Geurts1,
  8. D Naslain1,4,
  9. A Neyrinck1,
  10. D M Lambert4,
  11. G G Muccioli5,
  12. N M Delzenne1
  1. 1
    Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
  2. 2
    Laboratory of Microbial Ecology and Technology, Faculty of Bioscience Engineering, Ghent University, Gent, Belgium
  3. 3
    Department of Pathology, Université catholique de Louvain, Brussels, Belgium
  4. 4
    Medicinal Chemistry and Radiopharmacy Unit, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
  5. 5
    Laboratory of Chemical and Physico-chemical Analysis of Drugs (CHAM), Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
  1. Dr P D Cani, UCL, Unit PMNT-7369, Av E Mounier, 73/69, B-1200 Brussels, Belgium; patrice.cani{at}uclouvain.be; or Professor NM Delzenne, UCL, Unit PMNT-7369, Av R Mounier, 73/69, B-1200 Brussels, Belgium; nathalie.delzenne{at}uclouvain.be

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.

https://doi.org/10.1136/gut.2008.165886

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    Footnotes

    • Competing interests: None.

    • Funding: PDC is Postdoctoral Researcher from the FRS-FNRS (Fonds de la Recherche Scientifique) Belgium. NMD and PDC are recipients of FSR and FRSM subsidies (Fonds speciaux de recherches, UCL, Belgium; Fonds de la recherché scientifique medicale, Belgium). SP and TVDW are Postdoctoral Researchers from the Research Foundation – Flanders (Fonds voor Wetenschappelijk Onderzoek (FWO) – Vlaanderen).

    • See Commentary, p 1044

    • Ethics approval: Animal experiments were approved by the local ethics committee and housing conditions were as specified by the Belgian Law of 14 November 1993 on the protection of laboratory animals (agreement n° LA 1230314).

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