title: Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. patrice.cani@uclouvain.be
authors.forename: P D
authors.initials: PD
authors.lastname: Cani
authors.forename: S
authors.initials: S
authors.lastname: Possemiers
authors.forename: T
authors.initials: T
authors.lastname: Van de Wiele
authors.forename: Y
authors.initials: Y
authors.lastname: Guiot
authors.forename: A
authors.initials: A
authors.lastname: Everard
authors.forename: O
authors.initials: O
authors.lastname: Rottier
authors.forename: L
authors.initials: L
authors.lastname: Geurts
authors.forename: D
authors.initials: D
authors.lastname: Naslain
authors.forename: A
authors.initials: A
authors.lastname: Neyrinck
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: G G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: N M
authors.initials: NM
authors.lastname: Delzenne
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001419:Bacteria / Q000302:isolation & purification; D002432:Cecum / Q000382:microbiology* / Q000503:physiopathology; D019446:Endotoxemia / Q000209:etiology / Q000517:prevention & control; D053767:Glucagon-Like Peptide 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D006505:Hepatitis / Q000209:etiology / Q000517:prevention & control; D007249:Inflammation / Q000209:etiology / Q000382:microbiology / Q000517:prevention & control*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications* / Q000382:microbiology / Q000503:physiopathology; D062793:Occludin; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D019936:Probiotics / Q000627:therapeutic use*; D052336:Proglucagon / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D053767:Glucagon-Like Peptide 2; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D052336:Proglucagon