1. Gut. 2009 Aug;58(8):1091-103. Epub 2009 Feb 24.

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

Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L,
Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM.

Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Louvain Drug
Research Institute, Université catholique de Louvain, Brussels, Belgium.
patrice.cani@uclouvain.be

Comment in:
    Gut. 2009 Aug;58(8):1044-5.

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.

PMCID: 2702831
PMID: 19240062 [PubMed - indexed for MEDLINE]