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Nat Commun. 2014 Dec 5;5:5648. doi: 10.1038/ncomms6648.

Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status.

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Université Catholique de Louvain, Louvain Drug Research Institute, WELBIO (Walloon Excellence in Life sciences and BIOtechnology), Metabolism and Nutrition Research Group, B-1200 Brussels, Belgium.
1] Wallenberg Laboratory/Sahlgrenska Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg 40530, Sweden [2] Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg 41345, Sweden.
Université Paris Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRS, F-75205 Paris, France.
Université Catholique de Louvain, Ludwig Institute for Cancer Research, Experimental Medicine Unit, B-1200 Brussels, Belgium.
Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144, F-75005 Paris, France.
Université Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, B-1200 Brussels, Belgium.


Obesity is associated with a cluster of metabolic disorders, low-grade inflammation and altered gut microbiota. Whether host metabolism is controlled by intestinal innate immune system and the gut microbiota is unknown. Here we report that inducible intestinal epithelial cell-specific deletion of MyD88 partially protects against diet-induced obesity, diabetes and inflammation. This is associated with increased energy expenditure, an improved glucose homeostasis, reduced hepatic steatosis, fat mass and inflammation. Protection is transferred following gut microbiota transplantation to germ-free recipients. We also demonstrate that intestinal epithelial MyD88 deletion increases anti-inflammatory endocannabinoids, restores antimicrobial peptides production and increases intestinal regulatory T cells during diet-induced obesity. Targeting MyD88 after the onset of obesity reduces fat mass and inflammation. Our work thus identifies intestinal epithelial MyD88 as a sensor changing host metabolism according to the nutritional status and we show that targeting intestinal epithelial MyD88 constitutes a putative therapeutic target for obesity and related disorders.

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