title: Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status.
abstract: 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.
authors.affiliation: 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.
authors.forename: Amandine
authors.initials: A
authors.lastname: Everard
authors.affiliation: 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Geurts
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Caesar
authors.affiliation: 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.
authors.forename: Matthias
authors.initials: M
authors.lastname: Van Hul
authors.affiliation: 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.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Matamoros
authors.affiliation: 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.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRS, F-75205 Paris, France.
authors.forename: Raphael G P
authors.initials: RG
authors.lastname: Denis
authors.affiliation: Université Catholique de Louvain, Ludwig Institute for Cancer Research, Experimental Medicine Unit, B-1200 Brussels, Belgium.
authors.forename: Perrine
authors.initials: P
authors.lastname: Cochez
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Pierard
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRS, F-75205 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Castel
authors.affiliation: 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.
authors.forename: Laure B
authors.initials: LB
authors.lastname: Bindels
authors.affiliation: 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.
authors.forename: Hubert
authors.initials: H
authors.lastname: Plovier
authors.affiliation: Institut Curie, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 144, F-75005 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.affiliation: Université Catholique de Louvain, Louvain Drug Research Institute, Bioanalysis and Pharmacology of Bioactive Lipids Research Group, B-1200 Brussels, Belgium.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: Université Catholique de Louvain, Ludwig Institute for Cancer Research, Experimental Medicine Unit, B-1200 Brussels, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: Université Catholique de Louvain, Ludwig Institute for Cancer Research, Experimental Medicine Unit, B-1200 Brussels, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Dumoutier
authors.affiliation: 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.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, BFA, UMR8251, CNRS, F-75205 Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
authors.affiliation: 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.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: 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.
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009752:Nutritional Status; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D005947:Glucose