title: High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine.
abstract: Diet is among the most important factors contributing to intestinal homeostasis, and basic functions performed by the small intestine need to be tightly preserved to maintain health. Little is known about the direct impact of high-fat (HF) diet on small-intestinal mucosal defenses and spatial distribution of the microbiota during the early phase of its administration. We observed that only 30 d after HF diet initiation, the intervillous zone of the ileum-which is usually described as free of bacteria-became occupied by a dense microbiota. In addition to affecting its spatial distribution, HF diet also drastically affected microbiota composition with a profile characterized by the expansion of Firmicutes (appearance of Erysipelotrichi), Proteobacteria (Desulfovibrionales) and Verrucomicrobia, and decrease of Bacteroidetes (family S24-7) and Candidatus arthromitus A decrease in antimicrobial peptide expression was predominantly observed in the ileum where bacterial density appeared highest. In addition, HF diet increased intestinal permeability and decreased cystic fibrosis transmembrane conductance regulator (Cftr) and the Na-K-2Cl cotransporter 1 (Nkcc1) gene and protein expressions, leading to a decrease in ileal secretion of chloride, likely responsible for massive alteration in mucus phenotype. This complex phenotype triggered by HF diet at the interface between the microbiota and the mucosal surface was reversed when the diet was switched back to standard composition or when mice were treated for 1 wk with rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ). Moreover, weaker expression of antimicrobial peptide-encoding genes and intervillous bacterial colonization were observed in Ppar-γ-deficient mice, highlighting the major role of lipids in modulation of mucosal immune defenses.
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France; Institut National de la Recherche Agronomique, UMR 1319 MICALIS, F-78350 Jouy-en-Josas, France; AgroParisTech, UMR 1319 MICALIS, F-78350 Jouy-en-Josas, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Tomas
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Mulet
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Saffarian
authors.affiliation: INSERM UMRS 1149, Centre de Recherche sur l'inflammation, Unité de Formation et de Recherche de Medecine Paris Diderot, F-75018 Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cavin
authors.affiliation: INSERM UMRS 1149, Centre de Recherche sur l'inflammation, Unité de Formation et de Recherche de Medecine Paris Diderot, F-75018 Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ducroc
authors.affiliation: Plate-forme de Génotypage des Eucaryotes, Biomics Pole, Centre d'Innovation et Recherche Technologique, Institut Pasteur, Paris F-75015, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Regnault
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Chek
authors.initials: C
authors.lastname: Kun Tan
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Kalina
authors.initials: K
authors.lastname: Duszka
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048 F-31432 Toulouse, France; Université Paul Sabatier, F-31432 Toulouse, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France; Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75005 Paris, France philippe.sansonetti@pasteur.fr.
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pédron
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002432:Cecum / Q000382:microbiology; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D059305:Diet, High-Fat; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects / Q000382:microbiology* / Q000502:physiology*; D061346:Laser Capture Microdissection; D008297:Male; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D023181:Antimicrobial Cationic Peptides; D002712:Chlorides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; PPAR-γ; antimicrobial peptides; high-fat diet; microbiota