title: Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits.
abstract: Soluble dietary fibers promote metabolic benefits on body weight and glucose control, but underlying mechanisms are poorly understood. Recent evidence indicates that intestinal gluconeogenesis (IGN) has beneficial effects on glucose and energy homeostasis. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate, which are generated by fermentation of soluble fiber by the gut microbiota, activate IGN via complementary mechanisms. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit involving the fatty acid receptor FFAR3. The metabolic benefits on body weight and glucose control induced by SCFAs or dietary fiber in normal mice are absent in mice deficient for IGN, despite similar modifications in gut microbiota composition. Thus, the regulation of IGN is necessary for the metabolic benefits associated with SCFAs and soluble fiber.
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
authors.forename: Filipe
authors.initials: F
authors.lastname: De Vadder
authors.affiliation: Wallenberg Laboratory and Department of Molecular and Clinical Medicine, University of Gothenburg 41345, Sweden.
authors.forename: Petia
authors.initials: P
authors.lastname: Kovatcheva-Datchary
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
authors.forename: Daisy
authors.initials: D
authors.lastname: Goncalves
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vinera
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Zitoun
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Duchampt
authors.affiliation: Wallenberg Laboratory and Department of Molecular and Clinical Medicine, University of Gothenburg 41345, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Institut de la Santé et de la Recherche Médicale, U855, Lyon 69372, France; Université de Lyon, Lyon 69008, France; Université Lyon 1, Villeurbanne 69622, France. Electronic address: gilles.mithieux@inserm.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Mithieux
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004043:Dietary Fiber / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000294:innervation*; D051379:Mice; D064307:Microbiota; D009765:Obesity / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism; D051381:Rats
chemical_list: D004041:Dietary Fats; D004043:Dietary Fiber; D005232:Fatty Acids, Volatile; D009844:Oligosaccharides; C116580:fructooligosaccharide; D005952:Glucose-6-Phosphatase; D005947:Glucose