title: Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells.
abstract: The use of short chain fatty acids to modulate gastrointestinal inflammatory conditions such as ulcerative colitis has produced encouraging results either in animal models or also in clinical trials. Identifying the key cellular and molecular targets of this activity will contribute to establish the appropriate combinations/targeting strategies to maximize the efficacy of anti-inflammatory interventions. In the present work, we evaluated in vitro the interaction of lactate, acetate, propionate and butyrate on cells relevant for innate immune response of the gastrointestinal tract. All molecules tested regulate the production of proinflammatory cytokines by TLR-4 and TLR-5 activated intestinal epithelial cells in a dose response manner. Furthermore SCFAs and lactate modulate cytokine secretion of TLR-activated bone marrow derived macrophages and also TLR-dependent CD40 upregulation in bone marrow derived dendritic in a dose-dependent manner. Butyrate and propionate have been effective at concentrations of 1 to 5mM whereas acetate and lactate produced modulatory effects at concentrations higher than 20-50mM in different assays. Our results indicate that in concentrations similar to found in large bowel lumen, all SCFAs tested and lactate can modulate activity of relevant sentinel cell types activated by TLR signals. Modulatory activity was not inhibited by pertussis toxin treatment indicating that the effects are not related to Gi signaling. The use of these molecules in combined or separately as intervention strategy in conditions where epithelial or myeloid cells are main triggers of the inflammatory situation seems appropriate.
authors.affiliation: Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA, UNLP-CONICET), Calle 47 y 116, (1900) La Plata, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Iraporda
authors.affiliation: Instituto de Estudios Inmunológicos y Fisopatológicos (IIFP, UNLP-CONICET), Calle 47 y 115, (1900) La Plata, Argentina.
authors.forename: Agustina
authors.initials: A
authors.lastname: Errea
authors.affiliation: Instituto de Estudios Inmunológicos y Fisopatológicos (IIFP, UNLP-CONICET), Calle 47 y 115, (1900) La Plata, Argentina.
authors.forename: David E
authors.initials: DE
authors.lastname: Romanin
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59000 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59000 Lille, France; Université Lille Nord de France, F-59000 Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Cayet
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME, CONICET), Vuelta de Obligado 2490, CABA (1428), Bs. As., Argentina.
authors.forename: Elba
authors.initials: E
authors.lastname: Pereyra
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME, CONICET), Vuelta de Obligado 2490, CABA (1428), Bs. As., Argentina; Departamento de Química Biológica - Facultad de Ciencias Exactas y Naturales (FCEyN, UBA), Argentina.
authors.forename: Omar
authors.initials: O
authors.lastname: Pignataro
authors.affiliation: Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France; Institut National de la Santé et de la Recherche Médicale, U1019, F-59000 Lille, France; Centre National de la Recherche Scientifique, UMR 8204, F-59000 Lille, France; Université Lille Nord de France, F-59000 Lille, France.
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Sirard
authors.affiliation: Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA, UNLP-CONICET), Calle 47 y 116, (1900) La Plata, Argentina. Electronic address: ggarrote@biol.unlp.edu.ar.
authors.forename: Graciela L
authors.initials: GL
authors.lastname: Garrote
authors.affiliation: Centro de Investigación y Desarrollo en Criotecnología de Alimentos (CIDCA, UNLP-CONICET), Calle 47 y 116, (1900) La Plata, Argentina; Área Bioquímica y Control de Alimentos, Facultad de Ciencias Exactas, UNLP. Calle 47 y 115, (1900) La Plata, Argentina.
authors.forename: Analía G
authors.initials: AG
authors.lastname: Abraham
authors.affiliation: Instituto de Estudios Inmunológicos y Fisopatológicos (IIFP, UNLP-CONICET), Calle 47 y 115, (1900) La Plata, Argentina.
authors.forename: Martín
authors.initials: M
authors.lastname: Rumbo
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D018938:Caco-2 Cells; D015536:Down-Regulation / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D005227:Fatty Acids / Q000276:immunology*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D019344:Lactic Acid / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D005227:Fatty Acids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D019344:Lactic Acid
keywords: Immunomodulation; Inflammation; Innate immunity; Lactate; Short chain fatty acids