title: Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication.
abstract: Emerging evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Germ-free mice and antibiotic-induced gut dysbiosis are two approaches to establish causality in gut microbiota-brain relationships. However, both models have limitations, as germ-free mice display alterations in blood-brain barrier and brain ultrastructure and antibiotics may act directly on the brain. We hypothesized that the concerns related to antibiotic-induced gut dysbiosis can only adequately be addressed if the effect of intragastric treatment of adult mice with multiple antibiotics on (i) gut microbial community, (ii) metabolite profile in the colon, (iii) circulating metabolites, (iv) expression of neuronal signaling molecules in distinct brain areas and (v) cognitive behavior is systematically investigated. Of the antibiotics used (ampicillin, bacitracin, meropenem, neomycin, vancomycin), ampicillin had some oral bioavailability but did not enter the brain. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics revealed that gut dysbiosis was associated with depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Importantly, novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive deficit was associated with brain region-specific changes in the expression of cognition-relevant signaling molecules, notably brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. We conclude that circulating metabolites and the cerebral neuropeptide Y system play an important role in the cognitive impairment and dysregulation of cerebral signaling molecules due to antibiotic-induced gut dysbiosis.
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria. Electronic address: esther.froehlich@medunigraz.at.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Fröhlich
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Aitak
authors.initials: A
authors.lastname: Farzi
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Mayerhofer
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Reichmann
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Jačan
authors.affiliation: Institute of Biomedical Science, FH JOANNEUM University of Applied Sciences, Eggenberger Allee 13, 8020 Graz, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Institute of Biomedical Science, FH JOANNEUM University of Applied Sciences, Eggenberger Allee 13, 8020 Graz, Austria.
authors.forename: Erwin
authors.initials: E
authors.lastname: Zinser
authors.affiliation: Center for Biomarker Research in Medicine, CBmed GmbH, Stiftingtalstrasse 5, 8010 Graz, Austria.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bordag
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: Core Facility Microscopy, Center for Medical Research, Medical University of Graz, Stiftingtalstrasse 24/1, 8010 Graz, Austria.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria; Theodor Escherich Laboratory for Medical Microbiome Research, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria; BioTechMed-Graz, Krenngasse 37/1, 8010 Graz, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Gorkiewicz
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria. Electronic address: peter.holzer@medunigraz.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001921:Brain / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D003106:Colon / Q000378:metabolism*; D004195:Disease Models, Animal; D064806:Dysbiosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D021641:Recognition, Psychology; D065852:Spatial Memory
chemical_list: D000900:Anti-Bacterial Agents
keywords: Antibiotic; Brain; Cognition; Dysbiosis; GRIN2B; Gut; Metabolome; Microbiome; Neuropeptide Y; Serotonin transporter