title: Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats.
abstract: Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease. This study aimed to evaluate whether experimental depression presents with bacterial translocation that in turn can lead to the TLR-4 in the brain affecting the mitogen-activated protein kinases (MAPK) and antioxidant pathways. Male Wistar rats were exposed to chronic mild stress (CMS) and the intestinal integrity, presence of bacteria in tissues and plasma lipopolysaccharide levels were analyzed. We also studied the expression in the prefrontal cortex of activated forms of MAPK and some of their activation controllers and the effects of CMS on the antioxidant Nrf2 pathway. Our results indicate that after exposure to a CMS protocol there is increased intestinal permeability and bacterial translocation. CMS also increases the expression of the activated form of the MAPK p38 while decreasing the expression of the antioxidant transcription factor Nrf2. The actions of antibiotic administration to prevent bacterial translocation on elements of the MAPK and Nrf2 pathways indicate that the translocated bacteria are playing a role in these effects. In effect, our results propose a role of the translocated bacteria in the pathophysiology of depression through the p38 MAPK pathway which could aggravate the neuroinflammation and the oxidative/nitrosative damage present in this pathology. Moreover, our results reveal that the antioxidant factor Nrf2 and its activators may be involved in the consequences of the CMS on the brain.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-Hernández
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain; Department of Psychiatry, School of Medicine, Universidad Complutense de Madrid, Avda. Complutense, 28040 Madrid, Spain. Electronic address: jrcaso@med.ucm.es.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Álvaro G
authors.initials: ÁG
authors.lastname: Bris
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Maus
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: José L M
authors.initials: JL
authors.lastname: Madrigal
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Karina S
authors.initials: KS
authors.lastname: MacDowell
authors.affiliation: Department of Medicine - Microbiology, School of Medicine, Universidad Complutense de Madrid, Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.affiliation: Department of Medicine - Microbiology, School of Medicine, Universidad Complutense de Madrid, Avda. Complutense, 28040 Madrid, Spain.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Gómez-Lus
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense, 28040 Madrid, Spain. Electronic address: jcleza@med.ucm.es.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D018988:Bacterial Translocation / Q000187:drug effects; D003866:Depressive Disorder / Q000378:metabolism* / Q000382:microbiology*; D004660:Encephalitis / Q000378:metabolism* / Q000382:microbiology*; D008070:Lipopolysaccharides / Q000097:blood; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D064307:Microbiota; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological; D062725:Tight Junction Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D062725:Tight Junction Proteins; C569044:Tjp1 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D062826:Zonula Occludens-1 Protein; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Bacterial translocation; DUSPs; Depression; Mitogen-activated protein kinases; Oxidative damage; Transcription factor Nrf2