title: Intestinal Dysbiosis, Barrier Dysfunction, and Bacterial Translocation Account for CKD-Related Systemic Inflammation.
abstract: CKD associates with systemic inflammation, but the underlying cause is unknown. Here, we investigated the involvement of intestinal microbiota. We report that collagen type 4 α3-deficient mice with Alport syndrome-related progressive CKD displayed systemic inflammation, including increased plasma levels of pentraxin-2 and activated antigen-presenting cells, CD4 and CD8 T cells, and Th17- or IFNγ-producing T cells in the spleen as well as regulatory T cell suppression. CKD-related systemic inflammation in these mice associated with intestinal dysbiosis of proteobacterial blooms, translocation of living bacteria across the intestinal barrier into the liver, and increased serum levels of bacterial endotoxin. Uremia did not affect secretory IgA release into the ileum lumen or mucosal leukocyte subsets. To test for causation between dysbiosis and systemic inflammation in CKD, we eradicated facultative anaerobic microbiota with antibiotics. This eradication prevented bacterial translocation, significantly reduced serum endotoxin levels, and fully reversed all markers of systemic inflammation to the level of nonuremic controls. Therefore, we conclude that uremia associates with intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation, which trigger the state of persistent systemic inflammation in CKD. Uremic dysbiosis and intestinal barrier dysfunction may be novel therapeutic targets for intervention to suppress CKD-related systemic inflammation and its consequences.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Andersen
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Marie Sophie
authors.initials: MS
authors.lastname: Kesper
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Marschner
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Lukas
authors.initials: L
authors.lastname: Konrad
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Mi
authors.initials: M
authors.lastname: Ryu
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Kumar Vr
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Shrikant R
authors.initials: SR
authors.lastname: Mulay
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and.
authors.forename: Simone
authors.initials: S
authors.lastname: Romoli
authors.affiliation: Walther Straub Institut für Pharmakologie und Toxikologie and.
authors.forename: Jana
authors.initials: J
authors.lastname: Demleitner
authors.affiliation: Max von Pettenkofer Institut, Universität München, Munich, Germany.|German Center for Infection Research, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schiller
authors.affiliation: Walther Straub Institut für Pharmakologie und Toxikologie and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Pathologisches Institut, Ludwig Maximilians Universität, Munich, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Müller
authors.affiliation: Clinic of Nephrology and Rheumatology, University Medical Centre Göttingen, Göttingen, Germany; and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
authors.affiliation: Centre for Bioinformatics, Tübingen University, Tübingen, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Ruscheweyh
authors.affiliation: Centre for Bioinformatics, Tübingen University, Tübingen, Germany.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Huson
authors.affiliation: Max von Pettenkofer Institut, Universität München, Munich, Germany.|German Center for Infection Research, Ludwig Maximilians University Munich, Munich, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Stecher
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität and hjanders@med.uni-muenchen.de.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D064806:Dysbiosis; D007249:Inflammation / Q000209:etiology* / Q000382:microbiology*; D007422:Intestines / Q000382:microbiology*; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000150:complications*
keywords: chronic kidney disease; inflammation; microbiota