The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.
A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver's own arterial supply. Damage to the liver firewall in mice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits.
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Maria L
ML
Balmer
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Emma
E
Slack
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Andrea
A
de Gottardi
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Melissa A E
MA
Lawson
Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 51, CH-3010 Bern, Switzerland.
Siegfried
S
Hapfelmeier
Institute of Internal Medicine, Catholic University of Rome, Largo Agostino Gemelli 8, 00168 Rome, Italy.
Luca
L
Miele
Institute of Internal Medicine, Catholic University of Rome, Largo Agostino Gemelli 8, 00168 Rome, Italy.
Antonio
A
Grieco
Department of Hepatology and Gastroenterology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
Hans
H
Van Vlierberghe
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
René
R
Fahrner
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Nicola
N
Patuto
Division of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Christine
C
Bernsmeier
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Francesca
F
Ronchi
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Madeleine
M
Wyss
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Deborah
D
Stroka
Institute of Pathology, University Bern, Murtenstrasse 31, Postfach 62, CH-3010 Bern, Switzerland.
Nina
N
Dickgreber
Division of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Markus H
MH
Heim
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
Kathy D
KD
McCoy
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland. andrew.macpherson@insel.ch.
Andrew J
AJ
Macpherson
D000328:Adult; D000368:Aged; D000818:Animals; D058491:Bacterial Load; D018988:Bacterial Translocation; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D005243:Feces / Q000382:microbiology; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007422:Intestines / Q000098:blood supply* / Q000276:immunology / Q000382:microbiology*; D007728:Kupffer Cells / Q000382:microbiology; D008099:Liver / Q000098:blood supply* / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D008102:Liver Circulation; D008107:Liver Diseases / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D012189:Retrospective Studies; D013997:Time Factors