Antibiotic pretreatment alleviates liver transplant damage in mice and humans.

Adult Animals Anti-Bacterial Agents / pharmacology Endoplasmic Reticulum Stress / drug effects Female Hepatocytes / metabolism Humans Liver / metabolism Liver Transplantation Male Mice Mice, Inbred BALB C Reperfusion Injury / drug therapy
Immunology Innate immunity Organ transplantation Transplantation

Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
22 07 2019
Historique:
received: 19 01 2019
accepted: 21 05 2019
entrez: 23 7 2019
pubmed: 23 7 2019
medline: 27 5 2020
Statut: epublish

Résumé

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified "Abx-free/Abx <10 days" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.

Identifiants

DOI: 10.1172/JCI127550 PMID: 31329160 PMC: PMC6668671
pubmed: 31329160
pii: 127550
doi: 10.1172/JCI127550
pmc: PMC6668671
doi:
pii:

Substances chimiques

Anti-Bacterial Agents 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3420-3434

Subventions

Organisme : NIAID NIH HHS
ID : P01 AI120944
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062357
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn

Références

Essays Biochem. 2017 Dec 12;61(6):565-584
pubmed: 29233869
Digestion. 2006;73 Suppl 1:13-27
pubmed: 16498249
Infect Immun. 2002 Jan;70(1):400-2
pubmed: 11748207
Hepatology. 2008 May;47(5):1725-36
pubmed: 18311843
Transplantation. 2019 Apr;103(4):668-678
pubmed: 30507741
Nat Rev Mol Cell Biol. 2005 Jun;6(6):505-10
pubmed: 15928714
Nat Rev Gastroenterol Hepatol. 2013 Feb;10(2):79-89
pubmed: 23229329
Mol Cell Biol. 2005 Nov;25(21):9554-75
pubmed: 16227605
Am J Physiol Gastrointest Liver Physiol. 2008 Feb;294(2):G498-505
pubmed: 18174271
Hepatology. 2018 Jul;68(1):258-273
pubmed: 29350771
Diabetes. 2008 Jun;57(6):1470-81
pubmed: 18305141
Transplant Proc. 1989 Oct;21(5):3833-41
pubmed: 2510378
Am J Transplant. 2018 May;18(5):1110-1121
pubmed: 29136322
Microbiome. 2018 May 25;6(1):96
pubmed: 29793539
Am J Physiol Renal Physiol. 2009 Nov;297(5):F1457-65
pubmed: 19675178
Gastroenterology. 1981 Aug;81(2):211-7
pubmed: 7239130
J Chemother. 2008 Apr;20(2):186-94
pubmed: 18467244
J Clin Invest. 2016 Dec 1;126(12):4430-4443
pubmed: 27775551
Hepatology. 2005 Sep;42(3):608-17
pubmed: 16108069
Curr Opin Gastroenterol. 2017 May;33(3):128-133
pubmed: 28257306
Liver Transpl. 2015 Jul;21(7):873-80
pubmed: 25902933
Liver Transpl. 2017 Oct;23(10):1282-1293
pubmed: 28719070
Gastroenterology. 2015 Feb;148(2):307-23
pubmed: 25224524
Gastroenterology. 2011 Dec;141(6):2188-2199.e6
pubmed: 21854730
JCI Insight. 2018 Oct 4;3(19):
pubmed: 30282817
Liver Transpl. 2018 May;24(5):645-654
pubmed: 29524333
J Hepatol. 2017 Dec;67(6):1232-1242
pubmed: 28842295
J Clin Invest. 2016 Jul 1;126(7):2736-44
pubmed: 27322054
Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):434-9
pubmed: 26712011
Transplantation. 2014 Oct 27;98(8):844-52
pubmed: 25321166
Biochem Biophys Res Commun. 2018 Mar 4;497(2):564-570
pubmed: 29448096
Hepatology. 2011 May;53(5):1752-63
pubmed: 21384408
Autophagy. 2013 Aug;9(8):1131-58
pubmed: 23774882
Curr Opin Organ Transplant. 2017 Aug;22(4):356-363
pubmed: 28548995
Cell. 2016 Dec 1;167(6):1469-1480.e12
pubmed: 27912057
Am J Physiol Cell Physiol. 2015 Nov 15;309(10):C639-49
pubmed: 26310818
N Engl J Med. 1991 Feb 14;324(7):429-36
pubmed: 1988827
PLoS One. 2017 Aug 25;12(8):e0183680
pubmed: 28841673
Transplantation. 1993 Jun;55(6):1265-72
pubmed: 7685932
Am J Respir Crit Care Med. 2016 Jan 15;193(2):186-97
pubmed: 26417909
Cell Host Microbe. 2014 Jan 15;15(1):95-102
pubmed: 24439901
Transplant Direct. 2017 Mar 10;3(4):e144
pubmed: 28405600
Gut. 2009 Aug;58(8):1091-103
pubmed: 19240062
Gastroenterology. 2014 May;146(6):1489-99
pubmed: 24560869
Br J Surg. 2017 Jan;104(2):e172-e181
pubmed: 28121031
J Immunol. 2013 Jan 15;190(2):565-77
pubmed: 23241891
Transplantation. 2016 Feb;100(2):365-72
pubmed: 26683513
N Engl J Med. 2010 Mar 25;362(12):1071-81
pubmed: 20335583
Am J Pathol. 2013 Jan;182(1):180-91
pubmed: 23159949
Am J Transplant. 2004 Oct;4(10):1567-73
pubmed: 15367211
EMBO Mol Med. 2019 Feb;11(2):
pubmed: 30591521
Mol Med Rep. 2016 Apr;13(4):3363-9
pubmed: 26935864
Liver Transpl. 2010 Feb;16(2):222-8
pubmed: 20104499
J Clin Invest. 2014 Oct;124(10):4204-11
pubmed: 25271725
Cell. 2006 Feb 24;124(4):837-48
pubmed: 16497592
Clin Transplant. 2012 Nov-Dec;26(6):849-52
pubmed: 22432742
Nat Commun. 2014 Nov 10;5:5416
pubmed: 25382660
Arthritis Res Ther. 2009;11(2):R48
pubmed: 19327173
Physiol Rev. 1999 Oct;79(4):1193-226
pubmed: 10508233
Transplantation. 2015 Jan;99(1):48-55
pubmed: 25340604
Am J Transplant. 2013 Apr;13(4):829
pubmed: 23551627
Transplantation. 2012 Aug 15;94(3):211-7
pubmed: 22790388
Am J Transplant. 2018 Jul;18(7):1755-1763
pubmed: 29464890
J Gastroenterol Hepatol. 2014 May;29(5):1109-18
pubmed: 24329600
Hepatology. 1998 Jan;27(1):123-7
pubmed: 9425927
Mucosal Immunol. 2018 Mar;11(2):319-332
pubmed: 28589946
Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):3844-9
pubmed: 27001836
J Immunol. 1998 Sep 15;161(6):3019-25
pubmed: 9743366
FASEB J. 2014 Jan;28(1):56-66
pubmed: 24072780
Science. 2014 Jul 4;345(6192):98-101
pubmed: 24994655
Liver Transpl. 2014 May;20(5):544-51
pubmed: 24493238

Auteurs

Kojiro Nakamura (K)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Shoichi Kageyama (S)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Takahiro Ito (T)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Hirofumi Hirao (H)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Kentaro Kadono (K)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Antony Aziz (A)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Kenneth J Dery (KJ)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Matthew J Everly (MJ)

Terasaki Research Institute, Los Angeles, California, USA.

Kojiro Taura (K)

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Shinji Uemoto (S)

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Douglas G Farmer (DG)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Fady M Kaldas (FM)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Ronald W Busuttil (RW)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Jerzy W Kupiec-Weglinski (JW)

Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

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Classifications MeSH

Recherchemedicale.com › Personnes › Tranches d'âge › Adulte › Antibiotic pretreatment alleviates liver...
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Recherchemedicale.com › Phénomènes physiologiques cellulaires › Stress du réticulum endoplasmique › Antibiotic pretreatment alleviates liver...
Recherchemedicale.com › Cellules › Cellules épithéliales › Hépatocytes › Antibiotic pretreatment alleviates liver...
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