PMID- 33189892
OWN - NLM
STAT- MEDLINE
DCOM- 20220307
LR  - 20230919
IS  - 2352-345X (Electronic)
IS  - 2352-345X (Linking)
VI  - 11
IP  - 4
DP  - 2021
TI  - Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury.
PG  - 909-933
LID - S2352-345X(20)30181-8 [pii]
LID - 10.1016/j.jcmgh.2020.11.002 [doi]
AB  - BACKGROUND & AIMS: Acute liver failure (ALF) represents an unmet medical need in 
      Western countries. Although the link between intestinal dysbiosis and chronic 
      liver disease is well-established, there is little evidence for a functional role 
      of gut-liver interaction during ALF. Here we hypothesized that intestinal 
      dysbiosis may affect ALF. METHODS: To test this hypothesis, we assessed the 
      association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, 
      which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 
      500,000 participants of the UK BioBank population-based cohort. For functional 
      studies, male Nlrp6(-/-) mice were used as a dysbiotic mouse model and injected 
      with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to 
      induce ALF. RESULTS: Multivariate Cox regression analyses revealed a 
      significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank 
      participants with PPI or ABx. Similarly, dysbiotic Nlrp6(-/-) mice displayed 
      exacerbated APAP- and LPS-induced liver injury, which was linked to significantly 
      reduced gut and liver tissue microbiota diversity and correlated with increased 
      intestinal permeability at baseline. Fecal microbiota transfer (FMT) from 
      Nlrp6(-/-) mice into wild-type (WT) mice augmented liver injury on APAP treatment 
      in recipient WT mice, resembling the inflammatory phenotype of Nlrp6(-/-) mice. 
      Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6C(hi) 
      inflammatory phenotype, suggesting a critical function of these cells as sensors 
      of gut-derived signals orchestrating the inflammatory response. CONCLUSIONS: Our 
      data show an important yet unknown function of intestinal microbiota during ALF. 
      Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated 
      liver injury. Our study highlights intestinal microbiota as a targetable risk 
      factor for ALF.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Schneider, Kai Markus
AU  - Schneider KM
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; 
      Department of Microbiology; Institute for Immunology; and Institute for Diabetes, 
      Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, Pennsylvania.
FAU - Elfers, Carsten
AU  - Elfers C
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Ghallab, Ahmed
AU  - Ghallab A
AD  - Leibniz Research Centre for Working Environment and Human Factors at the 
      Technical University Dortmund, Dortmund, Germany; Department of Forensic Medicine 
      and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, 
      Egypt.
FAU - Schneider, Carolin Victoria
AU  - Schneider CV
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Galvez, Eric J C
AU  - Galvez EJC
AD  - Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover 
      Medical School, Hannover, Germany.
FAU - Mohs, Antje
AU  - Mohs A
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Gui, Wenfang
AU  - Gui W
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Candels, Lena Susanna
AU  - Candels LS
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Wirtz, Theresa Hildegard
AU  - Wirtz TH
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Zuehlke, Sebastian
AU  - Zuehlke S
AD  - Department of Chemistry and Chemical Biology, Institute of Experimental Research 
      (INFU), TU Dortmund University, Dortmund, Germany.
FAU - Spiteller, Michael
AU  - Spiteller M
AD  - Department of Chemistry and Chemical Biology, Institute of Experimental Research 
      (INFU), TU Dortmund University, Dortmund, Germany.
FAU - Myllys, Maiju
AU  - Myllys M
AD  - Leibniz Research Centre for Working Environment and Human Factors at the 
      Technical University Dortmund, Dortmund, Germany.
FAU - Roulet, Alain
AU  - Roulet A
AD  - Vaiomer, Labege, France.
FAU - Ouzerdine, Amirouche
AU  - Ouzerdine A
AD  - Vaiomer, Labege, France.
FAU - Lelouvier, Benjamin
AU  - Lelouvier B
AD  - Vaiomer, Labege, France.
FAU - Kilic, Konrad
AU  - Kilic K
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
FAU - Liao, Lijun
AU  - Liao L
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; 
      Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji 
      University, Shanghai, China.
FAU - Nier, Anika
AU  - Nier A
AD  - Department of Nutritional Sciences, R.F. Molecular Nutritional Science, 
      University of Vienna, Vienna, Austria.
FAU - Latz, Eicke
AU  - Latz E
AD  - Institute for Innate Immunity, University of Bonn, Bonn, Germany.
FAU - Bergheim, Ina
AU  - Bergheim I
AD  - Department of Nutritional Sciences, R.F. Molecular Nutritional Science, 
      University of Vienna, Vienna, Austria.
FAU - Thaiss, Christoph A
AU  - Thaiss CA
AD  - Department of Microbiology; Institute for Immunology; and Institute for Diabetes, 
      Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, Pennsylvania.
FAU - Hengstler, Jan G
AU  - Hengstler JG
AD  - Leibniz Research Centre for Working Environment and Human Factors at the 
      Technical University Dortmund, Dortmund, Germany.
FAU - Strowig, Till
AU  - Strowig T
AD  - Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover 
      Medical School, Hannover, Germany.
FAU - Trautwein, Christian
AU  - Trautwein C
AD  - Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany. 
      Electronic address: ctrautwein@ukaachen.de.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201112
PL  - United States
TA  - Cell Mol Gastroenterol Hepatol
JT  - Cellular and molecular gastroenterology and hepatology
JID - 101648302
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Nod-like receptor pyrin domain-containing protein 6, mouse)
RN  - 0 (Receptors, Cell Surface)
RN  - 362O9ITL9D (Acetaminophen)
SB  - IM
MH  - Acetaminophen/*toxicity
MH  - Analgesics, Non-Narcotic/toxicity
MH  - Animals
MH  - Chemical and Drug Induced Liver Injury/etiology/*pathology
MH  - *Disease Models, Animal
MH  - Dysbiosis/*complications
MH  - Female
MH  - *Gastrointestinal Microbiome
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Permeability
MH  - Receptors, Cell Surface/*physiology
PMC - PMC7900526
OTO - NOTNLM
OT  - Acute Liver Failure
OT  - Dysbiosis
OT  - Gut-Liver-Axis
OT  - Microbiota
EDAT- 2020/11/16 06:00
MHDA- 2022/03/08 06:00
PMCR- 2020/11/12
CRDT- 2020/11/15 20:25
PHST- 2020/06/02 00:00 [received]
PHST- 2020/10/31 00:00 [revised]
PHST- 2020/11/02 00:00 [accepted]
PHST- 2020/11/16 06:00 [pubmed]
PHST- 2022/03/08 06:00 [medline]
PHST- 2020/11/15 20:25 [entrez]
PHST- 2020/11/12 00:00 [pmc-release]
AID - S2352-345X(20)30181-8 [pii]
AID - 10.1016/j.jcmgh.2020.11.002 [doi]
PST - ppublish
SO  - Cell Mol Gastroenterol Hepatol. 2021;11(4):909-933. doi: 
      10.1016/j.jcmgh.2020.11.002. Epub 2020 Nov 12.