Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury

Autor(en)

Kai Markus Schneider, Carsten Elfers, Ahmed Ghallab, Carolin Victoria Schneider, Eric J.C. Galvez, Antje Mohs, Wenfang Gui, Lena Susanna Candels, Theresa Hildegard Wirtz, Sebastian Zuehlke, Michael Spiteller, Maiju Myllys, Alain Roulet, Amirouche Ouzerdine, Benjamin Lelouvier, Konrad Kilic, Lijun Liao, Eicke Latz, Ina Bergheim, Christoph A. Thaiss, Jan G. Hengstler, Till Strowig, Anika Nier, Christian Trautwein

Abstrakt

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.

Organisation(en)

Department für Ernährungswissenschaften

Externe Organisation(en)

Universitätsklinikum Aachen, University of Pennsylvania, South Valley University, Helmholtz-Zentrum für Infektionsforschung, Medizinische Hochschule Hannover (MHH), Rheinische Friedrich-Wilhelms-Universität Bonn, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Vaiomer, Tongji University, Technische Universität Dortmund

Journal

CMGH

Band

Seiten

909-933

Anzahl der Seiten

DOI

https://doi.org/10.1016/j.jcmgh.2020.11.002

Publikationsdatum

11-2020

Peer-reviewed

ÖFOS 2012

303009 Ernährungswissenschaften

Schlagwörter

ASJC Scopus Sachgebiete

Gastroenterology, Hepatology

Link zum Portal

https://ucris.univie.ac.at/portal/de/publications/intestinal-dysbiosis-amplifies-acetaminopheninduced-acute-liver-injury(19e88bc3-5851-4624-824f-5573a6a83594).html