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Cited by 108Drug-Induced Hepatotoxicity and ProtectionGut microbiota and healthLiver physiology and pathology

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury

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Schneider, Kai Markus, Elfers, Carsten, Ghallab, Ahmed, Schneider, Carolin Victoria, Galvez, Eric J.C., Mohs, Antje, Gui, Wenfang, Candels, Lena Susanna +16 more·2021·Cellular and Molecular Gastroenterology and Hepatology
DOI 10.1016/j.jcmgh.2020.11.002PMC PMC7900526
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Abstract

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.

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  • APAP-induced liver injury causes impairment of intestinal barrier integrity and increased bacterial translocation in mice.

    “Recent studies in mice have demonstrated that APAP-induced liver injury causes impairment of intestinal barrier integrity and increased bacterial translocation29–31”

    From Multimodal decoding of human liver regeneration (2024) · cites this paper as [31]

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Authors
Schneider, K. M., Elfers, C., Ghallab, A., Schneider, C. V., Galvez, E. J. C., Mohs, A., Gui, W., Candels, L. S., Wirtz, T. H., Zuehlke, S., Spiteller, M., Myllys, M., Roulet, A., Ouzerdine, A., Lelouvier, B., Kilic, K., Liao, L., Nier, A., Latz, E., Bergheim, I., Thaiss, C. A., Hengstler, J. G., Strowig, T., & Trautwein, C.
Affiliations
  • Universitätsklinikum Aachen (DE)
  • South Valley University (EG)
  • TU Dortmund University (DE)
  • Tongji University (CN)
  • University of Vienna (AT)
  • University of Bonn (DE)
  • University of Pennsylvania (US)
  • Medizinische Hochschule Hannover (DE)
Corresponding author
Trautwein, Christian
ORCID
Venue
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2021
Volume
11
Issue
4
Pages
909-933
ISSN
2352-345X (ISSN-L)
DOI
10.1016/j.jcmgh.2020.11.002
PMC
PMC7900526
OpenAlex
W3104287035
Cited by
108
References
10
Citations by year
2026: 14 · 2025: 16 · 2024: 24 · 2023: 27 · 2022: 20 · 2021: 7
FWCI
11.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by-nc-nd)
  • RWTH Publications (RWTH Aachen) (submittedVersion, other-oa)
  • HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by)
Funders
  • Helmholtz Association (VH-NG-933, DFG SCHN 1626/1-1)
  • Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg (691438)
  • Bundesministerium für Bildung und Forschung (01KU1214A, FKZ 031L0052, 031L0045)
  • Studienstiftung des Deutschen Volkes
  • Deutsche Forschungsgemeinschaft (SFB/TRR 57, CRC1382, TR285/10-2)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
gut dysbiosis, acute liver failure, acetaminophen hepatotoxicity, gut-liver axis, fecal microbiota transplantation, proton pump inhibitors, long-term antibiotic use, intestinal permeability, monocyte polarization, Ly6C, lipopolysaccharide, liver injury, microbiome diversity
MeSH terms
Gastrointestinal Microbiome, Acetaminophen, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Permeability, Receptors, Cell Surface, Mice, Knockout, Analgesics, Non-Narcotic, Mice, Chemical and Drug Induced Liver Injury, Dysbiosis

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