4.7 Article

Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury

出版社

ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.11.002

关键词

Acute Liver Failure; Gut-Liver-Axis; Microbiota; Dysbiosis

资金

  1. German Research Foundation [CRC1382, TR285/10-2, SFB/TRR 57, DFG SCHN 1626/1-1]
  2. Federal Ministry of Education and Research (ObiHep) [01KU1214A]
  3. Liver-LiSyM grant (BMBF) [FKZ 031L0052, 031L0045]
  4. HDHL-INTIMIC Di-Mi-Liv
  5. the Interdisciplinary Centre for Clinical Research (START Grant) within the Faculty of Medicine at RWTH Aachen University [691438]
  6. German National Academic Foundation
  7. Helmholtz Association [VH-NG-933]

向作者/读者索取更多资源

The study revealed an important yet unknown role of intestinal microbiota during ALF. Intestinal dysbiosis was transferable to healthy wild-type mice via fecal microbiota transfer (FMT) and aggravated liver injury, highlighting intestinal microbiota as a targetable risk factor for ALF.
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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