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Intestinal dysbiosis amplifies acetaminophen induced acute liver injury 肠道菌群失调会加剧对乙酰氨基酚所致的急性肝损伤 10.1016/j.jcmgh.2020.11.002 11-12, Article Abstract & Authors:展开 Abstract:收起
Background&Aims: Acute liver failure (ALF) represents an unmet medical need in Western countries. While 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 intake (ABx) – which have both been linked to intestinal dysbiosis – and occurrence of ALF in the 500k 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 (OR 2.3-3) for developing ALF in UKB participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to a significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into WT mice augmented liver injury upon APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response.
Conclusions: In conclusion, 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.
First Authors:
Kai Markus Schneider,Carsten Elfers Correspondence Authors:
Christian Trautwein All Authors:
Kai Markus Schneider,Carsten Elfers,Ahmed Ghallab,Carolin Victoria Schneider,Eric JC Gálvez,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,Anika Nier,Eicke Latz,Ina Bergheim,Christoph A Thaiss,Jan G Hengstler,Till Strowig,Christian Trautwein
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