Differential gut microbiota modulates the susceptibility to acetaminophen‐induced hepatotoxicity

Abstract

Acetaminophen (APAP) is a commonly used analgesic and antipyretic. APAP‐induced hepatotoxicity is the most frequent cause of acute liver failure in the US. Individual susceptibility to APAP hepatotoxicity is highly variable, and the risk factors for developing severe APAP hepatotoxicity are not well understood. The objective of this study is to investigate a potential role of gut microbiota in modulating susceptibility to APAP toxicity by using a mouse model. C57BL/6 mice from two different vendors [Jackson (JAX) and Taconic (TAC)] were cohoused with mice from the same or the other vendor for 4 weeks, creating the following 4 groups: JAX, TAC, CoJAX (i.e., JAX mice cohoused with TAC) and CoTAC (i.e., TAC mice cohoused with JAX). In parallel, separate 4 groups of mice were co‐housed (n=6–7/group) as untreated controls. Fecal samples were collected at the end of cohousing and subject to next‐generation sequencing analysis of bacterial 16S rRNA gene amplicons. The mice were treated with APAP (600 mg/kg, oral, n=19–21/group) and sacrificed at 24 h post‐dosing, followed by collection of the liver and serum samples. Hepatotoxicity was determined by measuring serum levels of liver enzymes (i.e., alanine aminotransferase, ALT). Results from gut microbiome analysis showed the differences in gut microbiota composition between JAX and TAC at the end of cohousing and indicated the transfer of gut microbiota between cohoused mice. After APAP dosing, JAX mice exhibited 16‐fold higher hepatotoxicity as compared to TAC mice. This difference was abrogated upon cohousing, suggesting that differential gut microbiota between JAX and TAC may modulate susceptibility to APAP hepatotoxicity. Correlation analysis between ALT and different gut microbiota taxa revealed that the relative abundance of bacteria from the genera Mucispirillum, Turicibacter and Ruminococcus in fecal samples prior to APAP dosing is associated with increased APAP hepatotoxicity. The basal mRNA expression levels of Cyp2e1 and Cyp1a2 in the liver did not differ among 4 groups of mice, and the basal hepatic glutathione level was 1.3‐fold higher in JAX compared to TAC, suggesting that neither differential glutathione nor Cyp2e1/Cyp1a2 level is responsible for the difference in APAP hepatotoxicity. Taken together, our data suggest that differential gut microbiota may modulate susceptibility to APAP‐induced hepatotoxicity. This finding may shed a light on identifying potential risk factors for APAP hepatotoxicity.Support or Funding InformationThis study was supported by Chicago Biomedical Consortium.