Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

ABSTRACT Acetaminophen (APAP) overdose causes hepatic injury and is major contributor to acute liver injury cases. To investigate potential roles of gut microbiota in APAP-induced liver injury, C57BL/6 mice from Jackson (JAX) or Taconic (TAC) were challenged with APAP. TAC mice were more susceptible to APAP toxicity, and this disappeared upon co-housing of JAX and TAC mice. When the cecum contents from JAX and TAC mice were transplanted to germ-free mice, the mice that received TAC gut microbiota exhibited more significant hepatotoxicity after APAP administration. Non-targeted metabolomic analysis using portal vein serum and liver tissue of the mice led to identification of 19 metabolites the levels of which are associated with JAX or TAC gut microbiota. A gut bacteria-derived metabolite phenylpropionic acid (PPA) levels in cecum contents and blood were higher in mice harboring JAX gut microbiota. PPA supplementation in drinking water alleviated APAP-induced hepatotoxicity in TAC mice. This was accompanied by reduced hepatic protein levels of cytochrome P450 (CYP) 2E1, the enzyme responsible for APAP bioactivation to a toxic metabolite. This illustrates a gut microbe-liver interaction mediated by a gut bacteria-derived metabolite in modulating drug-induced liver injury.