Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

Acetaminophen (APAP) overdose causes hepatic injury. 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 into germ-free mice, the mice that received JAX gut microbiota exhibited less toxicity after APAP administration. Unbiased metabolomic analysis using portal vein serum and liver tissue of the mice led to identification of 19 metabolites whose levels differ between JAX and TAC mice as well as between mice transplanted with JAX or TAC gut microbiota, and this includes gut bacteria-derived metabolite phenylpropionic acid (PPA). PPA levels in cecum and portal vein were higher in mice harboring JAX gut microbiota. PPA supplementation in drinking water led to decreased APAP toxicity in TAC mice. This illustrates a gut microbe-liver interaction mediated by a gut bacteria-derived metabolite in modulating drug-induced liver injury.