Role Of Gut Microbiota-host Tryptophan Co-metabolism In D-GalN/LPS-induced Acute Liver Failure In C57BL/6 Mice

Acute liver failure(ALF)has an abrupt onset with a frequently fatal outcome,but it has not been studied in large and randomized clinical trials.Previous studies have found that oral probiotics or antibiotics prevent drug-induced liver injury in animal,indicating that the gut microbiota plays a critical role in drug-induced liver injury.However,the underlying mechanism has not been fully understood.This study explored the comprehensive role of the gut microbiota in ALF using multi-omics.A cocktail of broad-spectrum antibiotics(Abx)pretreatment by gavage for four weeks improved the survival of D-(+)-galactosamine hydrochloride(D-Gal N)/lipopolysaccharide(LPS)-induced ALF in C57BL/6 mice.RNA sequencing showed that inflammatory responses were inhibited and metabolic pathways were upregulated in the liver of Abx-treated ALF mice.The 16 S r RNA gene sequencing revealed that Abx reshaped the composition and function of the gut microbiota,with an increased tryptophan(Trp)metabolism.In addition,global metabolic profiling by ultra-performance liquid chromatography-mass spectrometry(UPLC-MS)indicated that the gut microbiota post-Abx intervention reduced Trp excretion,liberated more Trp to the host,and enhanced the kynurenine(Kyn)pathway with increased production of Kyn.As an endogenous aryl hydrocarbon receptor(Ah R)ligand,Kyn has anti-inflammatory and immunosuppressive effects.Furthermore,Ah R antagonist(CH223191)and agonist(FICZ)affected the outcome of ALF mice with and without Abx pretreatment respectively,indicating that Ah R signal regulated susceptibility to ALF,at least in part.This study demonstrates that the gut microbiota-dependent control of the Trp metabolism could regulate host susceptibility to ALF by modulating the activity of Ah R,and thus provides a promising target for better management of ALF.