Phenylpropionc acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity

Abstract

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.Acute liver injury after APAP ingestion exhibits large interindividual variability (17). This is not fully explained by currently available knowledge such as genetic polymorphisms in phase I and phase II enzymes (15,(18)(19)(20)(21)(22)(23). Results from previous studies suggest that altered gut microbiota may impact the susceptibility to APAP hepatotoxicity. Metabolomics results of pre-and post-dose urinary metabolite profiles after the administration of a therapeutic dose of APAP suggest that gut bacteria metabolite p-cresol may competitively inhibit APAP sulfonation and potentially diverting APAP towards CYP-mediated bioactivation (24). Diurnal variations in gut microbiota abundance and composition were shown to be associated with altered susceptibility to APAP-induced hepatotoxicity (25,26). Also, a probiotic Enterococcus lactis IITRHR1 was shown to alleviate APAP hepatotoxicity potentially by its antioxidant effects (27). Despite the accumulating evidence, systematic investigation of the roles of gut microbiota in APAP-induced hepatotoxicity and detailed mechanistic investigations have been lacking.In this study, we demonstrated that differential gut microbiota alters susceptibility to APAPinduced hepatotoxicity in mice. Using unbiased metabolomics profiling, we identified a gut microbeassociated metabolite that alleviates APAP hepatotoxicity.

Anwulignan Alleviates the Acute Liver Injury Induced by Acetaminophen in Mice

“…Toxicity of APAP arises from the formation of cytochrome P450 enzyme, especially reactive metabolite NAPQI formed by CYP2E1, which accumulates in the liver and binds with cysteine residues of cellular proteins, causing cell damage in liver tissues. Many studies have shown that the expression of CYP2E1 in the liver increases after APAP treatment (Cho et al, 2023; Masubuchi & Mikami, 2023). Whereas the inhibition of CYP2E1 expression can reduce the formation of NAPQI and thus alleviate liver injury, which is consistent with those reported above, CYP2E1 expression increased significantly, while decreased significantly in the liver tissue of mice treated with APAP after the administration of Anwulignan, so we hypothesized that Anwulignan might reduce liver tissue damage by inhibiting CYP2E1 expression in the liver of APAP-treated mice, thereby reducing the production of toxic substances such as NAPQI.…”

Probiotics: Evolving as a Potential Therapeutic Option against Acetaminophen-Induced Hepatotoxicity

“…Furthermore, because the lysosome is a major regulator of autophagy, lysosomal instability leads to autophagy dysfunction. APAP-induced hepatotoxicity has been linked to abnormal autophagy and mitophagy, which causes hepatocyte damage [ 50 , 51 ]. The mechanism of APAP hepatotoxicity has been depicted in Figure 2 .…”

“…PPA (0.4% in drinking water) treatment for 4 weeks, followed by a sub-lethal dose of APAP (300 mg/kg, i.p. ), could reduce susceptibility toward APAP hepatotoxicity in mice [ 50 ]. PPA was shown to suppress the hepatic CYP2E1 protein that catalyzes APAP metabolism to form its toxic metabolite NAPQI.…”

The role of bacterial metabolites derived from aromatic amino acids in non-alcoholic fatty liver disease

“…Известно, что количество бактериальной ФПК зависит от общего количества кишечных бактерий, имеющих гены восстановительного пути (Clostridium sporogenes, Peptostreptococcus anaerobius), и доступности субстрата фенилаланина. Кроме того, ФПК может образовываться в результате расщепления флавоноидов растительного происхождения кишечными бактериями, высвобождающими или метаболизирующими агликон [44]. Производные ФПК могут служить агонистами рецептора СЖК 4-го типа (FFA4) [45], который играет важную роль в снижении воспаления в печени, повышении чувствительности к инсулину и регулировании энергетического метаболизма.…”