Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism

Area of Science:

• Hepatology
• Microbiome Research
• Pharmacology

Background:

• Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF).
• CYP2E1 metabolizes APAP into toxic reactive species, causing oxidative stress and liver damage.
• The gut microbiome's role in APAP-induced ALF is increasingly recognized.

Purpose of the Study:

• To investigate the protective effects of oral magnesium (Mg) against APAP-induced ALF.
• To elucidate the mechanisms by which Mg modulates gut microbiota to prevent liver injury.
• To identify specific microbial metabolites and enzymes involved in Mg's hepatoprotective effects.

Main Methods:

• Administered oral Mg to mice and humans, then induced APAP-related ALF.
• Analyzed changes in gut microbiota composition and metabolism using metagenomics and metabolomics.
• Utilized knockout and engineered bacterial strains to confirm the role of specific microbial pathways.
• Assessed CYP2E1 activity and oxidative stress markers in liver tissues.

Main Results:

• Oral Mg significantly alleviated APAP-induced ALF in mice.
• Mg supplementation altered gut microbiota, increasing indole-3-carboxylic acid (I3C) levels.
• A key Bifidobacterium enzyme, formate C-acetyltransferase (pflB), was identified as crucial for I3C generation.
• I3C directly inhibited CYP2E1, reducing toxic metabolite formation and hepatocyte damage.

Conclusions:

• Mg exerts hepatoprotective effects against APAP-induced ALF through gut microbiota modulation.
• Enrichment of I3C via Bifidobacterium pflB is a critical mechanism for Mg's beneficial action.
• Targeting the gut microbiome, specifically I3C production, offers a novel therapeutic strategy for ALF.