Zinc promotes microbial p-coumaric acid production that protects against cholestatic liver injury.

Cholestatic liver disease (CLD) is a common liver disorder with limited treatment options. Here, we demonstrate that zinc (Zn) supplementation can alter the gut microbiome to mitigate cholestatic liver injury. Oral Zn altered the microbiota of mice and humans (this study was registered at clinicaltrials.gov [NCT05597137]), increasing the abundance of Blautia producta (B. producta) and promoting the generation of p-coumaric acid. Additionally, p-coumaric acid concentrations were negatively correlated with liver injury parameters in CLD patients. In mice, the protective effects of Zn were partially mediated by p-coumaric acid, which directly bound to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and suppressed the production of reactive oxygen species (ROS) in hepatocytes, thus preventing hepatocyte cell death and liver damage. Additionally, knocking out the histidine ammonia-lyase, which catalyzes the conversion of tyrosine to p-coumaric acid in B. producta, blunted the protective effects of Zn. These findings highlight a host-microbiota interaction that is stimulated by Zn supplementation, providing potential benefits for CLD.