Lacticaseibacillus paracasei 36 attenuates D-GalN/LPS-induced acute liver injury in mice via suppressing the TLR4/NF-κB/MAPK pathway and NLRP3 inflammasome activation through modulating the intestinal microbiota.

INTRODUCTION

Acute liver injury (ALI) is a severe clinical syndrome with high mortality, often triggered by toxins, viruses, or immune-mediated injury. The gut-liver axis serves as a key mediator in the progression of hepatic disorders, and probiotics are considered viable treatment options owing to their impact on modulating intestinal microbiota, reducing inflammation, and alleviating oxidative stress.

OBJECTIVES

This study was designed to elucidate the hepatoprotective mechanisms of L. paracasei 36 against D-GalN/LPS-induced ALI in mice, with a specific focus on its roles in inflammation, oxidative stress, apoptosis, and intestinal microbiota regulation.

METHODS

The mice were pretreated with L. paracasei 36 for three weeks prior to the D-GalN/LPS challenge. Serum biomarkers, oxidative damage indicators, inflammatory cytokines, and apoptosis-related genes were measured. Intestinal microbiota composition was analyzed via 16S rRNA sequencing, and hepatic transcriptomics and metabolomics were performed to identify key pathways and metabolites.

RESULTS

L. paracasei 36 pretreatment significantly reduced serum AST, ALT, and TBil levels, alleviated histopathological damage, and decreased oxidative stress and inflammatory cytokine production. It inhibited hepatocyte apoptosis by modulating Bcl-2/Bax expression and suppressed NLRP3 inflammasome activation. L. paracasei 36 restored intestinal microbiota balance, increasing beneficial genera (Ligilactobacillus, Akkermansia) and reducing harmful ones (Alistipes, Parasutterella). Multi-omics analysis revealed suppression of NF-κB/MAPK pathways along with an increase in hepatoprotective metabolites like berberine and flavin nucleotides.

CONCLUSION

L. paracasei 36 exerts potent hepatoprotective effects against D-GalN/LPS-induced ALI by mitigating inflammation, oxidative damage, and apoptosis, and by restoring intestinal microbiota homeostasis. Collectively, these results suggest that L. paracasei 36 represents a potential therapeutic strategy for ALI.