Lactobacillus plantarum ameliorates intrahepatic cholestasis by modulating the gut microbiota and tryptophan metabolism

Lactobacillus plantarum (L. plantarum ) has shown protective effects in various liver diseases, yet its therapeutic potential and mechanisms in intrahepatic cholestasis remain unelucidated. This study aimed to investigate the therapeutic efficacy and mechanism of L. plantarum in intrahepatic cholestasis using two well-established mouse models induced by α-naphthylisothiocyanate (ANIT) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The results indicated that L. plantarum significantly alleviated cholestasis-related hepatic inflammation, ductular proliferation, fibrosis, and improved gut barrier integrity. The 16S rRNA sequencing and untargeted metabolomics analysis revealed that the intestinal abundance of L. plantarum was significantly increased after intervention and showed a positive correlation with the level of indole-3-acetic acid (IAA), a key functional metabolite of tryptophan ( r  = 0.712, p  = 0.003). The elevated IAA levels were closely associated with the improvement of key liver injury indicators. Exogenous IAA supplementation replicated the hepatoprotective effects of L. plantarum in intrahepatic cholestasis. Transcriptome analysis indicated that IAA mediated these benefits primarily through aryl hydrocarbon receptor (AHR) activation, and AHR inhibition markedly attenuated its protective effects. This study reveals that L. plantarum ameliorates intrahepatic cholestasis by enhancing tryptophan metabolism to promote IAA production, which in turn activates the IAA-AHR axis, providing new insights into probiotic and metabolite-based therapies for intrahepatic cholestasis.