Hierarchy-Assembled Dual Probiotics System Ameliorates Cholestatic Drug-Induced Liver Injury via Gut-Liver Axis Modulation

Cholestatic drug-induced liver injury (DILI) induced by drugs or other xenobiotics is a severe and even fatal clinical syndrome. Here, living materials of hierarchy-assembled dual probiotics system are fabricated by sequentially encapsulating probiotic Lactobacillus delbrueckii subsp. bulgaricus (LDB) and Lactobacillus rhamnosus GG (LGG) into Ca2+-complexed polymer microspheres for effective prevention of cholestatic DILI. Upon entering intestinal tract of the constructed living materials, LGG is released because of pH-triggered dissolution of outer enteric polymer coating. The released LGG can inhibit hepatic bile acids (BAs) synthesis by activating intestinal farnesoid X receptor-fibroblast growth factor 15(FGF-15) signaling pathway. BAs excretion is also facilitated by LGG through increasing the abundance of bile salt hydrolase (BSH)-active gut commensal bacteria. Furthermore, exposed positively-charged chitosan shell can absorb the excessive BAs via electrostatic interaction, which leads to steady BAs fixation by the imprisoned LDB, decreasing the total BAs amounts in enterohepatic circulation. Together, the fabricated living materials, obtained here, can effectively prevent cholestatic DILI through dredging cholestasis via gut-liver axis modulation. The therapeutic effect is demonstrated in alpha-naphthylisothiocyanate and clinical antiepileptic drug valproate acid-induced cholestatic DILI mouse models, which reveal the great potential for effective cholestatic DILI management.