Gut Microbiota and Metabolomic Profiles of Tacrolimus-Induced DILI in Renal Transplant Recipients: A population-based case control study

Background: In clinical practice, cases of drug-induced liver injury (DILI) often occur in renal transplant recipients treated with tacrolimus (Tac) as an immunosuppressive therapy. Numerous studies have confirmed the close relationship between gut microbiota (GM) and DILI. However, systematic studies on the GM and metabolomic characteristics of Tac-associated DILI are lacking, and the role of GM and its metabolites in DILI remains incompletely understood.Methods: Renal transplant recipients receiving Tac at the Organ Transplantation Center of Sichuan Provincial People's Hospital were enrolled. Patients with DILI were assigned to the DILI group, and those with stable liver function to the control group. Stool samples were analyzed by 16S rRNA gene sequencing and LC-MS non-targeted metabolomics, and blood samples were collected to measure Tac trough concentrations.Results: Seventy-two renal transplant recipients were included, comprising 32 DILI patients and 40 controls. Oscillibacter and Ruminococcus gnavus group were significantly enriched in the DILI group, whereas Bacteroides, Lachnospiraceae NK4A136 group, Anaerostipes, Subdoligranulum, Eubacterium coprostanoligenes group, and Megamonas were significantly decreased in the DILI group. Metabolites such as icosadienoic acid and 1-acyl-sn-glycerol-3-phosphate were significantly elevated in the DILI group, while glycyrrhetinate, S-adenosylmethionine, and other related metabolites were significantly reduced.