Abstract / Summary
Abstract BACKGROUND The imbalance between immunity and inflammation plays a crucial role in the progression of ACLF, and the value of the tryptophan-AhR pathway, which has significant regulatory effects, remains unclear. AIM To investigate the regulatory role and underlying mechanism of tryptophan metabolism-activated aryl hydrocarbon receptor (AhR) signaling in liver inflammation and immunity during acute-on-chronic liver failure (ACLF). METHODS An ACLF Wistar rat model was established. Rats were treated with intraperitoneal injection of 1-MT (IDO inhibitor) (3 mg/kg) or gavage administration of Leflunomide (AhR agonist) (10 mg/kg). Serum liver function parameters were measured using a biochemical analyzer; liver histopathological damage was observed using HE staining and Masson staining; serum tryptophan and its metabolites were detected using targeted metabolomic assays; the proportion of Treg and Th17 cells in liver was detected by flow cytometry; CD4 and SOCS3 co-expression in liver and lymphoid tissue were detected using fluorescence double staining; and AhR expression level in liver was detected by immunohistochemistry. RESULTS Compared with normal rats, ACLF rats exhibited impaired liver function, significant pathological damage in liver tissue, an increased Th17/Treg ratio, and decreased AhR and SOCS3 expression. Intervention with IDO inhibitor exacerbated these changes, while intervention with AhR agonist attenuated them. In addition, targeted metabolomics analysis in each group showed that differentially expressed metabolites were concentrated in the tryptophan metabolic pathway. CONCLUSION IDO inhibitors can aggravate liver injury and inflammatory response in ACLF rats. Meanwhile, AhR agonists are associated with the increase in SOCS3 expression and can affect the Th17/Treg balance, inhibiting the inflammatory response, thereby alleviating the inflammation and immune imbalance in ACLF rats.