Modulation of anti-tuberculosis drug-induced liver injury by gut microbiota metabolites: Insights from network pharmacology

Effective treatment of tuberculosis is often hampered by anti-tuberculosis drug-induced liver injury (ATB-DILI). This study aimed to identify the key targets and mechanisms by which gut microbiota metabolites regulate ATB-DILI. Integrative bioinformatics was used to screen for common targets shared by gut microbiota metabolites and ATB-DILI. The target list was refined through protein-protein interaction network and hub gene analyses. Functional enrichment analysis was performed on the core targets, followed by construction of a microbe–metabolite–target regulatory network and evaluation of drug-like properties of candidate metabolites. A total of 58 common targets were identified, which were further narrowed down to 14 important targets. Six core targets (IL-6, NFE2L2, CXCL8, VEGFA, TLR4, and EGFR) were distinguished through hub gene analysis. Functional enrichment indicated that these targets are centrally involved in xenobiotic metabolism, oxidative stress regulation, and inflammatory responses. Network analysis revealed that specific gut microbes and their metabolites, particularly short-chain fatty acids, jointly regulate these core targets. Butyrate and equol emerged as promising candidates based on drug-like property screening. This study presents a multi-target immune-metabolic network through which gut microbiota influences ATB-DILI, providing a mechanistic basis for microbiota-targeted interventions. Future preclinical studies are warranted to validate these targets and assess the effectiveness of the identified metabolites.