Akkermansia muciniphila attenuates anti-tuberculosis drug-induced liver injury through gut-liver axis by promoting Nr4a1 transcription.

Drug-induced liver injury (DILI) is a frequent adverse event associated with anti-tuberculosis therapy, and current clinical management options remain limited. Given the pivotal role of the gut-liver axis in liver pathophysiology, this study investigated the potential and underlying roles of Akkermansia muciniphila (A.muc) in ameliorating anti-tuberculosis drug-induced liver injury (ADLI). A reduction in the abundance of A. muc was observed during ADLI progression, suggesting its possible involvement in the modulation of liver injury. This study demonstrated that A. muc intervention ameliorated anti-tuberculosis drug-triggered gut microbiota imbalance, repaired intestinal barrier function and lowered serum lipopolysaccharide (LPS). Moreover, A. muc supplementation inhibited the expression of pro-inflammatory cytokines, alleviated oxidative stress, decreased serum transaminases, and attenuated hepatic pathological damage, possibly via inhibiting the TLR4/MyD88/NF-κB pathway and activating the Nrf2 antioxidant pathway. In addition, A. muc enriched short-chain fatty acid (SCFA)-producing bacteria and increased butyric acid concentrations in the intestine and serum. RNA-seq analysis identified the core transcription factor Nr4a1. Mechanistically, butyric acid derived from A. muc suppressed histone deacetylase 1 (HDAC1), promoted H3K9ac/H3K27ac modification at the Nr4a1 promoter to stimulate Nr4a1 transcription, and further suppressed NF-κB signaling to modulate inflammation and liver injury. Collectively, we systematically uncover a new gut microbiota-SCFAs-HDAC1-Nr4a1 axis mediating the protective effect of A. muc against ADLI, which offers theoretical support and promising therapeutic approaches for probiotic intervention of DILI.