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.