*Purpose: We recently reported modifications of the gut microbiota by amoxicillin influences liver allograft function. Rifaximin (RFX), a nonabsorbable oral antimicrobial agent with a low risk of bacterial resistance, is commonly used to treat hepatic encephalopathy in patients awaiting liver transplantation (LT). Here we aimed to investigate the effects of RFX pretreatment in mice and human LT recipients.

*Methods: Mouse allogenic LT (BALB/c to C57BL/6, and C57BL/6 to C3H) was performed in three groups: Gr.1, untreated; Gr.2, 7d RFX treatment prior to LT; Gr.3, 7d RFX treatment + fecal microbiota transplant (FMT) from naive mice. Genomic DNA of fecal samples were isolated and subjected to microbiome 16S rRNA gene sequencing. In parallel, retrospective analyses of 447 adult human LT recipients were classified based on the duration of pre-LT RFX therapy: Gr.1, RFX ≥ 7d; Gr.2, RFX < 7d, and then, 150 patients (Gr.1: n=75, Gr.2: n=75) were selected by propensity score matching for clinical recipients and donor factors.

*Results: In the experimental arm, Gr.2 RFX pretreatment mitigated hepatocellular injury after LT in mouse recipients, evidenced by significantly lower serum ALT levels (Gr.1 vs Gr.2 vs Gr.3: 11867±2203 vs 5339±1324 vs 13006±3339 U/L, p<0.05) and Suzuki’s histological scoring of LT damage (Gr.1 vs Gr.2 vs Gr.3: 8.3±1.3 vs 5.5±0.6 vs 7.8±1.1, p<0.05), compared with either Gr.1 or 3. The Chao1 and Shannon index significantly decreased with RFX treatment (p<0.001 and p=0.003, respectively). Taxonomic classification using 16S sequencing revealed Akkermansia muciniphila was enriched in conditions that alleviated hepatocellular damage in LT. In the clinical arm, patients (n=75) who underwent ≥7d RFX treatment had significantly lower levels of early postoperative serum AST/ALT levels (p<0.05). Notably, the rate of early allograft dysfunction (EAD) in RFX Gr.1 was significantly lower than that in control Gr.2 (16.0 vs 37.3%, p=0.003).

*Conclusions: This study identifies the effectiveness of RFX therapy prior to LT in mice and humans as assessed by graft hepatocellular damage and EAD. As RFX-mediated benefits were negated by concomitant FMT from naive mice, targeting gut microbiota has therapeutic potential to prevent post-LT injury and improve clinical outcomes. Further study will reveal the specific target produced by gut microbiota in LT recipients.

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