*Purpose: The human intestinal microbiome contains more than 100 trillion commensal microorganisms, exceeding the number of cells in the human body by 10-fold. Although recent evidence shows that modifications of gut microbiota by antibiotics (Abx) may influence liver allograft function in mice and humans, its compositional role in orthotopic liver transplantation (OLT) remains unknown. Here, we aimed to determine whether and how the recipient commensal microbiota composition may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes.

*Methods: Balb/c livers subjected to cold storage (18 h) were transplanted to C57/BL6 mouse recipients, which were treated with/without amoxicillin (50mg/ml x10 days/drinking water) in the following groups: 1/Sham-treated (n=4), 2/Recipient Abx (n=6), 3/Abx+ Fecal Microbiota Transplantation (FMT; n=6), and 4/OLT (n=3). For FMT experiments, stool collected from naive untreated C57BL/6 mice was administered to amoxicillin-fed C57BL/6 mice (days -11 to -1). These were conditioned with/without FMT (200 mg/ml by gavage) on day -1 and 0 prior to OLT. Genomic DNA of fecal samples were isolated (day +1) and subjected to microbiome 16S rRNA gene sequencing.

*Results: Taxonomic classification using principal component analysis revealed significant differences between the Abx-treated and untreated groups in the family-, genus, and species-level analyses. Faith’s Phylogenetic Diversity index, Shannon Index, and Chao1 Index all revealed significant declines in taxon richness, species diversity, and overall abundance after Abx-treatment alone. By contrast, FMT re-established the microbiota to Sham and OLT-levels, suggesting that our normal commensal flora is antagonistic to liver IRI-resistance. The bacterial phyla Verrucomicrobia and Firmicutes showed the largest decline of representation in the Abx-treated microbiota as compared to Sham-treated controls. At the genus level, Akkermansia muciniphila and Bacteroides thetaiotaomicron were among the most abundant while Clostridium sensu stricto and Romboutsia were the least abundant bacteria in the Abx-pretreatment mice characterized with well-preserved post-OLT hepatocellular function.

*Conclusions: This novel study identifies how Abx recipient pretreatment fundamentally alters the microbiome composition pre- and post-OLT. Selective compositional changes rather than overall bacteria levels are indicative of OLT resistance against IR-stress. Hence, Bacteroides, Akkermansia, and Turicibacter are identified as putative cytoprotective microbes; while Firmicutes, Clostridium and Ruminococcaceae are candidates that play a cytotoxic role in OLT recipients.

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