*Purpose: Microbiome has emerged as a key modulator of organ homeostasis and immune system function with altered microbiota and microbiome – host interactions contributing to disease. To identify signatures associated with operational tolerance in liver transplant (LT) patients we examined plasma microbiome using RNA-seq.

*Methods: The cross-sectional patient cohort consisted of LT recipients with stable liver allograft function who were free of infections and autoimmunity: Maintenance immunosuppression (MI, n=12) group on tacrolimus, weaning immunosuppression (WI, n=26) group on monitored tacrolimus withdrawal, and operational tolerance (OT, n=17) group off all immunosuppression. We employed next generation sequencing of small RNAs from plasma. Following quality filtering, human reads were removed, and the remaining small RNA were aligned to bacterial and fungal databases. Alpha and beta diversity, taxonomic composition, and taxonomic relative abundance were assessed between groups using Calypso.

*Results: OT displayed the highest level of alpha diversity compared with MI and WI. Spearman correlation heatmap of the 40 most abundant taxa displayed the largest separation between OT and MI while WI shared similarity to both groups (Fig. 1). Candida albicans, Flavobacterium, and Phialophora were enriched in MI and WI, but scarce in OT, whereas Desulfitobacterium was significantly enriched in OT. In addition, OT patients showed greater relative abundance of Cystofilobasidium, Helicogloea, and an uncultured Sebacina than those in MI and WI groups. Also, OT patients shared similarities with healthy controls suggesting that differences in species diversity are not due to immunosuppression. The observed distinct alterations in OT patients are potentially a consequence of microbial – host immune system interactions possibly influencing the emergence of tolerance, and can be further elucidated by longitudinal and prospective analyses of circulating microbiome.

*Conclusions: A plasma microbiome is detectable in LT patients. OT in LT recipients showed significant differences in global microbial composition than those on immunosuppression. These findings have implications for unraveling the nexus of microbial interactions with host immunity and transplant outcomes or tolerance with important mechanistic and therapeutic implications.

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