*Purpose: Normothermic ex-vivo liver perfusion (NEVLP) is a powerful platform for organ preservation and assessment. It induces metabolic reactivation that potentially helps clear accumulated toxic compounds and translocated gut bacteria. The gut microbiome and its metabolites are involved with immune regulation and host health. Gut dysbiosis and bacterial translocation are common in organ donors which may affect the recipient via the graft. The purpose of this study was to test if different organ preservation techniques affect recipients’ microbiome and/or metabolomics profile.

*Methods: This was a single-center, non-randomized prospective pilot study comparing the microbiota, metabolome, volatile organic compounds (VOCs) and outcomes of patients transplanted either with liver graft preserved by static cold storage (SCS; n=8) or NEVLP (n=25). Stool and breath samples were collected at 3 time points (pre-transplant, post-operative months (POM) 3 and 6). Samples were also collected from healthy controls (HC) and donors. Stool microbiota and metabolomics (short-chain fatty acids – SCFA) was analyzed by sequencing the V3-V4 hypervariable regions of 16S rRNA and gas chromatography-mass spectrometry, respectively. VOCs were analyzed via selected ion flow tube-mass spectrometry.

*Results: The groups had similar age, BMI, MELD score, and rejection rates. However, hospital stay was longer in the SCS group (p<0.01). Expansion of several opportunistic bacteria occurred in the SCS compared to NEVLP group (e.g., Enterococcus, Enterobacteriacea, Peptoclostridium, Tyzzerella). By POM6, graft recipient and donor microbiota were similar. Pre-transplant SCFA levels were similar between the groups. However, the SCS group had higher SCFA levels (acetate, propionate, butyrate, isovalerate) at POM3 (p<0.05) compared to the NEVLP group and HC. SCS SCFA levels were similar in both groups at POM6. SCFA producing bacteria (e.g., Lachnospiraceae, Rosburia, Ruminococcus, Coprococcus, Anaerostipes) were elevated in the SCS group and positively correlated to SCFA levels compared to NEVLP patients (p<0.05). Several breath VOCs varied between NEVLP and SCS groups at POM3 (ethane, isoprene, acetone) and POM6 (carbon disulfide, acetaldehyde, trimethylamine).

*Conclusions: These data show differences in gut microbes, metabolites, and breath VOCs between patients receiving a liver transplant following two different graft preservation methods. Further analysis into whether these differences contribute to immunosuppressant therapy efficacy and patient outcomes, or if gut microbial manipulation improves graft and patient outcomes is warranted.

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