Association of FUT2 rs601338 Genotype with Colonic Mucosal Microbiome Composition, Post-Transplant Bacteremia, and All-Cause Mortality After Liver Transplantation for Primary Sclerosing Cholangitis: A Retrospective Cohort Study

Background/Objectives: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease frequently requiring liver transplantation (LTx). The gut–liver axis, host genetics, and microbial dysbiosis are thought to contribute to disease progression and post-transplant outcomes. The FUT2 rs601338 polymorphism influences mucosal fucosylation, host–microbial interactions, and susceptibility to infection. This study aimed to investigate the association between FUT2 genotype, colonic mucosal microbiome composition, post-transplant bacteremia, and all-cause mortality in a retrospective single-center PSC cohort. Methods: This retrospective cohort study included PSC patients who underwent LTx at Erasmus MC University Medical Center (Rotterdam, The Netherlands) between 1987 and 2015. Pre-transplant archival formalin-fixed paraffin-embedded (FFPE) colonic biopsy specimens were available for microbiome analysis. Of 169 transplanted patients, FFPE tissue was available for 98 individuals, and FUT2 rs601338 genotyping was successfully performed in 87 patients. Patients were classified as FUT2 non-secretors (AA, n = 28) and secretors (GA/GG, n = 59). Post-transplant bacteremia was assessed based on clinically indicated blood cultures during follow-up. Colonic mucosal microbiome composition was analyzed using 16S rRNA gene sequencing. Results: FUT2 non-secretors showed a distinct colonic mucosal microbiome profile compared with secretors, characterized by differential abundance of selected taxa within Proteobacteria, Firmicutes, and Bacteroidetes. Post-transplant bacteremia occurred in 30 patients and was more frequent among non-secretors (43%) compared with secretors (15%). Both FUT2 non-secretor status and post-transplant bacteremia were associated with reduced all-cause post-transplant survival in Kaplan–Meier analysis and remained associated with mortality in multivariable regression models. Specific microbial taxa were also showed associations with bacteremia, mortality, and established prognostic scores, including the Amsterdam–Oxford Model and Mayo Risk Score. Conclusions: FUT2 genotype is associated with alterations in colonic mucosal microbiome composition, post-transplant bacteremia, and all-cause mortality in PSC patients undergoing liver transplantation. These findings suggest a potential interplay between host genetics, intestinal microbiota, and infectious complications after transplantation. Given the retrospective design, limited sample size, and use of archival FFPE tissue, all findings should be interpreted as exploratory and hypothesis-generating. Prospective multicenter studies using standardized sampling and high-resolution metagenomic approaches are warranted for validation.