The Gut Microbiome and Tacrolimus Dosing in the Peri-Heart Transplant Period

Abstract

<h3>Purpose</h3> Recent evidence suggest that the gut microbiome may influence tacrolimus dosing requirements, potentially through direct metabolism. The impact of the gut microbiome on tacrolimus requirements among heart transplant (HT) recipients during medication initiation is unknown. We aimed to evaluate the effect of the gut microbiome on tacrolimus dosing requirements among HT recipients in the peri-HT period. <h3>Methods</h3> We conducted a prospective, observational cohort study of all single organ HT recipients at a single center from 2020-2021. Stool samples were collected within 2 weeks of HT and underwent shotgun metagenomic analysis. Measures of microbial diversity, composition, and metabolomics were correlated to the ratio of tacrolimus serum level (L) to the total 24-hour dose (D) at time of post-HT discharge. HT recipients were further divided into 2 groups: above-median L/D ratio (slow metabolizers) and below-median L/D ratio (fast metabolizers). <h3>Results</h3> Thirty-two patients were included in the study. Stool samples were collected a median of 8 days (IQR [5, 11]) post-HT. Median time to discharge was 18 days (IQR [12, 23]). Median L/D ratio was 0.86 (IQR [0.52, 1.13]) with 18 patients in the slow metabolizer group and 16 in the fast metabolizer group (median L/D 1.28 vs 0.61, p = 0.001). The fast metabolizer group was on a higher tacrolimus dose at discharge than the slow metabolizer group (19 vs 9 mg/day, p<0.001). Demographic factors and within sample microbial diversity, i.e. α-diversity, as measured by inverse Simpson index was similar between groups. The fast metabolizer group was found to have lower abundance of the phylum <i>Bacteroidetes</i> (19% vs 39%, p = 0.03) and higher abundance of <i>Firmicutes</i> (67% vs 47%, p = 0.04) (Fig. 1). Both groups had similar levels of the gut microbial metabolites, secondary bile acids and short chain fatty acids. <h3>Conclusion</h3> HT recipients have variable tacrolimus dosing requirements in the immediate post-HT period. Differences in the abundance of gut microbes in the peri-HT period may influence these needs.