Vancomycin Exposure is Associated with Protection from Acute Graft-vs-Host Disease (aGVHD) Through Microbiome-dependent Mechanisms

BackgoundEnterococcus and Akkermansia species enhance immune function through T-cell dependent mechanisms. This suggests vancomycin exposure and consequently the relative abundance of Enterococcus may have repercussions on immune-related outcomes such as GVHD. To test this hypothesis we assessed the a) association between vancomycin exposure and aGVHD b) association between stool Enterococcus abundance and aGVHD c) in-vitro effect of vancomycin on T-cell function. MethodsTwo distinct cohorts were evaluated. 1) A "derivation" cohort comprising 46 patients where vancomycin exposure data was correlated with aGVHD 2) A "validation" cohort of 26 patients where metagenomic sequencing assessed the correlation between enterococcal abundance and aGVHD. Additionally, ELISPOT assays evaluated the impact of vancomycin exposure on T-cell function. ResultsIn the "derivation" cohort, aGVHD was associated with lower vancomycin exposure; (IQR 4.5 days) compared to (IQR 10.5 days) in patients without aGHVD (p-value 0.0072). Among five out of fourteen patients who developed aGVHD in "validation" cohort, significant genus enrichment for Enteroccocus and Akkermansia (5.75 and 7.59 log2fold change resp. p<0.05) was noted. Elispot assays demonstrated that T-cell exposure to vancomycin did not affect function. ConclusionsVancomycin exposure is associated with protection from aGVHD through microbiome-intrinsic processes but not direct impairment of T-cell function.