Microbial metabolites and graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplant

Abstract

Allogeneic hematopoietic cell transplantation (HCT) can cure hematologic malignancies, but 30-70% of recipients experience acute graft-versus-host disease (GvHD). GvHD is associated with changes in the gut microbiome, but the mechanistic relationship remains unclear. The gut microbiota produces gut metabolites, which may indicate or modulate GvHD. In a longitudinal case-control study of patients with and without acute gut GvHD, we characterized bile acid concentrations and the gut microbiome in stool. Endogenous secondary bile acid concentrations were associated with gut GvHD (p=0.009). We observed 4.4-fold lower levels of endogenous secondary bile acids in GvHD, particularly lithocholic acid and derivatives (p=0.004/padjusted = 0.02, fold change (FC) = 0.23). There was a 100-fold lower median abundance (p=0.002 and FC < 0.01) and 20-fold lower median diversity of bacterial bile acid 7α-dehydroxylation (bai) genes (p=0.0007 and FC < 0.05) in patients with GvHD, indicating that acute gut GvHD patients are deficient in microbial bai genes that make secondary bile acids. This work also covers the microbial metabolites short-chain fatty acids (SCFAs) and other compounds associated with GvHD. One SCFA, butyric acid, linked with protection against GvHD pre-HCT (p = 0.02) and several unidentified metabolites were associated with protection against GvHD. These findings suggest that microbial metabolites are markers and potentially mediators of GvHD.