Prolonged suppression of butyrate producing bacteria is associated with acute gastrointestinal graft-versus-host disease and transplant related mortality after allogeneic stem cell transplantation.

Abstract

BACKGROUND\nButyrogenic bacteria play an important role in gut microbiome homeostasis and intestinal epithelial integrity. Previous studies have demonstrated an association between administration of short chain fatty acids like butyrate and protection from acute graft-versus-host disease (aGvHD) after allogeneic stem cell transplantation (ASCT).\n\n\nMETHODS\nHere we examined the abundance and butyrogenic capacity of butyrate producing bacteria in 28 healthy donors and 201 patients after ASCT. We prospectively collected serial stool samples and performed PCR analysis of the butyrate producing bacterial enzyme butyryl-CoA:acetate CoA-transferase (BCoAT) in fecal nucleic acid extracts.\n\n\nRESULTS\nOur data demonstrate a strong and prolonged suppression of butyrogenic bacteria early in the course of ASCT. In a multivariable analysis, early use of broad-spectrum antibiotics before day 0 (d 0, day of transplantation) was identified as independent factor associated with low BCoAT copies (odds ratio 0.370 (0.175-0.783), p=0.009). Diminished butyrogens correlated with other biomarkers of microbial diversity such as low 3-indoxyl sulfate (3-IS) levels, reduced abundance of Clostridiales and low inverse Simpson and effective Shannon indices (p<0.001, respectively). Low BCoAT copies at GvHD-onset correlated with GI-GvHD severity (p=0.002) and were associated with significantly higher GvHD associated mortality (p=0.040). Furthermore, low BCoAT copies at d 30 were associated with significantly higher transplant related mortality (p=0.017).\n\n\nCONCLUSIONS\nOur results are consistent with the hypothesis that alterations in the microbiome play an important role in GvHD pathogenesis and that microbial parameters such as BCoAT might serve as biomarkers to identify patients at high risk for developing lethal GI-GvHD.