Lactose drives <i>Enterococcus</i> expansion to promote graft-versus-host disease

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that <i>Enterococcus</i> also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. <i>Enterococcus</i> growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates <i>Enterococcus</i> outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic <i>Enterococcus</i> domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.