Microbiome and Diseases: Graft-Versus-Host Disease

Abstract

Acute graft-versus-host disease (GvHD) of the gastrointestinal (GI) tract is still a major cause of severe morbidity and mortality following allogeneic stem cell transplantation (ASCT). The intestinal “microflora” has been in the focus of the pathophysiology of acute GI GvHD since many years. In 1974 van Bekkum and colleagues reported a possible role of microbiota as they observed that mice kept under germ-free conditions did not develop acute GI GvHD. Clinical studies showed a reduction of GvHD severity with total or selective gut decontamination and isolation which became standard for years. However, with deeper insights obtained by new molecular techniques, our understanding of the association between microbiota and GI GvHD has changed. During ASCT an early loss of intestinal microbiome diversity especially with regard to commensal Clostridiales and a shift toward an enteropathogenic flora was observed which associated with increased GvHD-related mortality. A major risk factor for the loss of commensal bacteria is the use of systemic broad-spectrum antibiotics for prophylaxis and therapy of neutropenic infections which occur frequently in ASCT patients. Both the kind of antibiotics and the timing of antibiotic treatment influence the outcome of patients after ASCT. The damage and destruction of Paneth cells by GvHD itself reduce antimicrobial peptides further aggravating intestinal dysbiosis during GvHD. These results indicate that microbiota manipulation could be a promising future approach not only for prophylaxis and treatment of acute GI GvHD but also for eradication of a colonization with multiple antibiotic-resistant pathogens to prevent infections or even to prevent relapse.