Alteration of the intestinal microbiota by broad-spectrum antibiotic use correlates with the occurrence of intestinal graft-versus-host disease

Abstract Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently receive empiric antibiotics during the neutropenic period before engraftment. Several recent studies have shown that anaerobes in the intestine are important mediators of intestinal homeostasis and that commensal bacteria can be potent modulators of the severity of acute graft-versus-host disease (aGvHD). However, the relationships between the type of antibiotic used during the neutropenic period, changes in the intestinal microbiota, and subsequent occurrence of aGvHD are not clear. A total of 211 patients receiving HSCT were stratified into three groups: patients who were not treated with any antibiotics during the neutropenic period (group 1, n = 43); patients treated with cefepime only (group 2, n = 87); and patients treated with carbapenem antibiotics, defined as meropenem or prepenem with/without prior cefepime therapy (group 3, n = 81). Intestinal microbiota analyses were performed on pre- and post-HSCT stool samples and immunophenotypic analyses were performed on pre- and post-HSCT peripheral blood samples. Among the 211 patients, 95 patients (45%) developed aGvHD (≥grade 2), including 54 with intestinal GvHD. Patients in group 3 had a higher incidence of intestinal aGvHD (32.1%) than patients in group 1 (11.6%) and group 2 (26.4%), respectively (P = 0.044). After adjusting for potentially significant variables identified by univariate analysis, multivariate analyses revealed that broad-spectrum antibiotic use during the neutropenic period was associated with the occurrence of intestinal GvHD [HR (95% CI) 3.25 (1.13-9.34), P=0.029]. Accordingly, loss of bacterial diversity in terms of alterations in intestinal microbiota after HSCT was observed in patients who received broad-spectrum antibiotics. Moreover, alterations in the frequencies of several intestinal bacteria phyla were associated with the occurrence of intestinal GvHD. When we evaluated circulating immune cell subsets according to type of antibiotic used during the neutropenic period, delayed recovery of myeloid-derived suppressor cells was observed in the broad-spectrum antibiotic group. Our data indicate that use of broad-spectrum antibiotics during the neutropenic period is associated with a higher incidence of intestinal GvHD via loss of microbiome diversity. Further studies are needed to determine whether maintaining bacterial diversity prevents aGvHD development.