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 among the type of antibiotic used during the neutropenic period, changes in the intestinal microbiota, and subsequent occurrence of aGVHD are not clear. In this study, a total of 211 patients undergoing HSCT were stratified into 3 groups: patients 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 or without previous 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 (45%) developed aGVHD (grade II), including 54 with intestinal GVHD. The incidence of intestinal GVHD was higher in group 3 compared with group 1 and group 2 (32.1%, 11.6%, and 26.4%, respectively; P = .044). After adjusting for potentially significant variables identified by univariate analysis, multivariate analyses identified broad-spectrum antibiotic use during the neutropenic period as associated with the occurrence of intestinal GVHD (hazard ratio, 3.25; 95% confidence interval, 1.13 to 9.34; P = .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. Evaluation of circulating immune cell subsets according to type of antibiotic used during the neutropenic period revealed delayed recovery of myeloid-derived suppressor cells in the broad-spectrum antibiotic use group. Our data indicate that the 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 can help prevent the development of aGVHD.

A gut microbiota score predicting acute graft-versus-host disease following myeloablative allogeneic hematopoietic stem cell transplantation

“…21,23,25,26 However, the relevant microbiota found to be related to aGVHD was not consistent among different transplant centers. 5,15,22,[25][26][27][28] It may be interpreted that gut microbiota are impacted by many factors, such as antibiotics, conditioning, diet, and geographic environment, 11,15,[29][30][31] and our previous studies have demonstrated such phenomena. 11 The present study demonstrates that the microbiota negatively (eg, Lachnospiraceae and Peptostreptococcaceae) or positively (eg, Enterobacteriaceae) correlate with aGVHD occurrence.…”

The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation

“…In a mouse allo-HSCT model, clindamycin administration was associated with AIC decrease and more severe GvHD, while re-administration of AIC increased its levels in the gut and improved survival. 93 Additionally, Lee et al 94 compared patients who did not require any systemic antibiotic treatment during the transplantation course with those who received cefepime and those who were treated with carbapenem antibiotics. The carbapenem group displayed a significant loss of microbial diversity at engraftment and an increased rate of acute GI GvHD (32.1%) compared to the noantibiotics group (11.6%).…”

The Value of Predictive Nursing in Perioperative Period of Allogeneic Hematopoietic Stem Cell Transplantation

“…In clinical practice, the traditional preventative treatment including systemic drug bath and negative pressure aseptic laminar flow ward monitoring, both have been widely accepted. However, the prophylactic use of antibiotics is still controversial [9]. In addition, predictive nursing is a new concept proposed in recent years, which refers to the simple way before the occurrence of adverse events to block the initiation of the event, so as to improve the prognosis of patients and reduce the cost of treatment [5].…”