The Gut Microbiota Strikes Again

Hematopoietic stem cell transplantation (HSCT) is a lifesaving intervention in malignant and nonmalignant disease. However, as is the case with many good things, there is a dark side. For allogeneic HSCT, these include infection and graft vs host disease (GVHD), common complications associated with substantial morbidity and mortality although these have decreased in recent years [1, 2]. A number of strategies aimed at preventing each of these complications have been studied and some adopted into clinical practice. Preventive strategies for infection that have been studied include gut decontamination, administration of hematopoietic colony stimulating factors and prophylactic antibiotics, most specifically fluoroquinolones (reviewed in [3]). Current and potential strategies to reduce the incidence of acute GVHD (aGVHD) have been recently reviewed [4]. Levinson et al postulate in their study published in the current issue of CID that acute gut GVHD (aG-GVHD) increases the risk of blood stream infection with enteric organisms (EB-BSI) [5]. From a pathophysiological perspective, this hypothesis makes sense: damage resulting from attack of the stem cell graft on the host’s gut epithelium provides a portal of entry for enteric organisms. In this retrospective study of pediatric allogeneic HSCT recipients, EB-BSI developed in almost half of all patients. The strongest predictor of EB-BSI was time to neutrophil engraftment. Additionally, there was a trend to aG-GVHD as a predictor. EB-BSI was more common after the onset of aG-GVHD than before in the group that developed aG-GVHD. It was also more common in those with aG-GVHD than in patients who did not develop any aGVHD, when the first 30 days after HSCT were excluded to account for the confounding variable of neutrophil engraftment. The development of EB-BSI was significantly associated with mortality in the entire cohort but not in those who developed aGGVHD, likely due to the small numbers involved as pointed out by the authors. In their discussion, the authors noted the relationship between antibiotic usage and reduced gut microbial diversity observed by others, the latter of which is associated with mortality after HSCT [6]. They acknowledge that a limitation of their study was the lack of antibiotic data because such information might have had an impact on their analysis of mortality. Based on these data, the authors highlight the seriousness of EB-BSI in HSCT patients and theneed for preventivemeasures. The potential strategy proposed by them was the use of probiotics, presumably by stabilizing or restoring the gut microbiota after HSCT. The gut microbiota performs important homeostatic functions systemically and locally, including supporting intestinal epithelial health, host nutritional status, colonization resistance, and immune system functioning [7]. These considerations tie in directly with the Levinson study because maintenance of intact intestinal epithelium and colonization resistance by a healthy gutmicrobiotawould presumably guard against systemic invasion by enteric bacteria. Therefore, is it a good idea to disrupt these homeostatic functions with prophylactic antibiotics used in HSCT? Recent data suggest that it is not. The disarray in the gastrointestinal (GI) microbiota that occurs during HSCT contributes to aGVHD in mice and humans [8]. Microbial diversity, a marker of a healthy microbiota, diminishes during HSCT, in large part due to frequent antibiotic usage, and is associated with increased mortality after HSCT [6]. Presumably through the loss of colonization resistance provided by a diverse microbiota, there is overgrowth of potential pathogens such as Enterococcus species and Gram negative bacilli during HSCT [9–12]. Eventually, blood stream infections with these pathogens ensue, as shown by Levinson and others [5, 11, 12]. Another consideration is the role of the gut microbiota in the genesis of GVHD Received 1 April 2015; accepted 5 April 2015; electronically published 5 May 2015. Correspondence: Debra D. Poutsiaka, MD, PhD, Division of Geographic Medicine and Infectious Disease, Box 041, Tufts Medical Center, 800 Washington St, Boston, MA 02111 (dpoutsiaka@tuftsmedicalcenter.org). Clinical Infectious Diseases 2015;61(3):358–60 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/civ292