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Which species are in your feces?
Colby Zaph
Biomedical Research Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Address correspondence to: Colby Zaph, Biomedical Research Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Phone: 604.822.7231; Fax: 604.822.7815; E-mail: colby@brc.ubc.ca.
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Published November 22, 2010 - More info
J Clin Invest. 2010;120(12):4182–4185. https://doi.org/10.1172/JCI45263.
© 2010 The American Society for Clinical Investigation
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Abstract
Bloodstream infection by highly antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a growing clinical problem that increasingly defies medical intervention. Identifying patients at high risk for bacterial sepsis remains an important clinical challenge. Recent studies have shown that antibiotics can alter microbial diversity in the intestine. Here, we characterized these effects using 16s rDNA pyrosequencing and demonstrated that antibiotic treatment of mice enabled exogenously administered VRE to efficiently and nearly completely displace the normal microbiota of the small and large intestine. In the clinical setting, we found that intestinal domination by VRE preceded bloodstream infection in patients undergoing allogeneic hematopoietic stem cell transplantation. Our results demonstrate that antibiotics perturb the normal commensal microbiota and set the stage for intestinal domination by bacteria associated with hospital-acquired infections. Thus, high-throughput DNA sequencing of the intestinal microbiota could identify patients at high risk of developing bacterial sepsis.
Authors
Carles Ubeda, Ying Taur, Robert R. Jenq, Michele J. Equinda, Tammy Son, Miriam Samstein, Agnes Viale, Nicholas D. Socci, Marcel R.M. van den Brink, Mini Kamboj, Eric G. Pamer
Nosocomial infections are infections acquired as a result of treatment in a hospital or health care unit. They are increasingly becoming a significant public health problem. It is thought that 5%–10% of patients entering hospitals worldwide develop a hospital-acquired infection (HAI) (1). The global growth of antibiotic-resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), has complicated the control of HAIs and highlights the need for a better understanding of how HAIs develop, are acquired, and may be controlled.
Intestinal Enterococcus infections are among the most common type of infection acquired by hospitalized patients. While enterococcal infections are much less capable of causing disease than HAIs such as Clostridium difficile and S. aureus, they still cause complications, prolong hospital stays, and can be fatal, particularly those caused by VRE. Fatal VRE infections, which occur upon bacterial invasion of the bloodstream, primarily affect immunocompromised patients such as those undergoing bone marrow or hematopoietic stem cell transplantation (HSCT) (2). It has been estimated that up to 50% of HSCT patients acquire VRE, and infection with VRE is independently associated with increased mortality in these patients (3). Identifying high-risk patients and developing novel methods to combat VRE are critical components in combating HAIs. The study by Ubeda et al. in this issue of the JCI begins to address this in both mice and humans using high-throughput sequencing analysis of commensal flora populations (4).
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Commensal flora and susceptibility to infection
Over the past several years, interest in understanding the relationship between the commensal flora and disease states has increased markedly. It is clear that changes in the flora have a dramatic effect on the outcomes of many diseases and directly or indirectly affect immune homeostasis and function (5). For example, mice lacking all commensal bacteria (germ-free mice) have dramatically altered immune systems (6, 7) and immune responses at enteric and peripheral sites (8, 9). Furthermore, it has been shown in humans and animals that antibiotic-induced changes in the commensal flora are dramatic and long-lived (10) and have consequences for susceptibility to intestinal infections, including VRE (11).
While the exact role of the commensal flora in intestinal homeostasis is unclear, there are several studies that have identified components of this regulatory network (Figure 1). First, interactions between the host and the commensal flora via MyD88-dependent Toll-like receptor (TLR) activation are critical for maintenance of intestinal homeostasis (12, 13). Whether commensal bacteria are recognized by intestinal epithelial cells (IECs) or by intestinal antigen-presenting cells such as DCs and macrophages is not clear. However, mice with an IEC-specific deletion of the gene encoding IκB kinase-γ (IKK-γ; also known as NEMO) spontaneously develop intestinal inflammation (14), suggesting that NF-κB activation — possibly initiated by TLR activation by commensal bacteria — is playing a critical role in maintaining the host-commensal homeostatic relationship. The regulatory role of commensal bacteria may be to activate the intestinal immune response to control potentially pathogenic bacteria, as it has been shown that colonization of germ-free mice with a defined flora leads to the expression of several antimicrobial peptides, including the secreted C-type lectin regenerating islet–derived IIIγ (REGIIIγ), which is directly toxic to Gram-positive commensal and pathogenic bacteria (15, 16), and the goblet cell–specific protein resistin-like molecule-β (RELMβ) (17). In addition, antibiotic treatment of mice leads to a reduction in total numbers of bacteria, loss of REGIIIγ and RELMβ expression (11, 18), and increased susceptibility to outgrowth of, or infection with, intestinal bacterial pathogens such as Salmonella typhimurium (19–21) and VRE (11). Thus, the commensal flora are a critical component in maintaining the steady state as well as in preventing the outgrowth of potentially pathogenic species. However, the dynamics of the commensal flora prior to colonization by a pathogenic species is not known, and whether any predictions about disease progression can be made is unclear.
Figure 1Antibiotic treatment leads to long-term changes in the commensal flora and susceptibility to VRE. (A) In the steady state, interactions between commensal bacteria and host cells in the intestine — primarily epithelial cells — result in the production of antimicrobial effector proteins (AMPs), such as REGIIIγ and RELMβ, that shape the commensal populations. The production of AMPs in this context may be dependent on NF-κB, which is presumed to be activated by TLR recognition of commensal bacterial products. In this state, mice are resistant to VRE infection. (B and C) Following transient antibiotic treatment, the numbers and diversity of the bacterial populations are severely reduced. Antibiotic treatment — presumably through a reduction in commensal bacteria — also results in decreased expression of AMPs. These changes result in long-lived increased susceptibility to VRE.
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Relevance to human disease
To directly test whether a bacterial population signature could identify patients predisposed to fatal VRE infections, Ubeda et al. examined the microbiomes of human patients undergoing allogeneic HSCTs, a group at high risk for developing HAIs (4). All HSCT patients received prophylactic antibiotic treatment upon admission, during fever episodes, and at any point when neutrophil numbers decreased, so as to protect them against potential bacterial infections caused by neutropenia. Antibiotic use was not consistent, although most patients received ciprofloxacin, vancomycin, and trimethoprim-sulfamethoxazole at some point during the observation period. During the course of the study, two patients developed systemic VRE infections. The patients that developed VRE bacteremia displayed a striking change in the intestinal flora immediately prior to VRE infection, with a total shift toward bacteria from the genus Enterococcus as the dominant microbial population. Thus, the intestinal domination by Enterococcus species that preceded bloodstream invasion suggests that monitoring of fecal bacterial populations may provide a warning of impending systemic infections in immunocompromised patients and offer an opportunity for therapeutic intervention.
The shift in commensal flora to a single genus in immunocompromised patients is in striking contrast to data in healthy volunteers treated with ciprofloxacin, who lost bacterial diversity but did not acquire overgrowth by a single species (10). This highlights the important role of the host immune response in regulating commensal bacterial populations (Figure 2). The production of immune mediators in the gut — such as IgA (22); effector T cell– and DC-derived cytokines, including IL-17A, IL-22, and IL-23 (23, 24); and regulatory molecules, including TGFβ and retinoic acid (25) — may all contribute to maintaining a balanced commensal flora. Thus, the status of the immune system is also a critical component in commensal homeostasis, further highlighting the closely linked host-commensal relationship.
Figure 2The role of the immune system in regulation of the commensal microflora. (A) In healthy subjects, recovery from antibiotic treatment results in minor changes to the diversity of the commensal flora. Immune mechanisms, including production of commensal-specific IgA, effector and regulatory cytokines, and retinoic acid that can act on IECs and other immune cells, may all contribute to the maintenance of intestinal homeostasis. (B) In contrast, immunocompromised patients that have impaired B cell, T cell, and DC responses often do not recover bacterial diversity following antibiotic treatment; in some cases, a single genus dominates the flora.
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