Jenq, R.R. et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903-911

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 04/2012; 209(5):903-11. DOI: 10.1084/jem.20112408
Source: PubMed


Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients.

Download full-text


Available from: Raya Khanin, Oct 02, 2015
40 Reads
  • Source
    • "Another study showed a marked expansion of Lactobacillales in murine GVHD. Elimination of this species from the flora of mice before allo-HSCT aggravated GVHD, whereas its reintroduction mediated significant protection, indicating that the microbiota can modulate the severity of intestinal inflammation (18). A recent study suggested that not only bacteria but also host fungal communities (mycobiome) can critically shape acute GVHD (19). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment with curative potential for certain aggressive hematopoietic malignancies. Its success is limited by acute graft-versus-host disease (GVHD), a life-threatening complication that occurs when allo-reactive donor T cells attack recipient organs. There is growing evidence that microbes and innate pattern-recognition receptors (PRRs) such as toll-like receptors (TLR) and nod-like receptors (NLR) are critically involved in the pathogenesis of acute GVHD. Currently, a widely accepted model postulates that intensive chemotherapy and/or total-body irradiation during pre-transplant conditioning results in tissue damage and a loss of epithelial barrier function. Subsequent translocation of bacterial components as well as release of endogenous danger molecules stimulate PRRs of host antigen-presenting cells to trigger the production of pro-inflammatory cytokines (cytokine storm) that modulate T cell allo-reactivity against host tissues, but eventually also the beneficial graft-versus-leukemia (GVL) effect. Given the limitations of existing immunosuppressive therapies, a better understanding of the molecular mechanisms that govern GVHD versus GVL is urgently needed. This may ultimately allow to design modulators, which protect from GvHD but preserve donor T-cell attack on hematologic malignancies. Here, we will briefly summarize current knowledge about the role of innate immunity in the pathogenesis of GVHD and GVL following allo-HSCT.
    Frontiers in Immunology 07/2014; 5:337. DOI:10.3389/fimmu.2014.00337
  • Source
    • "These include the human commensal bacteria Bacteroides fragilis (Round and Mazmanian, 2010), Faecalibacterium prausnitzii (Sokol et al. 2008), several Lactobacillus spp. (Jenq et al. 2012; Shimazu et al. 2012; van Baarlen et al. 2013) and Bifidobacterium spp. (Imaoka et al. 2008; Khokhlova et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: SUMMARY Human gastrointestinal bacteria often share their environment with parasitic worms, allowing physical and physiological interaction between the two groups. Such associations have the potential to affect host health as well as the bacterial and helminth populations. Although still in its early stages, research on the interaction between the microbiome and parasitic helminths in humans offers the potential to improve health by manipulating the microbiome. Previously, supplementation with various nutritional compounds has been found to increase the abundance of potentially beneficial gut commensal bacteria. Thus, nutritional microbiome manipulation to produce an environment which may decrease malnutrition associated with helminth infection and/or aid host recovery from disease is conceivable. This review discusses the influence of the gut microbiota and helminths on host nutrition and immunity and the subsequent effects on the human host's overall health. It also discusses changes occurring in the microbiota upon helminth infections and the underlying mechanisms leading to these changes. There are still significant knowledge gaps which need to be filled before meaningful progress can be made in translating knowledge from studying the human gut microbiome into therapeutic strategies. Ultimately this review aims to discuss our current knowledge as well as highlight areas requiring further investigation.
    Parasitology 06/2014; 141(10):1-17. DOI:10.1017/S0031182014000699 · 2.56 Impact Factor
  • Source
    • "As a possible intervention to reduce the risk of GVHD, gut flora manipulation and nutritional intervention strategies might be promising. Previous reports showed that gut flora manipulation by Lactobacillales may reduce intestinal inflammation and improve outcomes for allogeneic HSCT recipients in a murine model (33, 34). It is worthy to test whether the manipulation of intestinal microbiome is able to reduce the risk of acute GVHD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.
    Frontiers in Oncology 04/2014; 4:89. DOI:10.3389/fonc.2014.00089
Show more