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.
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"Hence, we now know that there are three different enterotypes (Arumugam et al, 2011) and that dysbiosis has important impact on auto-immunity, allergy and auto-inflammatory diseases. There are also strong indications that the microbiota varies amongst patients with cancer and has an impact on the occurrence of MBI and the related inflammatory response (Manichanh et al, 2008; Jenq et al, 2012). Moreover, oral and colonization with Candida species have been related to the occurrence of GVHD, especially of the gut (van der Velden et al, 2013). "
[Show abstract][Hide abstract]ABSTRACT: Infection remains one of the most prominent complications after cytotoxic treatment for cancer. The connection between neutropenia and both infections and fever has long been designated as ‘febrile neutropenia’, but treatment with antimicrobial agents and haematopoietic growth factors has failed to significantly reduce its incidence. Moreover, emerging antimicrobial resistance is becoming a concern that necessitates the judicious use of available antimicrobial agents. In addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury (MBI) or ‘mucositis’. MBI creates a port-de-entrée for resident micro-organisms to cause blood stream infections and contributes directly to the occurrence of fever by disrupting the highly regulated host-microbe interactions, which, even in the absence of an infection, can result in strong inflammatory reactions. Indeed, MBI has been shown to be a pivotal factor in the occurrence of inflammatory complications after cytotoxic therapy. Hence, the concept ‘febrile neutropenia’ alone may no longer suffice and a new concept ‘febrile mucositis’ should be recognized as the two are at least complementary. This review we summarizes the existing evidence for both paradigms and proposes new therapeutic approaches to tackle the perturbed host-microbe interactions arising from cytotoxic therapy-induced tissue damage in order to reduce fever in neutropenic patients with cancer.
Full-text · Article · Sep 2014 · British Journal of Haematology
"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.
Full-text · Article · Jul 2014 · Frontiers in Immunology
"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.