Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation

Weber, Daniela; Oefner, Peter J.; Dettmer, Katja; Hiergeist, Andreas; Koestler, Josef; Gessner, André; Weber, Markus; Stämmler, Frank; Hahn, J.; Wolff, Daniel; Herr, Wolfgang; Holler, Ernst

doi:10.1038/bmt.2016.66

Cited by 96 publications

(84 citation statements)

References 28 publications

(33 reference statements)

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“…82 The use of rifaximin in HCT patients has been found to preserve intestinal diversity and associates with lower TRM rates compared with patients treated with a combination of ciprofloxacin and metronidazole in a retrospective study. 83 Despite standard prophylaxis with antibiotics after HCT, many days of neutropenia leaves patients vulnerable to bacterial infections including BSI. 84 The incidence of BSI increases with acute GVHD, 85 and treatment of acute GVHD with corticosteroids such as methylprednisolone further suppresses the immune system and is associated with a higher risk of infection after transplant.…”

Section: Diversity Loss Gvhd and Posttransplant Infectionsmentioning

confidence: 99%

The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease

Staffas

Silva

Brink

2017

Blood

169

131

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Hematopoietic cell transplantation (HCT) is a critical treatment of patients with high-risk hematopoietic malignancies, hematological deficiencies, and other immune diseases. In allogeneic HCT (allo-HCT), donor-derived T cells recognize host tissues as foreign, causing graft-versus-host disease (GVHD) which is a main contributor to morbidity and mortality. The intestine is one of the organs most severely affected by GVHD and research has recently highlighted the importance of bacteria, particularly the gut microbiota, in HCT outcome and in GVHD development. Loss of intestinal bacterial diversity is common during the course of HCT and is associated with GVHD development and treatment with broad-spectrum antibiotics. Loss of intestinal diversity and outgrowth of opportunistic pathogens belonging to the phylum Proteobacteria and Enterococcus genus have also been linked to increased treatment-related mortality including GVHD, infections, and organ failure after allo-HCT. Experimental studies in allo-HCT animal models have shown some promising results for prebiotic and probiotic strategies as prophylaxis or treatment of GVHD. Continuous research will be important to define the relation of cause and effect for these associations between microbiota features and HCT outcomes. Importantly, studies focused on geographic and cultural differences in intestinal microbiota are necessary to define applicability of new strategies targeting the intestinal microbiota.

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Section: Diversity Loss Gvhd and Posttransplant Infectionsmentioning

confidence: 99%

The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease

Staffas

Silva

Brink

2017

Blood

169

131

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“…The choice of antibiotic can determine the degree of microbiota disruption, and agents with more limited spectra of activity appear to be associated with reduced acute GVHD severity. 96,97 For example, rifaximin was recently reported to perform favorably as bacterial prophylaxis in comparison with a historical cohort treated with a prophylactic combination of ciprofloxacin and metronidazole. 97 Rifaximin use was associated with both better preservation of intestinal commensal bacteria and reduced transplant-related mortality.…”

Section: Commensal Aspects Of the Intestinal Mucosa In Gvhdmentioning

confidence: 99%

“…96,97 For example, rifaximin was recently reported to perform favorably as bacterial prophylaxis in comparison with a historical cohort treated with a prophylactic combination of ciprofloxacin and metronidazole. 97 Rifaximin use was associated with both better preservation of intestinal commensal bacteria and reduced transplant-related mortality. Similarly, antibiotics used to treat neutropenic fever that spare obligate anaerobes, including cefepime and aztreonam, produce less perturbation to intestinal bacterial composition compared with broaderspectrum antibiotics with increased anaerobic activity such as piperacillin-tazobactam and carbapenems.…”

Section: Commensal Aspects Of the Intestinal Mucosa In Gvhdmentioning

confidence: 99%

Role of the intestinal mucosa in acute gastrointestinal GVHD

Peled

Hanash

Jenq

2016

Blood

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Intestinal graft-versus-host disease (GVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation. The intestinal mucosa comprises the inner lining of the intestinal tract and maintains close proximity with commensal microbes that reside within the intestinal lumen. Recent advances have significantly improved our understanding of the interactions between the intestinal mucosa and the enteric microbiota. Changes in host mucosal tissue and commensals posttransplant have been actively investigated, and provocative insights into mucosal immunity and the enteric microbiota are now being translated into clinical trials of novel approaches for preventing and treating acute GVHD. In this review, we summarize recent findings related to aspects of the intestinal mucosa during acute GVHD.

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“…In contrast, cefepime and aztreonam, which have very limited anaerobic activity, were not associated with GVHD-related mortality (93). Interestingly, prophylaxis with rifaximin, a nonabsorbed broad-spectrum oral antibiotic, was associated with a decrease in Enterococcus species, higher levels of urinary 3-indoxyl sulfate, which is associated with the presence of Clostridiales, and improved survival compared with ciprofloxacin and the antianaerobic antibiotic metronidazole (94).…”

Section: Inflammatory Cytokinesmentioning

confidence: 96%

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

Ferrara¹,

Smith²,

Sheets³

et al. 2017

Journal of Clinical Investigation

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Acute graft-versus-host disease (aGVHD) was noted as a complication of allogeneic bone marrow (BM) transplantation in animal models more than six decades ago (1, 2). The initial descriptions of aGVHD differentiated it from the complications of BM aplasia and focused on the severe consequences of GVHD for lower gastrointestinal (GI) tract function, as manifested by weight loss and profound diarrhea. Subsequent studies clearly identified donor T cells as the critical cells required for the induction of aGVHD (3)(4)(5). aGVHD was shown to predominantly involve the skin, liver, and lower GI tract and, later, the upper GI tract (6). In the absence of approaches to prevent aGVHD, this complication occurs in close to 100% of recipients of allogeneic BM/stem cell transplants (allogeneic hematopoietic cell transplantation, allo-HCT), greatly limiting the survival of the first cohort of patients who underwent allo-HCT. Lower GI tract GVHD: clinical findingsDespite the use of prophylaxis to prevent aGVHD, without rigorous T cell depletion this complication occurs in 30%-70% of patients undergoing allo-HCT (7-9). Standard treatment of aGVHD is the administration of systemic corticosteroids and additional immunosuppressive agents, which, as primary therapy, do not substantially improve patient outcomes (10). Thirty to seventyfive percent of patients who develop aGVHD will have a complete response to corticosteroid therapy (11).The outcome for patients with severe aGVHD (grades III-IV) of the lower GI tract is poor, with 25% overall survival (12). Four risk factors (corticosteroid resistance, age under 18 years at time of transplant, GI tract bleeding, and total bilirubin greater than 3 mg/dl) were found on multivariate analysis to be statistically associated with poor survival; no patients with all 4 factors survived, highlighting the critical need to improve survival for these patients. This Review will focus on recent findings regarding the homeostatic mechanisms of the lower GI tract that relate to the pathophysiology of aGVHD involving the distal small intestine and colon. Immune homeostasis in the GI tractThe immune balance of the human small intestine and colon is complex. There are over 100 trillion bacteria that are critical to the function of the GI tract, and individuals are exposed to a huge number of food-borne antigens on a daily basis. Thus, there must exist dynamic and robust mechanisms that mediate immune responses to pathogenic organisms but that prevent immune responses to normal flora and dietary antigens.Antigen-presenting cells in the GI tract. Specialized hematopoietic antigen-presenting cells (APCs) in the GI tract include multiple subpopulations of dendritic cells (DCs) and macrophages ( Figure 1). DCs in the lamina propria (LP) and Peyer's patch sample luminal antigens and migrate to regional lymph nodes (LNs) to activate immune responses (13,14). Macrophages are sessile and are the most abundant innate immune cells in the intestine; they maintain homeostasis by phagocytosing microorganisms and apop...

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Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation

Cited by 96 publications

References 28 publications

The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease

The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease

Role of the intestinal mucosa in acute gastrointestinal GVHD

Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis

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