Decreased secretion of Paneth cell α‐defensins in graft‐versus‐host disease

Eriguchi, Yoshihiro; Nakamura, Kiminori; Hashimoto, Daigo; Shimoda, Shinji; Shimono, Nobuyuki; Akashi, Koichi; Ayabe, Tokiyoshi; Teshima, Takanori

doi:10.1111/tid.12423

Cited by 51 publications

(56 citation statements)

References 21 publications

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“…Antibiotic treatment has been shown to suppress production of Reg3α in Paneth cells, which prevents colonization by pathogens; 22, 23 similarly, metabolites of commensal Clostridiales mediate colonization resistance and maintain a microbiota supporting integrity of the intestinal epithelial barrier. Furthermore, commensal Clostridiales have been identified as important producers of short chain fatty acids (SCFAs) such as butyrate, which maintain intestinal regulatory T cells.…”

Section: Discussionmentioning

confidence: 99%

Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

Weber

Jenq

Peled

et al. 2017

Biology of Blood and Marrow Transplantation

206

150

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In allogeneic stem cell transplantation (ASCT), systemic broad-spectrum antibiotics are frequently used for treatment of infectious complications, but their effect on microbiota composition is still poorly understood. Here, in a retrospective analysis of 621 patients, who underwent ASCT at the University Medical Center of Regensburg and Memorial Sloan Kettering Cancer Center in New York, we assessed the impact of timing of peri-transplant antibiotic treatment on intestinal microbiota composition as well as transplant-related mortality (TRM) and overall survival. Early exposure to antibiotics was associated with lower urinary 3-indoxyl sulfate levels (p<0.001) and a decrease in fecal abundance of commensal Clostridiales (p=0.03) compared to late antibiotic treatment, which was particularly significant (p=0.005) for Clostridium cluster XIVa in the Regensburg group. Earlier antibiotic treatment prior to ASCT was further associated with a higher TRM (34%, n=79/236) compared to post-ASCT (21% n=62/297, p=0.001) or no antibiotics (7% n=6/88, p<0.001). Timing of antibiotic treatment was the dominant independent risk factor for TRM (HR 2.0, p≤0.001) in multivariate analysis beside increase age (HR 2.15, p=0.004), reduced Karnofsky performance status (HR 1.47, p=0.03) and female donor/ male recipient sex combination (HR 1.56, p=0.02) A competing-risk analysis revealed the independent effect of early initiation of antibiotics on GvHD-related TRM (p=0.004) in contrast to infection-related TRM and relapse (p=ns). The poor outcome associated with early administration of antibiotic therapy that is active against commensal organisms, and specifically the possibly protective Clostridiales calls for the use of Clostridiales-sparing antibiotics and rapid restoration of microbiota diversity after cessation of antibiotic treatment.

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Section: Discussionmentioning

confidence: 99%

Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

Weber

Jenq

Peled

et al. 2017

Biology of Blood and Marrow Transplantation

206

150

View full text Add to dashboard Cite

show abstract

“…A previous report [12] demonstrated that GI-GVHD predisposed to enteric bacterial BSIs; the incidence of enteric bacterial BSI was almost 3 times greater after GI-GVHD development than before in the first 120Àdays after allo-HSCT. In a mouse model, loss of Paneth cells led to reduced secretion of a-defensins, antimicrobial peptides required for maintaining intestinal microbial ecology, resulting in a profound loss of diversity and an expansion of gramnegative bacteria in the intestinal microbiome [26][27][28][29]. Alterations in the intestinal microbiome have also been observed in allo-HSCT recipients with GI-GVHD [30].…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Mori

Yoshimoto

Nishida

et al. 2018

Biology of Blood and Marrow Transplantation

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Bloodstream infection (BSI) is a well-known cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Here, we conducted a retrospective study to assess the morbidity, etiology, risk factors, and outcomes of BSI in the postengraftment period (PE-BSI) after allo-HSCT. Forty-three of 316 patients (13.6%) developed 57 PE-BSI episodes, in which 62 pathogens were isolated: Gram-positive bacteria, gram-negative bacteria, and fungi, respectively, accounted for 54.8%, 35.5%, and 9.7% of the isolates. Multivariate analysis revealed methylprednisolone use for graft-versus-host disease (GVHD) prophylaxis (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.49 to 28.2; P = .013) and acute gastrointestinal GVHD (GI-GVHD) (OR, 8.82; 95% CI, 3.99 to 19.5; P < .0001) as risk factors for developing PE-BSI. This finding suggested that GI-GVHD increases the risk of bacterial translocation and subsequent septicemia. Moreover, among patients with GI-GVHD, insufficient response to corticosteroids, presumably related to an intestinal dysbiosis, significantly correlated with this complication. Patients with PE-BSI presented worse outcome compared with those without (3-year overall survival, 47.0% versus 18.6%; P < .001). Close microbiologic monitoring for BSIs and minimizing intestinal dysbiosis may be crucial to break the vicious cycle between GI-GVHD and bacteremia and to improve transplant outcomes especially in patients who require additional immunosuppressants.

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“…Changes to patients' gastrointestinal tracts during HCT may in turn affect the gut microbiota. For example, overgrowth of pathobionts may result from a loss of antimicrobial peptide-producing Paneth cells in the small intestine (71)(72)(73). Indeed, loss of Paneth cells is a marker of GvHD risk in humans (74).…”

Section: Il-22mentioning

confidence: 99%

The gut microbiota and graft-versus-host disease

Fredricks¹

2019

Journal of Clinical Investigation

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Decreased secretion of Paneth cell α‐defensins in graft‐versus‐host disease

Abstract: Background: Intestinal microbial ecology is actively regulated by Paneth cell-derived

Cited by 51 publications

References 21 publications

Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation

Gastrointestinal Graft-versus-Host Disease Is a Risk Factor for Postengraftment Bloodstream Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients

The gut microbiota and graft-versus-host disease

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