scholarly journals R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease

2017 ◽  
Vol 214 (12) ◽  
pp. 3507-3518 ◽  
Author(s):  
Eiko Hayase ◽  
Daigo Hashimoto ◽  
Kiminori Nakamura ◽  
Clara Noizat ◽  
Reiki Ogasawara ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Fecal Microbiota Transplantation ◽  
Paneth Cell ◽  
Fecal Microbiota ◽  
Paneth Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Functions ◽  
Therapeutic Benefits ◽  
Physiological Approach

The intestinal microbial ecosystem is actively regulated by Paneth cell–derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host–microbiota cross talk toward therapeutic benefits.

Tu1882 - Fecal Microbiota Transplantation Improves Gastrointestinal Graft-Versus-Host Disease and Restores the Microbiome: A Pediatric Experience

2018 ◽  
Vol 154 (6) ◽  
pp. S-1046-S-1047 ◽  
Author(s):  
Wing Fei Wong ◽  
Shrish Budree ◽  
Majdi Osman ◽  
Pratik Panchal ◽  
Zain Kassam ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Host Disease ◽  
Graft Versus Host

Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients

2020 ◽  
Vol 12 (556) ◽  
pp. eaaz8926 ◽  
Author(s):  
Yannouck F. van Lier ◽  
Mark Davids ◽  
Nienke J. E. Haverkate ◽  
Pieter F. de Groot ◽  
Marjolein L. Donker ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Dependent ◽  
Study Participants ◽  
Steroid Refractory

Disruption of the intestinal microbiota occurs frequently in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and predisposes them to development of graft-versus-host disease (GvHD). In a prospective, single-center, single-arm study, we investigated the effect of donor fecal microbiota transplantation (FMT) on symptoms of steroid-refractory or steroid-dependent, acute or late-onset acute intestinal GvHD in 15 individuals who had undergone allo-HCT. Study participants received a fecal suspension from an unrelated healthy donor via nasoduodenal infusion. Donor FMT was well tolerated, and infection-related adverse events did not seem to be related to the FMT procedure. In 10 of 15 study participants, a complete clinical response was observed within 1 month after FMT, without additional interventions to alleviate GvHD symptoms. This response was accompanied by an increase in gut microbial α-diversity, a partial engraftment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including Clostridiales and Blautia species. In 6 of the 10 responding donor FMT recipients, immunosuppressant drug therapy was successfully tapered. Durable remission of steroid-refractory or steroid-dependent GvHD after donor FMT was associated with improved survival at 24 weeks after donor FMT. This study highlights the potential of donor FMT as a treatment for steroid-refractory or steroid-dependent GvHD, but larger clinical trials are needed to confirm the safety and efficacy of this procedure.

Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 223-231 ◽  
Author(s):  
Yoshihiro Eriguchi ◽  
Shuichiro Takashima ◽  
Hideyo Oka ◽  
Sonoko Shimoji ◽  
Kiminori Nakamura ◽  
...  
Keyword(s):  
Microbial Communities ◽  
Graft Versus Host Disease ◽  
Paneth Cell ◽  
Polymyxin B ◽  
Paneth Cells ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Curative Therapy ◽  
Graft Versus Host ◽  
Close Relationship

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, α-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of α-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT.

scholarly journals Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fen Zhang ◽  
Tao Zuo ◽  
Yun Kit Yeoh ◽  
Frankie W. T. Cheng ◽  
Qin Liu ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Temporal Dynamics ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Cell Transplant ◽  
Fecal Microbiota Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Longitudinal Dynamics ◽  
Graft Versus Host

AbstractFecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.

scholarly journals Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality

Blood ◽  
2013 ◽  
Vol 122 (8) ◽  
pp. 1505-1509 ◽  
Author(s):  
John E. Levine ◽  
Elisabeth Huber ◽  
Suntrea T. G. Hammer ◽  
Andrew C. Harris ◽  
Joel K. Greenson ◽  
...  
Keyword(s):  
High Risk ◽  
Light Microscopy ◽  
Graft Versus Host Disease ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Numbers ◽  
Key Points ◽  
Histopathological Grading

Key Points Paneth cell numbers in the duodenum at onset of GVHD correlate with outcomes. Paneth cells are easy to identify and quantify with light microscopy and may supplement histopathological grading of GI GVHD.

scholarly journals Fecal Microbiota Transplantation As a Treatment of Severe Steroid-Resistant Acute and Chronic Graft Versus Host Disease. Spectrum of Responses and Complications

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5667-5667
Author(s):  
Jaroslaw Bilinski ◽  
Karol Lis ◽  
Agnieszka Tomaszewska ◽  
Pawel Grzesiowski ◽  
Aleksandra Pechcinska ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
General Condition ◽  
Fecal Microbiota Transplantation ◽  
Case Reports ◽  
Fecal Microbiota ◽  
Resistant Bacteria ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade 3

INTRODUCTION Only half of the patients with gut predominant acute graft-versus-host disease (aGvHD) respond to first-line treatment (corticosteroids). No consensus has yet been reached on treatment in the second and subsequent lines. There are several case reports supporting the role of fecal microbiota transplantation (FMT) in the treatment of steroid-resistant GvHD. Here we present the results of FMT in one of the largest cohorts of patients with acute (a) and chronic (c) GvHD, mostly with gut manifestation. MATERIAL AND METHODS 12 patients aged 26-67 years underwent a total of 15 FMTs to decolonize the gastrointestinal tract (GI) from antibiotic-resistant bacteria (ARB). In all of them steroid resistant GvHD (2 patients with cGvHD and 10 with aGvHD) coexisted. All patients with aGvHD had GI tract involvement (median grade: 3), 7 had skin (median grade: 3) and 5 had liver (median grade: 1) GvHD symptoms. Patients with cGvHD presented progressive involvement of the skin, lungs, pericardium and eyes. FMT was performed as two infusions by nasoduodenal tube of a 100g/200 ml solution of feces, on following days. OUTCOMES The median time from aGvHD diagnosis to the first FMT treatment was 46.5 days (8-489 days). Most patients were still on steroids during FMT (median dose 0.5 mg metyloprednisolone/kg of body weight). As a result, in 10/12 patients (83%) ARB decolonization was observed. Overall response rate (ORR) in the case of aGvHD reached 58% (7/12 performed FMTs), including CR in 4/12 (33%) cases. Median duration of response to relapse or death was 168 days (10-1080 days). The majority of patients who responded to FMT (5/6, 83%) underwent the procedure in a better general condition (ECOG≤2). Severe general condition (ECOG> 2) seemed to be related with the presence of serious complications after FMT. Both patients with cGvHD achieved stabilization or improvement of organ disease, which may be related with FMT procedure (there is no data on use FMT in cGvHD). COMPLICATIONS Among the complications of FMT with a possible cause-effect relationship there were: 1 death in close relation with FMT (respiratory failure in the course of pneumonia), 3 septic episodes, 2 subileus episodes and one case of diarrhea. In the latter case, the workup revealed norovirus infection originating from the fecal material of the donor (who was asymptomatic). CONCLUSIONS The described results indicate that FMT may be an effective treatment option for severe GvH disease. Patients undergoing the procedure should be qualified early enough to avoid life-threatening complications and maximize the likelihood of responding to treatment. Figure Disclosures Jedrzejczak: Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Takeda: Consultancy; Novartis: Research Funding; Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Basak:Teva: Honoraria; Celgene: Honoraria.

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