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Publication
Obesity induces gut microbiota alterations and augments acute graft-versus-host
disease after allogeneic stem cell transplantation.
Authors Khuat LT, Le CT, Pai CS, Shields-Cutler RR, Holtan SG, Rashidi A, Parker SL,
Knights D, Luna JI, Dunai C, Wang Z, Sturgill IR, Stoffel KM, Merleev AA, More
SK, Maverakis E, Raybould HE, Chen M, Canter RJ, Monjazeb AM, Dave M, Ferrara
JLM, Levine JE, Longo DL, Abedi M, Blazar BR, Murphy WJ
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Science translational medicine
Year 2020
Date Published 11/1/2020
Volume : Pages 12 : Not Specified
PubMed Reference 33239390
Abstract The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT)
is limited by acute and chronic graft-versus-host disease (GVHD). The impact of
obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity
had a negative and selective impact on acute gut GVHD after allo-HSCT in mice
with diet-induced obesity (DIO). These animals exhibited increased gut
permeability, endotoxin translocation across the gut, and radiation-induced
gastrointestinal damage after allo-HSCT. After allo-HSCT, both male and female
DIO mouse recipients showed increased proinflammatory cytokine production and
expression of the GVHD marker ST2 (IL-33R) and MHC class II molecules; they also
exhibited decreased survival associated with acute severe gut GVHD. This
rapid-onset, obesity-associated gut GVHD depended on donor CD4+ T cells and
occurred even with a minor MHC mismatch between donor and recipient animals.
Retrospective analysis of clinical cohorts receiving allo-HSCT transplants from
unrelated donors revealed that recipients with a high body mass index (BMI, >30)
had reduced survival and higher serum ST2 concentrations compared with nonobese
transplant recipients. Assessment of both DIO mice and allo-HSCT recipients with
a high BMI revealed reduced gut microbiota diversity and decreased
Clostridiaceae abundance. Prophylactic antibiotic treatment protected DIO mouse
recipients from endotoxin translocation across the gut and increased
inflammatory cytokine production, as well as gut pathology and mortality, but
did not protect against later development of chronic skin GVHD. These results
suggest that obesity-induced alterations of the gut microbiota may affect GVHD
after allo-HSCT in DIO mice, which could be ameliorated by prophylactic
antibiotic treatment.




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