Research ArticleGVHD

Obesity induces gut microbiota alterations and augments acute graft-versus-host disease after allogeneic stem cell transplantation

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Science Translational Medicine  25 Nov 2020:
Vol. 12, Issue 571, eaay7713
DOI: 10.1126/scitranslmed.aay7713

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Influencing stem cell transplant outcomes

Khuat et al. demonstrate that obesity worsens acute graft-versus-host disease (GVHD) outcomes in both mice and humans after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using a diet-induced obese (DIO) mouse model, the authors observed increased lethal GVHD targeting the gut. DIO mice had increased gut permeability, endotoxin translocation into the bloodstream, and proinflammatory cytokine production, which correlated with reduced gut microbiota diversity. Manipulating the gut microbiota by antibiotic treatment partially protected DIO mice from lethal GVHD after allo-HSCT. Clinically, the authors found that patients with a high body mass index showed decreased gut microbiota diversity and poorer overall survival after allo-HSCT.

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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