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

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.

The emerging roles of the gut microbiome in allogeneic hematopoietic stem cell transplantation

“…48 Obesity also impacts the microbiome with less diversity being reported. 49,50 Obesity of the recipient has been shown to correlate with poor outcomes after allogeneic HSCT in both mouse preclinical models and human clinical outcome data 50 in which high BMI was associated with a significantly greater risk of grade II-IV acute GVHD 51 (Figure 1). However, there are also clinical studies suggesting that obesity was associated with a higher survival rate after allo-HSCT 52 and auto-HSCT.…”

“…55 Possible reasons for microbiome shifts in aging could be explained based on diet adjustment, lessened exercise, reduced mobility, residence locations, less muscle mass (sarcopenia), etc. 56 Although obesity and aging correlate with restricted microbiota diversity in mouse and human 50,55,57,58 and the less-diverse microbiome profile has been proved to be associated with poor outcomes after HSCT, [59][60][61] recent studies suggested that there are certain types of bacteria that could serve as beneficial factor for health and longevity. 56,62 Bifidobacteria supplementation reduced the accumulation of aging biomarkers (carbonyls and lipofuscin), 63 while transfer of Christensenella minuta to germ-free mice significantly reduced adiposity gain.…”

“…In HSCT, together with microbiome diversity as an indicator for outcomes, 60 some pathogenic bacterial taxa have been shown to increase in the GVHD recipients such as Enterococcaceae, Akkermansia muciniphila, and Lactobacillales. 50,61,84,87 In contrast, Blautia has been shown as the beneficial bacterial genus for HSCT 88 as well as the correlation of increased GVHD with reduced abundances of some bacterial genera such as Faecalibacterium, Bacteroides, and Parabacteroides. 89 Certain bacterial taxa also have been shown to contribute to GI tract recovery after radiation.…”

“…We and others demonstrated in murine HSCT models that prior administration of broad spectrum antibiotics reduced acute GVHD post-allogeneic HSCT in part due to significantly decreased bacterial translocation into bloodstream. 50,94 Interestingly, increased expression of MHC class II in the intestinal epithelial cells after radiation was also reduced, likely affecting donor T cell priming for GVHD induction in HSCT. 95 Other possible mechanisms include reduced migration of neutrophils 96 or donor T cells 50 into the mesenteric lymph nodes where priming for gut GVHD occurs.…”

“…50,94 Interestingly, increased expression of MHC class II in the intestinal epithelial cells after radiation was also reduced, likely affecting donor T cell priming for GVHD induction in HSCT. 95 Other possible mechanisms include reduced migration of neutrophils 96 or donor T cells 50 into the mesenteric lymph nodes where priming for gut GVHD occurs. However, there is also recent evidence that antibiotics with specific activity targeting the ribosome demonstrated a direct immunosuppressive role against T H 17 cells, suggesting that antibiotics with no specific target on bacteria can directly exert immunological regulatory effects so caution must be exercised before assuming that the microbiome was the mechanism underlying the effects.…”