Obesity results in marked increases in gut permeability, inflammatory cytokines, and acute gut graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Abstract

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most applicable curative option for treating hematologic diseases. In this study, we assessed the impact of obesity on recipient graft-versus-host disease (GVHD) outcome post allogeneic HSCT using a minor histocompatibility antigens (miHA)-mismatched mouse model. Control or diet-induced obese (DIO) BALB/c mice received HSCT from H2-identical B10.D2 mice which is known for resulting in chronic skin GVHD. Strikingly, DIO mice rapidly succumbed to gut GVHD while control mice survived and developed sclerodermatous GVHD much later post-HSCT. The DIO recipient mice had higher expression of pro-inflammatory cytokines (IL-6 and TNF-α) in the gut and serum, as well as higher serum ST2. There were increased numbers of donor CD4+ T cells in the mesenteric lymph nodes of DIO mice compared to control mice. Untreated DIO mice also displayed increased gut permeability and lipopolysaccharide translocation, as well as having less-diverse microbiota which potentially contributed to the severe GVHD post-HSCT. Importantly, administration of anti-IL-6R monoclonal antibody and Enbrel significantly protected DIO mice from lethal gut GVHD, correlating with lower pro-inflammatory cytokine concentrations (IL-6 and TNF-α) and ST2 in the serum. In an initial evaluation, treating DIO mice with broad-spectrum antibiotics 2 weeks before HSCT also ameliorated GVHD. Taken together, these results indicate that obesity exacerbates GVHD, manifested primarily as gut pathology, and therapeutic intervention by blockade of pro-inflammatory cytokine signaling ameliorates GVHD post-HSCT.