Obesity predisposes to rapid gastrointestinal graft-versus-host disease lethality after allogeneic hematopoietic stem cell transplantation in mice

Abstract

Abstract Obesity is a form of chronic inflammation, termed “meta-inflammation”, resulting in the development of many chronic diseases such as diabetes and cancer. In this study, we assessed the impact of obesity on recipient graft-versus-host disease (GVHD) outcome post allogeneic HSCT using mouse models. In a model of sclerodermatous chronic GVHD, lean or diet-induced obese (DIO) BALB/c mice received 800 cGy total body irradiation (TBI), bone marrow cells, and splenocytes from H2-identical but minor MHC-mismatched B10.D2 mice. To mimic major MHC mismatch transplant which results in acute GVHD impacting gut, skin and liver, lean or DIO C57BL/6 mice received 1050 cGy TBI, bone marrow cells, and different doses of purified T cells from BALB/c mice. Strikingly, after the minor mismatch HSCT, all DIO mice succumbed to gut pathology while all lean mice survived and developed sclerodermatous GVHD at week 3 post transplant. In both models, pathological assessment indicated marked gut pathology in DIO mice correlating with lethality. Lean mice in the major MHC mismatch strain combination had significantly increased survival and less severe gut pathology compared to the DIO mice. The DIO mice had higher expression of pro-inflammatory cytokines in the gut, liver, visceral fat, and serum post-HSCT. Flow cytometric analysis demonstrated increased numbers of donor CD8+ T cells in the gut of DIO mice compared to lean mice. In an initial evaluation, untreated DIO mice displayed increased gut permeability as well as having limited diversity in their microbiome which would contribute to severe GVHD post-HSCT. Taken together, these results indicate that obesity exacerbates GVHD after allogeneic HSCT primarily affecting the gastrointestinal tract.