Dietary animal fat disrupts gut microbiota and aggravates Scl-cGVHD after allogeneic hematopoietic stem cell transfer

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is an effective treatment for high-risk or relapsed acute leukemia. However, the frequent occurrence of graft-versus-host disease (GVHD) poses significant complications. Modifiable factors such as the gut microbiome and dietary regimen have the potential to influence the frequency and severity of GVHD. Previous studies in mouse models have shown a direct link between obesity and increased severity of GVHD; however, analysis of human data has not suggested a causal relationship. We hypothesized that dietary fat content before transplantation, rather than obesity itself, might affect outcomes, given that increased dietary fat is associated with reduced gut microbiome diversity. In our study, we evaluated the effects of an animal fat-based diet (AFD) and a plant fat-based diet (PFD) in a mouse model of sclerodermatous chronic GVHD (Scl-cGVHD). Mice initially fed normal chow (∼10% kcal from fat) were switched to either an AFD or a PFD (each with ∼25% kcal from fat) 2 weeks before allo-HSCT. Mice on the AFD had an elevated serum cytokine response, more severe skin inflammation, and greater intestinal immune dysregulation than mice on the PFD. Although both diets reduced gut microbial diversity, the fat source led to distinct microbiota compositions that included 2 coabundance guilds that differentiated between the AFD and PFD groups. Our findings demonstrate that even short-term consumption of diets with equivalent macronutrient content, but different fat sources, can modulate the gut microbiome, disrupt intestinal homeostasis, and influence Scl-cGVHD outcomes.