Abstract
Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT), characterized by severe immune-mediated tissue damage. In recent years, global fructose consumption has increased substantially, largely driven by the widespread use of high-fructose corn syrup in processed foods. Emerging evidence suggests that excessive fructose intake may potentiate systemic inflammation. While dietary factors have been recognized as modulators of aGVHD severity, the precise role of fructose in aGVHD pathogenesis remains inadequately elucidated.Methods: To investigate the role of high-fructose diet (HFR) in aGVHD, recipient mice were fed an HFR before bone marrow transplantation. The severity of aGVHD was assessed by survival analysis, clinical scoring, and histopathological evaluation of target organs including ileum, colon, liver, and skin. The composition of the gut microbiota was analyzed using 16S rRNA sequencing, while intestinal barrier integrity was evaluated through bacterial translocation assays, FITC-dextran permeability tests, and immunohistochemical analysis of tight junction proteins. Bone marrow-derived macrophages (BMDMs) were cultured with fructose to evaluate inflammatory cytokine production and metabolic alterations (ECAR, OCR). Macrophage depletion with clodronate liposomes and gut microbiota ablation by broad-spectrum antibiotics were employed to confirm their roles in HFR-exacerbated aGVHD.Results:
In this study, we demonstrate that mice fed HFR exhibited increased mortality, elevated aGVHD scores, and worsening histological damage in target organs. Fructose exposure disrupted intestinal barrier integrity and altered gut microbial composition. HFR aggravated the severity of aGVHD after depletion of gut microbiota by antibiotics. Given the results that in vitro cultivated T-cells did not respond to fructose stimulation, we further investigated whether fructose overexposure affected macrophage activation. In BMDMs, fructose exposure stabilized HIF-1α through mitochondrial ROS accumulation, driving glycolysis and enhancing the production of proinflammatory cytokines, including IL-6, IL-12, TNF-α, and IL-1β. Notably, macrophages isolated from mice subjected to HFR exhibited an enhanced capacity to stimulate T-cell responses. Depletion of macrophages and gut microbiota effectively counteracted the high fructose–induced exacerbation of aGVHD.Conclusions:Taken together, our data indicate that high fructose intake aggravates aGVHD by disrupting gut microbiota and enhancing inflammatory macrophage responses. Our findings highlight dietary fructose restriction as a potential approach for mitigating aGVHD.
