P09.02 Oral administration of a TGF-β-enriched polymeric diet mitigates gastrointestinal acute GVHD

Background Gastrointestinal acute graft-versus-host disease (GI-aGVHD) is a major contributor to non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Standard immunosuppressive therapies risk compromising the beneficial graft-versus-leukemia effect. Nutritional interventions offer a non-immunosuppressive, tissue-protective adjunct. However, mechanistic preclinical evaluations of clinically administered nutritional formulas in aGVHD remain scarce. Addressing this gap, we evaluated whether Modulen® IBD (a casein-based formula enriched with transforming growth factor-beta (TGF-β)) could mitigate GI-aGVHD.Methods and Results Based on the metabolic signatures of aGVHD reported by Michonneau et al. (Nat. Commun., 2019), we assessed the effects of Modulen® IBD in a pilot clinical study. Allo-HCT recipients (n = 3 to 4) received daily prophylactic Modulen® IBD (1.5 kcal/ml), from the start of conditioning regimen until onset of conditioning-related toxicity. We observed increased levels of anti-inflammatory long-chain (LC) FAs like oleic and eicosatrienoic acids in the serum, as well as elevated kynurenic acid, a microbiota-derived aryl hydrocarbon receptor ligand implicated in intestinal barrier protection. These findings suggest a systemic metabolic shift toward reduced inflammation.In parallel, we employed a well-established major histocompatibility complex-mismatched murine allo-HCT model (BALB/c → C57BL/6) to validate and expand upon the immune, microbial, and metabolic mechanisms of our clinical study. We administered Modulen® IBD or vehicle orally daily from day 0 to day 14 post-transplant (1kcal/ml). Modulen® IBD treatment significantly reduced histological aGVHD scores in the colon, small intestine and liver of mice. Kaplan-Meier analysis indicated improved survival. Similar to patients, LC-MS analysis of serum from treated mice confirmed increased levels of oleic, linoleic and eicosatrienoic acids. Additionally, there was a reduction in pro-inflammatory LCFAs (palmitic, stearic, and arachidonic acids) and GVHD-associated amino acids (arginine, ornithine, leucine, and aspartate) in the colon. Notably, butyrate, known to promote epithelial TGF-β production, was significantly elevated in colon and stool. Stool 16S rRNA gene sequencing revealed an enrichment of Lactococcus and Bacillus, genera that support butyrate production. These microbial shifts were accompanied by increased TGF-β abundance in colonic epithelial cells, increased IL-10 in CD4+ T cells and Ly6C+ monocytes, and reduced CD3+ T cell infiltration in the colon, suggesting attenuated alloreactivity. Beyond the gut, Modulen® IBD treatment enhanced IL-10 production in peripheral CD4+ T cells and reduced CD8+ T cell infiltration in the brain, indicating systemic immune-regulatory effects.Conclusion Based on the above changes, we hypothesise that enrichment of Lactococcus and Bacillus contributes to increased colonic butyrate levels. This may support epithelial and innate immune-derived TGF-β production and IL-10 induction in CD4 + T cells. While our data demonstrate strong associations, further studies (for e.g. with gnotobiotic models) are needed to establish definitive causal links. Our findings support Modulen® IBD as a promising non-pharmacological adjunctive therapy, providing a rationale for integrating it into clinical GI-aGVHD management.