PROJECT SUMMARY/ABSTRACT For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic hematopoietic cell transplantation (allo HCT) is a critically important therapy that can produce cures when other treatments cannot. Roughly 20,000 patients undergo allo BMT world-wide each year. A major risk of allo HCT continues to be graft-versus-host disease (GVHD), which results from the donor immune system recognizing the transplant recipient’s organs as foreign, leading to life-threatening inflammation. Developing strategies that reduce GVHD but leave global immune function intact should produce a major benefit for patients. One promising approach that we propose testing is targeting the subset of intestinal commensal bacteria that are capable of consuming and degrading mucins, which play a critical role in maintaining the intestinal epithelial barrier and immunological homeostasis. In this proposal, we present preliminary data identifying two common scenarios during the allo HCT process: 1) poor oral dietary intake due to conditioning or development of GVHD, and 2) administration of broad-spectrum antibiotics. Both of these often lead to increases in mucolytic bacteria. Further, we have identified antibiotic and metabolic strategies to suppress mucolytic bacteria activity. We will apply these insights to guide a mucus-focused evaluation of GVHD, in both mouse models and in stool biospecimens collected from allo HCT patients. We and others have identified the microbiota as a potent modulator of acute GVHD severity. This project proposes capitalizing on a mechanistic insight into how this can occur, with clear translational potential.