PROJECT 2: SUMMARY There’s emerging evidence that the genetic diversity of the mucophylic gut commensal Akkermansia muciniphila contribute to this microbe’s overall impact on human health. Based on our collaborative findings that Akkermansia can exacerbate GVHD following HCT, we predict that the variance in genetic content among Akkermansia species and clades influences its impact on GVHD either through variances in its mucin degrading capabilities or through the regulation of intestinal epithelia and associated immune cells. We propose to define how the genomic variation among Akkermansia species and clades modulate the risk of developing neutropenic fever and GVDH following hemopoietic cell transplantation (HCT) in humans and mouse models of disease. We will test the premise that both mucin degradation by Akkermansia and other commensal bacteria compounded by capsular polysaccharide-mediated immunostimulation modulate the initiation and/or severity of disease. We will specifically ask: 1) How does the genetic diversity of Akkkermansia in humans impact the severity of HCT-induced GVDH; 2) What is the impact of mucin degradation by Akkermansia on the gut ecology and damage to the GI by other mucolytic bacteria during HCT; 3) Does immune signaling induced by the Akkermansia capsule modulate susceptibility to GVHD and 4) Does selective depletion of Akkermansia with bacteriophages decrease the severity of GVHD in mouse models of HCT?