Summary Inflammatory bowel disease (IBD) in African Americans (AA) is likely to progress towards complicated disease and debilitating outcomes. These outcomes are likely rooted in genetic, epigenetic, microbial, and metabolic factors. We have made substantial advances in this research area, and over the past two funding cycles as Ancillary contributors to the IBD-GC produced sufficient outcomes to drive new studies, and here propose a focused set of three aims building on those advances. (1) Differences in allele frequency and effect size substantially impact polygenic risk assessment, (2) Gene expression in the ileum of AA IBD patients tends to display significant up-regulation of markers associated with adverse disease progression, including TNF response. (3) Genomic DNA methylation patterns in the rectum of IBD patients is maintained, reflecting the dominance of epithelial contributions over transient inflammatory signatures from the immune compartment. (4) AA tend to have a reduced mucosal fibroblast component relative to European cases. (5) Polygenic risk scores (PRS) for IBD are substantially modified by diet, smoking and alcohol consumption, but these factors have not been evaluated in AA despite substantial cultural differences. (6) IBD is associated with changes in the gut microbiome and differs by ethnicity and urban/rural lifestyle, suggesting a butyrate-induced modulation of epithelial and immune function. (7) We can experimentally evaluate the impact of genetic and metabolic perturbations on cellular function using patient biopsy derived organoids. Taken together, these insights have led to the overarching hypothesis that environmental factors modulate the epigenome and microbiome, driving adverse health disparity in AA with IBD. To test this, we propose the following three Specific Aims. For Aim 1, we will define the genetic architecture of IBD in AA by expanding the IBD-GC sampling, developing an inception cohort, and evaluating PRS×Environment interactions. In Aim 2, we will test the hypothesis that a subset of ileo-colonic methylation signatures are consistent with a role in IBD onset and/or severity, rather than an outcome of IBD, and determine whether these signatures are independent of, or interacting with, the environmental factors of Aim 1. Finally, in Aim 3, we will use ileo-colonic biopsies and enteroid cultures to test the hypothesis that differences in the microbiome drive metabolic profiles that associate with gut dysbiosis in IBD. Together, our multi-omic approach and breadth of expertise across multiple disciplines will shed new light on disease outcomes of IBD related to differences in the genomics and metabolomics of AA ancestries.