Integrative and longitudinal multi-omic risk assessment in inflammatory bowel disease progression

Emory University, Atlanta GA

Investigators

Linked publications, trials & patents

Abstract

Inflammatory bowel disease (IBD) in certain individuals has an elevated likelihood of progressing in severity and causing debilitating outcomes. These outcomes are likely multifactorial, 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 IBDGC, we have produced sufficient outcomes to drive new studies. Here, we are proposing a set of three focused aims that are built on the following advances: (1) Differences in allele frequency and effect sizes that substantially impact polygenic risk assessment and allow for development of individualized specific-risk assessments, (2) Gene expression in the ileum across populations of IBD patients with more severe disease displays significant up-regulation of multiple pathways known to be markers of adverse disease progression, (3) Genomic DNA methylation in the rectal mucosa of IBD patients is stably maintained, reflecting the dominance of epithelial contributions over transient inflammatory signatures in the immune compartment, (4) there are differences in the cellular subtypes involved in severe disease, some of them genetically related, (5) Polygenic risk scores (PRS) for IBD are substantially modified by diet, smoking and alcohol consumption, but these factors have not been comprehensively evaluated across IBD populations in the USA (6) IBD is associated with changes in the gut microbiome and differs by urban/rural lifestyle, suggesting a butyrate-induced modulation of epithelial and immune function, and (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 more severe IBD. This will be tested across three aims: For Aim 1, we will define the genetic architecture of IBD across populations by expanding the IBDGC sampling, developing an inception cohort, and evaluating PRS×Environment. 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 interact with, the environmental factors of Aim1. 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 are associated with gut dysbiosis in IBD and drive more sever disease. 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 genomics and metabolomics.