Gut Microbial Functions that Impact Multiplex and Non-multiplex Crohn’s Disease Risk.

Project Summary/Abstract The cause of Crohn’s disease (CD) is believed to be rooted in the interactions between genetic susceptibilities and exposures to environmental factors, such as specific gut microbes. Unfortunately, the complexity of these interactions makes it difficult to understand what portion of CD risk is modifiable, and specifically whether gut microbiome compositions can be altered to overcome one’s underlying and fixed genetic predisposition. This proposal will generate additional data for an ongoing study addressing whether individuals at high genetic risk for CD, but who never develop the disease, harbor transferrable gut microbial signatures that mediate disease protection. Aim 1 of this proposal entails the generation of shotgun metagenomic sequencing data on samples already collected from multiplex CD families – with the rationale that families, sharing common living environments, meals, and behaviors, will minimize frequent confounders of human microbiome studies. Individuals have been stratified by a polygenic risk score to identify those at highest genetic risk but remain disease-free, and who are hypothesized as being most likely to harbor CD-protective intestinal microbes. The generated shotgun sequencing will allow us to determine bacterial community functions and thus integrate our 16S sequencing and fecal metabolomic data in an effort to develop a mechanistic understanding of the relationship between the gut microbiome and CD development. In Aim 2, we will leverage our access to pre- generated multi-omic data from a large biobank to extend our investigation beyond a multiplex family context. The data generated in this proposal, therefore, will provide key insights to our study of microbially-mediated modulators of CD risk and disease activity.