High-throughput functional analyses of the genetic drivers of Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) is a debilitating condition characterized by chronic inflammation, leading to the erosion of essential intestinal functions. The risk of developing IBD, including related diseases like Crohn's and ulcerative colitis, involves a complex interplay of over 250 genetic and environmental factors. Dysbiosis of the gut microbiome and pathogen proliferation often worsen the disease pathophysiology. While some common genetic risk factors, especially those related to the immune system, are well understood, the functional contributions of most risk alleles remain unclear. Moreover, the majority of known genetic risk factors have been identified in European ancestry populations, which may not translate to more diverse populations. Our long-term goal is to gain a comprehensive understanding of the genetic risk factors contributing to IBD development. We hypothesize that genetic alterations in intestinal gene function create conditions for persistent dysbiosis and inflammation, driving IBD. To achieve this, we have established a robust cross- organismal platform for high-throughput functional profiling of IBD candidate genes, advancing our understanding of the disease's mechanisms. We aim to address our hypothesis through two specific aims: 1) conducting high-throughput screening and phenotypic characterization of IBD risk genes in C. elegans, a nematode microbiome model; and 2) validating IBD risk alleles in human intestinal organoids (HIOs). Importantly, our research will encompass and integrate risk alleles from diverse populations, providing a more comprehensive assessment of IBD risk. This study is significant because it delves into the functional profiling of IBD risk genes at the organismal level, a less- explored area. Further, it extends its focus to diverse multi-ancestry cohorts, filling a critical gap in understanding of the disease. The platform developed also has the potential to be used in studying other microbiome-mediated diseases. Ultimately, this work can enhance our understanding of the genetic landscapes of IBD, offering both broad functional testing and specific mechanistic insights, which are vital for the diagnosis and treatment of this prevalent digestive disease.