Familial Inflammatory Bowel Disease Early Risk

Overview

Brief Summary The aim of the FIBER study is to identify potential triggers associated with the later development of IBD (inflammatory bowel disease) based on baseline characteristics and biosamples (blood, urine, stool, saliva, and tissue). Aim 1: To identify clinical, demographic, and immunologic factors associated with an increased risk of developing IBD in family members of IBD patients. This aim will investigate the role of clinical factors (e.g., age of onset, gender, and family history), demographic factors (e.g., socioeconomic status, geographical location), and immune system markers (e.g., inflammatory cytokine profiles, immune cell populations) in predicting the likelihood of family members developing IBD over time. Aim 2: To examine dietary, environmental, and immunologic influences on the development of IBD in family members of IBD patients. This aim will explore how dietary habits (e.g., fiber, fats, processed foods), environmental exposures (e.g., smoking, pollution, and antibiotic use), and immune responses (e.g., changes in T-cell activation, inflammatory markers) contribute to the risk of IBD in family members. Aim 3: To analyze the multi-omic (metagenomic, transcriptomic, proteomic) cellular signatures of host and microbial signatures in family members of IBD patients and their association with IBD onset. This aim will investigate changes in the gut microbiome and immune-related gene expression profiles (transcriptomics) in family members. Specifically, the aim will focus on how shifts in microbial composition and host immune response genes (e.g., those involved in inflammation and epithelial barrier function) correlate with an increased risk of IBD development. Aim 4: To investigate the multi-omic (metabolomic, transcriptomic, proteomic) cellular signature of host and microbial signatures in family members to identify biomarkers predictive of IBD development. This aim will involve examining the metabolic, protein, and transcriptomic signatures (e.g., circulating cytokines, immune receptor expression) in blood, urine, or stool samples. The study will seek to identify early biomarkers from these profiles that can predict the onset of IBD, even in asymptomatic family members.

The familial nature of IBD has long been identified. Observational studies have highlighted a positive family history of IBD as a major risk factor for developing IBD, with particularly high risk among first-degree relatives (FDRs) of patients with Crohn's disease (CD). Importantly, an additive risk increment of CD onset appears with each additional affected FDR. Therefore, individuals within families with multiple affected members, also known as multiplex families, harbor notably high risk of developing CD. Healthy individuals from multiplex families have been shown to have a higher number of risk alleles in IBD-associated genes compared with healthy individuals from the general population, with the mean number of risk alleles increasing alongside increasing numbers of affected FDRs. However, none of the genetic markers could discriminate between individuals from single-case families (so-called simplex families) and individuals from multiplex families. Thus, genetics is unlikely to represent the sole factor explaining the increased risk, raising the question of factors driving the increased risk of CD in multiplex families. As IBD involves pathological immune responses, detailed study of disease immunology is central to understanding pathogenesis and progression. Sc-RNAseq and other novel immunological techniques provide the capability to interrogate individual cellular transcripts to determine pathogenic pathways, even within rare cellular subpopulations previously inaccessible using conventional techniques and bulk RNA-seq. The novelty of single-cell technologies compared with previous technologies such as bulk sequencing lies in the ability to detect rare subsets of cells potentially representing aberrant drivers of disease. Available single-cell omic technologies are described in a research paper. The inherent advantage of single-cell techniques has led to continued popularity in IBD research 8-22. Previous work from the research group has shown that sc-RNAseq can detect changes in pediatric IBD gut tissue from dissociated tissue biopsies. The proposed study will use immunological assays, including single-cell omics, to investigate risk factors associated with development of IBD among family members of patients with already diagnosed IBD.