# Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

## TL;DR

This paper explores how rare, early-onset inflammatory bowel disease can reveal key immune system regulators and help understand complex diseases.

## Contribution

The paper highlights monogenic early-onset IBD as a model to uncover immune homeostasis mechanisms and genetic influences.

## Key findings

- Very early-onset IBD is driven by strong genetic factors and reveals key immune regulators.
- Monogenic IBD models show the connection between gut inflammation and systemic immune dysregulation.
- Comparing adult and early-onset IBD helps understand monogenic versus complex disease mechanisms.

## Abstract

Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.