We pursue a patient-centered, “bedside-to-bench-and-back” approach to translational genomics, placing patients with Very Early Onset Inflammatory Bowel Disease (VEO-IBD) - often facing severe, early-life-threatening conditions - at the starting point of discovery. By integrating multi-omics profiling with computational biology and advanced experimental modeling in state-of-the-art systems, we uncover molecular disease mechanisms, biomarkers, and therapeutic targets with direct clinical relevance.

Since monogenic IBD/VEO-IBD serve as precise models of human disease, our vision is to translate these insights beyond rare conditions, establishing a scalable blueprint for precision medicine that advances diagnosis, patient stratification, and targeted therapies across common immune and inflammatory disorders.

In collaboration with leading centers in Boston (Dr. Scott Snapper) and Toronto (Dr. Aleixo Muise), we have established an international VEO-IBD consortium that will be supported by world experts in the field of immunology, genetics, genetic engineering, gastroenterology, intestinal stem cell biology, microbiomics and bioinformatics.

To elucidate novel genetic signatures of VEO-IBD, we have established collaborations to more than 100 international clinical institutes and systematically screened one of the largest international cohorts of VEO-IBD by employing state-of-the-art next-generation sequencing. As proof-of-principle, our laboratory has characterized first VEO-IBD patients with IL10R deficiency (Glocker et al., N Engl J Med 2009; Kotlarz et al, Gastroenterology 2012), TGFB1 (Kotlarz et al., Nat Genet 2018), CASP8 (Lehle et al., Gastroenterology 2019), RIPK1 (Li et al., PNAS 2019), and LY96 (Li et al. J Allergy and Immunol) deficiency. Our ongoing computational analyses continue to unveil novel candidate genes implicated in VEO-IBD pathogenesis.

We investigate the molecular pathomechanisms of newly identified sequence variants by employing various experimental models (patient samples, heterologous model systems, mouse models) and state-of-the-art molecular and cell biological technologies.

We investigate the functional consequences of newly identified variants using an integrated experimental platform of patient-derived samples, engineered cellular systems, and in vivo models combined with state-of-the-art molecular and cell biological technologies. Our functional genomics approach enables us to define molecular disease mechanisms and translate genetic discoveries into biological insights and therapeutic opportunities.

Our group leverages advanced single-cell and spatial transcriptomic technologies, combining high-resolution molecular profiling with clinical and genetic data to uncover the cellular mechanisms driving VEO-IBD and translate these insights into targeted therapeutic strategies.

Using single-cell RNA sequencing (scRNA-seq), we dissect the intestinal mucosa at high resolution to identify common and rare disease-driving cell populations. A central focus is the reconstruction of the epithelial-immune interactome, revealing how genetic defects alter cell-cell communication and cause chronic inflammation, thereby linking genotype to tissue-level pathology. We also contribute to the Human Gut Cell Atlas, with expertise in reference atlas construction, cross-cohort dataset harmonization, and high-resolution cell type annotation to define cellular states across health and disease. To preserve tissue architecture, we complement single-cell approaches with spatial transcriptomics, enabling subcellular gene expression mapping and the identification of spatially organized inflammatory niches.

Our integrative approaches provide a systems-level understanding of mucosal inflammation. Our goal is to identify robust cellular and spatial biomarkers that improve patient stratification, refine diagnostics, and guide targeted therapies in pediatric IBD.

Our overarching goal is to advance the understanding of key drivers of IBD pathogenesis through an integrated discovery pipeline that combines multi-omics profiling, genetic perturbation platforms, and genome-wide CRISPR screening with preclinical disease models. This systems-level approach enables the identification of critical disease mechanisms and actionable targets, laying the foundation for personalized therapies that improve outcomes and quality of life for children with severe, life-threatening diseases.