Pathway Paradigms Revealed from the Genetics of Inflammatory Bowel Disease

Photo: DNA

By Dr.Katie E Golden, MD

Our understanding of Inflammatory Bowel Disease (IBD) has dramatically evolved over the last decade as a result of advanced genetic, immunology, and microbiome research. We have moved away from a traditional model that categorizes the disease into two subtypes (Ulcerative Colitis and Crohn’s Disease), to understand IBD as a heterogeneous condition with varied phenotypes resulting from a complex interaction between genetic and environmental factors. Investigating the underlying pathophysiology of an inherently complex condition has demanded the development of innovative research technology, particularly in functional genetics, which in turn has resulted in broader applications to human health and disease.

In a recently published paper, authors Graham and Xavier provide an eloquent and comprehensive review of the scientific advances that have brought us to our current understanding of IBD pathophysiology, and how this has provided valuable insights into the metabolic pathways that contribute to microbiome-related disorders on a larger scale. Their in-depth survey of the most relevant IBD discoveries inspires an appreciation of how the evolution of genetics-based research has successfully built a valuable framework for the biomedical research community to explore the clinical implications of the molecular pathways that contribute to disease development and progression.

The inherent complexity of IBD has long been apparent from the observed phenotypic variation, unpredictable treatment response from patient to patient, and even the extra-intestinal systemic manifestations of the disease. Identifying causal genes and their variants within risk loci was only the first step; scientists had to understand how genetic variants translated to causal disease mechanisms to make a clinical impact. This pressure inspired the development of exome sequencing, CRISPR technology, and single-cell genomics to capture in vivo data demonstrating how intestinal microbiota affect transcriptional activity. This expansion of functional genomics yielded a blueprint of IBD pathology as a complicated interplay between gut mucosal immunity and aberrant antimicrobial responses.

The elaboration of cellular and molecular pathways that lead to IBD pathogenesis has created opportunities for therapeutic intervention, as well as biomarker development to predict and monitor disease severity and treatment response.  This includes the identified roles of epithelial barrier function, mucosal immunity and stem cell response, microbe-sensing pathways, and cytokine networks that have important implications for both intestinal homeostasis as well as systemic inflammatory responses. In reviewing these discoveries, Graham and Xavier move us beyond the oversimplification of IBD as a genetic disease that is triggered by environmental conditions, to help us understand how it arises from a complicated relationship between host genetics, a dynamic microbiome that influences host metabolism, and resultant dysregulation of mucosal epithelium and immunity.

1. Graham, D.B., Xavier, R.J. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578, 527–539 (2020).