Pathway paradigms revealed from the genetics of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

Figure 1.. Strategies in human genetics and functional genomics to dissect mechanisms of disease.

a, Left, IBD is a complex genetic disease that is affected by many genetic risk factors defined in common variant association studies (CVAS). These genetic risk factors partially distinguish disease phenotypes associated with CD versus UC. Rare genetic variants associated with severe IBD and very early-onset (VEO)IBD exhibit Mendelian inheritance patterns and have helped to identify genes that control intestinal homeostasis. Similar insights have been gained from rare genetic variants associated with primary immunodeficiencies and hyperinflammatory disorders that manifest with intestinal pathologies or those that confer protection from these conditions. Right, mechanistic study of individual coding variants comprising an allelic series for a gene can reveal molecular functions at the protein level. Understanding the molecular function of a risk variant can reveal mechanisms of disease and conversely, study of protective variants can reveal mechanisms of health. b, Functional genetics has helped to mechanistically link risk genes and genetic variants with cellular and molecular functions underlying the disease process. KO, knockout; MOA, mechanism of action; WGS, whole genome sequencing.

Figure 2.. IBD genes and pathways controlling mucosal immunity.

IBD risk genes regulate a complex network of interconnected functional pathways. IBD genes (red text) have been implicated in key biological functions (grey circles) that are controlled by interconnected molecular pathways (coloured rectangles). Lines connecting nodes reflect overlapping molecular regulation by common genes. Several IBD risk genes regulate several distinct biological functions depending on their cell type-specific activities.

Figure 3.. Pathway paradigms highlighted by IBD genetics.

IBD risk genes listed at the bottom of each panel represent genetic vulnerabilities that perturb key pathways underlying intestinal homeostasis and drive inflammatory pathology in the gut mucosa (centre). a, Phagocytes have evolved numerous mechanisms to detect microorganisms and elicit effector responses that promote inflammation through cytokines and antimicrobicidal responses such as oxidative burst and xenophagy. b, Intestinal epithelial cells maintain barrier integrity through dynamic remodelling of junctional complexes. c, Coordinated interactions between dendritic cells, T cells and B cells facilitate the induction of antigen-specific immune responses and immunological memory directed against commensal microorganisms. d, Stromal cells—such as fibroblasts—are key mediators of tissue remodelling and healing that dynamically respond to inflammatory conditions. e, Cell-extrinsic and -intrinsic stressors associated with inflammation sensitize cells to death. The integrated stress response facilitates adaptation to these stressors by coordinating cellular responses to ER stress, oxidative stress, hypoxia, autophagy and cell death pathways. f, Intercellular communication among immune cells, stroma and epithelial cells is tightly controlled by elaborate cytokine networks. g, Microbe-sensing pathways that operate in the cytosol of host cells function to detect and respond to intracellular infection or exposure to bacterial toxins. Distinct inflammasome complexes mediate activation and secretion of IL-1β or IL-18 and elicit pyroptosis, a proinflammatory form of programmed cell death.

Figure 4.

Exome sequencing has identified many IBD risk genes (middle) with allelic series associated with a spectrum of phenotypes (left to right). Top, for example, CARD9^S12N is associated with risk of IBD, whereas CARD9^ΔCTD is associated with protection and CARD9^Q295X is associated with an immunodeficiency linked with chronic life-threatening fungal infections. Other IBD genes contain coding variants with distinct phenotypes and disease associations that may offer clues to understanding mechanisms of IBD pathology. FMF, familial Mediterranean fever; CGD, chronic granulomatous disease; CVD, cardiovascular disease; CDG, congenital disorder of glycosylation.