The emerging roles of autophagy in intestinal epithelial cells and its links to inflammatory bowel disease

Abstract

Landmark genome-wide association studies (GWAS) identified that mutations in autophagy genes correlated with inflammatory bowel disease (IBD), a heterogenous disease characterised by prolonged inflammation of the gastrointestinal tract, that can reduce a person's quality of life. Autophagy, the delivery of intracellular components to the lysosome for degradation, is a critical cellular housekeeping process that removes damaged proteins and turns over organelles, recycling their amino acids and other constituents to supply cells with energy and necessary building blocks. This occurs under both basal and challenging conditions such as nutrient deprivation. An understanding of the relationship between autophagy, intestinal health and IBD aetiology has improved over time, with autophagy having a verified role in the intestinal epithelium and immune cells. Here, we discuss research that has led to an understanding that autophagy genes, including ATG16L, ATG5, ATG7, IRGM, and Class III PI3K complex members, contribute to innate immune defence in intestinal epithelial cells (IECs) via selective autophagy of bacteria (xenophagy), how autophagy contributes to the regulation of the intestinal barrier via cell junctional proteins, and the critical role of autophagy genes in intestinal epithelial secretory subpopulations, namely Paneth and goblet cells. We also discuss how intestinal stem cells can utilise autophagy. Importantly, mouse studies have provided evidence that autophagy deregulation has serious physiological consequences including IEC death and intestinal inflammation. Thus, autophagy is now established as a key regulator of intestinal homeostasis. Further research into how its cytoprotective mechanisms can prevent intestinal inflammation may provide insights into the effective management of IBD.

Keywords: Crohns disease; autophagy; disease; gastrointestinal physiology; homeostasis; molecular basis of health and disease.

Figure 1.. Schematic of the autophagy molecular network showing the major complexes involved in autophagosome initiation (ULK and PI3K Class III) and the two ubiquitin-like conjugation systems (ATG12–ATG5–ATG16L, and ATG8 lipidation) required for autophagosome expansion and capture of cargo.

Figure 2.. Anatomy and physiology of the small intestinal mucosa showing the major cell types and their relative locations within the repeating crypt-villi structures.

Figure 3.. Autophagy genes and cellular processes such as intestinal epithelial barrier function and protection from cell death associated with xenophagy in response to pathogens.

Figure 4.. Autophagy genes and associated processes implicated in the maintenance of Paneth cells in response to bacterial infection.

Figure 5.. Autophagy genes are associated with goblet cell granule production and degranulation.

Figure 6.. In ISCs, autophagy genes are associated with the regulation of ROS and DNA damage-associated stress, and through non-autophagy mechanisms that have been associated with differentiation.