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.

BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking

“…The connection between endocytic trafficking and intestinal physiology has not been widely researched. Our data here characterizing Atg7 intestinal epithelial-specific knock-out mice are consistent with published roles of autophagy in the intestinal epithelium, where a loss of autophagy conjugation proteins including ATG5, ATG16 and ATG7, results in Paneth and goblet cell defects, minimally affects enterocytes, and mice do not develop enteritis unless a chemical or pathogenic agent is administered 1 , 14 . Interestingly, we did not observe apoptosis and loss of intestinal stem cells in our ATG7-deficient mice, as reported in Trentesaux et al 11 , but this is potentially due to our assessment of mice at a much earlier time point.…”

“…It encapsulates cytoplasmic material within autophagosomes and mediates their delivery to the lysosome for degradation. Critically, genome-wide association studies (GWAS) have identified that polymorphisms in genes that regulate autophagy correlate with a susceptibility to inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis 1 . Subsequent studies aiming to understand this connection between autophagy and intestinal health led to the generation of mice deficient for, or bearing, disease variants in autophagy regulators.…”

BECLIN1 is essential for intestinal homeostasis

“…The connection between endocytic trafficking and intestinal physiology has not been widely researched. Our data here characterising Atg7 intestinal epithelial-specific knock-out mice are consistent with published roles of autophagy in the intestinal epithelium, where a loss of autophagy conjugation proteins including ATG5, ATG16 and ATG7, results in Paneth and goblet cell defects, minimally affects enterocytes, and mice do not develop enteritis unless a chemical or pathogenic agent is administered 1,22 . Interestingly, we did not observe apoptosis and loss of intestinal stem cells in our ATG7-deficient mice, as reported in Trentesaux et al 11 , but this is potentially due to our assessment of mice at a much earlier time point.…”

Dietary macroalgae Chaetomorpha linum supplementation improves morphology of small intestine and pectoral muscle, growth performance, and meat quality of broilers

“…Several studies have shown that amino acids from poultry feed trigger protein synthesis during epithelial cell proliferation [ 64 – 66 ]. Moreover, protein content is responsible for epithelial cell regeneration and signal transduction in the small intestine [ 67 ], thus enhancing the efficiency of nutrient absorption [ 68 ]. In addition, flavonoid content plays a major role in antibacterial activity and stimulates epithelial cells to undergo mitosis.…”