Genetic features of many patients with Crohn’s disease affect the ability of their intestinal cells to undergo autophagy—a form of self-digestion that allows them to fight pathogenic bacteria, according to a study by Craig Homer et al. in the November issue of Gastroenterology.
Crohn’s disease is believed to be caused by an altered immune response to gut bacteria. In healthy individuals, the intestinal immune system regulates a complex balance of gut microflora—it allows good bacteria to exist and eliminates dangerous bacteria, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and adherent invasive Escherichia coli. Many patients with Crohn’s disease have variants in the genes ATG16L1 and NOD2 that alter the antimicrobial responses of intestinal epithelial cells and affect the composition of gut bacteria.
Homer et al. found that in normal intestinal cells, ATG16L1 and NOD2 regulate a cell process called autophagy, a mechanism by which cells degrade bacteria, breaking them down along with parts of the cell itself (i.e., self-eating) to activate an immune response. Cells with variants of NOD2 and ATG16L1 that are found in patients with Crohn’s disease had defects in autophagy-dependent killing of Salmonella. In mice, Nod2 deficiency increased the intestinal bacterial load and made the mice more susceptible to colonization with pathogenic bacteria.
The authors conclude that ATG16L1 and NOD2 functionally interact in an autophagy-dependent antibacterial pathway that is altered in patients with Crohn’s disease. Reduced clearance of pathogenic bacteria such as Salmonella might promote the chronic inflammatory response observed in these patients.
Crohn’s disease is complex and caused by many genetic and environmental factors. In an accompanying editorial, Ken Cadwell proposes that the pathogenesis of complex disorders involves defects in several regulatory pathways (e.g., autophagy, immunity) that each involve many factors. An individual would only need to acquire defects in a few of these factors—but in the right combination—to develop the disease.
Other genes associated with Crohn’s disease are also involved in autophagy—Homer et al. propose that these should be investigated to determine if they also regulate the intestinal response to pathogenic bacteria.
Read the article online:
Homer CR, Richmond AL, Rebert NA et al. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 2010;139:1630–1641.e2.
Read the accompanying editorial:
Cadwell K. Crohn’s disease susceptibility gene interactions, a NOD to the newcomer ATG16L1. Gastroenterology 2010;139:1448–1450.