A study (Nature. 2013; 14:272-6) led by Richard S. Blumberg, MD, chief of the BWH Division of Gastroenterology, Hepatology and Endoscopy, in collaboration with Arthur Kaser, MD, Addenbrooke Hospital, University of Cambridge, UK demonstrates how impairing certain functions in intestinal epithelial cells, specifically Paneth cells, can lead to severe spontaneous Crohn’s disease-like inflammation of the intestines.
Researchers noted that mutations in the human ATG16L1 gene, which is associated with risk for developing Crohn’s disease and involved in autophagy, or the homologous gene in mice, was observed to cause Paneth cell dysfunction. However, the way in which such a dysfunction in autophagy, as a result of ATG16L1 mutations, leads to Crohn’s disease is unknown.
The researchers provided an important clue to this understanding by showing that autophagy compensates for endoplasmic reticulum (ER) stress in Paneth cells. They found that under normal circumstances, ER stress was associated with an increase in autophagy as a mechanism to compensate for the cellular stress. This was especially important in Paneth cells of the small intestine which are highly secretory and involved in controlling the microbes in intestines. When this compensatory function of autophagy was lost via genetic deletion of ATG16L1 in the intestinal epithelium, mice developed severe spontaneous inflammation in the small intestine that was transmitted throughout the wall of the bowel and similar to human Crohn’s disease.
The researchers found that this was a consequence of massive overactivation of the inflammatory pathways in the ER due to the inability of ATG16L1 and autophagy to remove the inflamed ER membranes. They found that these inflammatory pathways in the stressed ER set into motion a cascade of events that involved nuclear factor kB signaling in intestinal crypts along with epithelial cell death downstream of a microbial signal, which converged on spontaneous inflammation that required tumor necrosis factor receptor signaling. Most importantly, genetic experiments unequivocally revealed that Paneth cells were the originators of this Crohn’s disease-like intestinal inflammation.
According to Dr. Blumberg, these studies provide evidence which implicates Crohn’s disease of the small intestine as a disorder of Paneth cells and that a specific set of genetically regulated pathways are involved in this process. This may help to create precise strategies for treating this specific subset of patients with Crohn’s disease.
- Richard S. Blumberg, MD
Chief, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital
