Scientists have discovered that processes taking place within a particular intestinal cell type called the Paneth cell are linked to the development of inflammation in a portion of the small intestine in mice. The resulting inflammation is similar to that seen in a form of human Crohn’s disease. Crohn’s disease, a form of inflammatory bowel disease that can affect the small or large intestines, is thought to result from an interplay between genetic susceptibility factors, such as those that affect immune function, and environmental factors, such as gut microbes. For example, one genetic mutation associated with Crohn’s disease occurs in the ATG16L1 gene, which is linked to an important process called “autophagy,” or “self-eating.” Cells use autophagy to reduce cellular stress by degrading and recycling extraneous or malfunctioning components. This genetic mutation also causes dysfunction in Paneth cells, which are known primarily for protecting against harmful gut microbes by secreting antimicrobial molecules. Why autophagy or Paneth cell dysfunction might be important in Crohn’s disease, however, was unknown.
A team of researchers delved into how problems with processes such as autophagy occurring in intestinal cells might relate to the development of gut inflammation. Working with a series of mouse models genetically engineered to lack certain proteins important for autophagy and other processes in their intestinal cells, the team showed that turning off both the Atg16L1 gene and a gene involved in monitoring proper protein structures resulted in reduced autophagy and increased stress in Paneth cells. Additionally, these animals exhibited a severe, spontaneous form of inflammation in the small intestine that closely mimicked cases of human Crohn’s disease. This study sheds new light on the key cellular and genetic factors, and processes such as autophagy, that are involved in intestinal inflammation, particularly in Crohn’s disease occurring within the small intestine. These findings offer important clues that may lead to better diagnosis and management of this form of inflammatory bowel disease in the future.
Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A, Blumberg RS. Paneth cells as a site of origin for intestinal inflammation. Nature 503: 272-276, 2013.