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Because of its very nature, the gastrointestinal tract is potentially subject to inflammation and infection. Much of its surface is designed to be highly exposed and absorptive, yet it faces a tremendous microbial population. Therefore, it is not surprising that various gastrointestinal disorders are linked to microbial infection or toxins. For example, peptic ulcers, affecting approximately 10% of the population in the United States, are caused in part by infection with Helicobacter pylori. Accordingly, treatment for this type of ulcer includes antibiotics.
Unfortunately, less success has been achieved in managing another often debilitating disorder, Crohn’s disease, an inflammatory disease affecting the small intestine. There is no cure for Crohn’s disease, and treatment is focused on limiting the recurrence and severity of the symptoms. Genomewide association studies have shown that Crohn’s disease is associated with at least 30 mutant loci,1 a finding that suggests that it may actually represent a spectrum of disorders that present with similar gross phenotypes. Three recent studies2–4 have linked Crohn’s disease with cellular autophagy, providing new insights that may eventually lead to therapeutic intervention.
To understand the role of autophagy (literally, “self-eating”) in the pathogenesis of Crohn’s disease, it is necessary to consider the mechanism of this process. The type of autophagy that is relevant to Crohn’s disease is macroautophagy (hereafter referred to as autophagy). The morphologic hallmark of this type of autophagy is the formation of double-membrane cytosolic vesicles, called autophagosomes, that sequester cytoplasmic contents and deliver them to the lysosome for subsequent degradation. The autophagosome does not bud off from preexisting organelles but, rather, is formed by a dynamic process of membrane expansion. This allows the autophagosome to sequester cargoes of almost any size, a capacity that is critical to many aspects of autophagic function, including the elimination of microbial pathogens from host cells. The ability to sequester invasive bacteria and deliver them to the lysosome would seem to be a potentially important role for epithelial and immune cells that encounter a heavy microbial load. The finding that a variant of ATG16L1, an orthologue of the yeast autophagy-related ATG16, is associated with Crohn’s disease1 suggests that the inability to eliminate intestinal microbes via autophagy might account for some types of this disease. The situation, however, appears to be more complex.
The three studies2–4 show that ATG16L1 mediates autophagy. The variation (T300A) in ATG16L1 associated with Crohn’s disease lies outside the region of homology with the yeast orthologue, and accordingly, when the mutant protein is over-expressed, it is not associated with defects in basal, nonselective autophagy (increased nonselective autophagy is a starvation response in yeast). Indeed, in vivo studies in mice suggest that rather than compromising the ability of the cell to sequester bacteria, T300A induces an autophagy-associated defect in Paneth cells, specialized cells in the crypts of Lieberkühn within the small intestine that secrete lysozyme and antimicrobial peptides (Fig. 1). The mutant Paneth cells show defects in the exocytic pathway. They also have degenerating mitochondria and an abnormal endoplasmic reticulum, which may reflect the loss of organelle degradative capacity associated with the autophagy defect, since autophagy plays an important role in removing damaged or dysfunctional organelles. These defects, which are also observed in mice engineered to lack either of the autophagy genes Atg5 or Atg7 in the intestinal epithelium, 2,5 correlate with the absence of lysozyme in the protective mucus layer of the ileum. Furthermore, microarray profiling indicates that genes associated with the inflammatory response, including leptin and adiponectin, are up-regulated in the autophagy-deficient Paneth cells. Analysis of tissue sections from human patients with the ATG16L1 risk allele confirms the presence of abnormal Paneth cells.
ATG16L1-dependent autophagy also mediates the endotoxin-induced inflammatory response.4 Mice with ATG16L1-deficient macrophages produce higher levels of the inflammatory cytokine interleukin-1β and are susceptible to acute colitis in response to the chemical damaging agent dextran sodium sulfate. The increased production of cytokines may reflect failure of an autophagic stress response.
All three studies suggest that a defect in autophagy may be the primary cause of ATG16L1-associated Crohn’s disease. It will be important to determine whether induction or up-regulation of autophagy, in particular in Paneth cells or macrophages, reverses the phenotypic abnormalities; restoration of their normal homeostasis may ameliorate the disease symptoms. From a clinical standpoint, treatment with neutralizing antibodies to inflammatory cytokines4 such as interleukin-1β or possibly the oral administration of an encapsulated (protease-protected) preparation that mirrors the contents of Paneth-cell secretory granules may help restore the microbial biota and intestinal milieu to its normal disease-free state.
Dr. Klionsky reports receiving lecture fees from Wyeth and having an equity interest in the journal Autophagy, of which he is editor-in-chief. No other potential conflict of interest relevant to this article was reported.