Inflammatory Bowel Disease (IBD) is a dysregulated response of the immune system associated with intestinal tissues to the commensal microbiota in a genetically susceptible host. The understanding of the genetic basis of IBD has been significantly expanded with the advent of genome-wide association studies (GWAS) which has resulted in the identification of more than 30 loci that are associated with Crohn’s disease (CD) and ulcerative colitis (UC). As anticipated, this unbiased approach of gene discovery has both confirmed previously established disease related pathways and led to new hypotheses of IBD pathogenesis that are currently being tested in biologic model systems to establish the precise mechanisms of action involved. One such potential pathway that was unexpectedly identified is that associated with autophagy; a cell biologic pathway important in the clearance of microbes and cellular proteins and organelles. Employing a GWAS of non-synonymous single nucleotide polymorphisms (nsSNPs) Schreiber and colleagues first identified and confirmed ATG16L1, a putative human orthologue of a yeast autophagy gene, as a susceptibility factor specifically for CD [1]. Haplotype and regression analysis further identified a single coding SNP (rs2241880, T300A) of unknown function that conferred virtually all the disease risk exerted by the ATG16L1 locus [1]. Reproduction by other groups of the association of ATG16L1 with CD [2, 3] together with the identification of IRGM and possibly LRKK2, additional autophagy genes, as risk factors for CD [3, 4], has strongly implicated autophagy as a pathway unique to CD but not UC. However, it has remained to be defined how these ATG16L1 genotypes confer the phenotypic development of CD. Two papers published in Nature online on October 5, 2008, shed some light on how Atg16l1 and autophagy may contribute to the development of CD [5, 6]. Using two different genetrap-mediated hypomorphic disruptions of Atg16l1 as well as mice with Atg5 conditionally deleted in the intestinal epithelium, Cadwell et al. report that Atg16l1 is indeed a bona fide autophagy protein as predicted from its homology to the yeast autophagy protein ATG16. By using a variety of morphological measures, they report that Atg16l1 and Atg5 play a major role in the formation of Paneth cell (Pc) granules that are rich in antimicrobial peptides and involved in host defense against infection and presumably the management of commensalism. Moreover, transcriptional profiling of Pc in hypomorphic Atg16l1 mice showed increased expression of genes involved in peroxisome proliferator-activated receptor-signaling as well as leptin and adiponectin, adipocytokines that have been linked to intestinal inflammation and are increased in CD [5]. Most interestingly, in patients homozygous for the disease-associated ATG16L1 variant (T300A), the authors report morphologic Pc abnormalities and increased leptin expression reminiscent of those observed in their hypomorphic Atg16l1 mouse models [5]. In the second paper, Saitoh et al. report that Atg16l1 regulates endotoxin-induced inflammosome activation [6]. Atg16l1 deficiency was shown to disrupt the recruitment of the Atg12-Atg5 conjugate to the isolation membrane resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3; homologue of yeast Atg8) conjugation to phosphatidylethanolamine [6]; an essential step in autophagosome formation. As a consequence, both autophagosome formation and degradation of long-lived proteins were severely impaired as shown by accumulation of the adaptor protein sequestosome (SQSTM1/P62)[6]. Stimulation of Atg16l1-deficient …