SNPs rs1800896, rs3024505 (IL-10); rs11209026 (IL23R); rs2066844, rs2066845 (NOD-2), and rs2241880 (ATG16L1) were assessed in 93 patients with IBD and 200 healthy controls by hybridization probes and quantitative PCR.
Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine.
These findings suggest that the IBD susceptibility gene ATG16L1 and the process of autophagy within the epithelium control inflammation-induced apoptosis and barrier integrity to limit chronic intestinal inflammation.
Cells harbouring the ATG16L1T300A allele associated with inflammatory bowel disease were also found to accumulate cholesterol and be defective in repair, linking a common inflammatory disease to plasma membrane integrity.
The autophagy-related 16-like 1 gene (Atg16l1) is associated with inflammatory bowel disease (IBD) and has been shown to play an essential role in paneth cell function and intestinal homeostasis.
Furthermore, TMAO-mediated effects were observably reversed by over-expression ATG16L1 and siRNA-mediated knockdown NLRP3.The present results support the hypothesis that TMAO may be involved in the pathogenesis of IBD by impacting ATG16L1-induced autophagy and activating NLRP3 inflammasome, suggesting a potential therapeutic targets for the treatment of IBD and TMAO-associated complications.
We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation.
Genetic polymorphisms in the known IBD-associated gene ATG16L1 correlate with requirement of treatment, suggesting a different IBD disease phenotype in these patients.
The discovery that several genes linked to IBD modulate microbial recognition and innate immune pathways, such as nucleotide oligomerization domain 2 (Nod2), and genes that mediate autophagy (ie, ATG16L1, IRGM), has highlighted the critical role of host-microbe interactions in controlling intestinal immune homeostasis.
Actively inflamed intestinal biopsies from CD patients carrying either ATG16L1 or PTPN2 genetic variants revealed aberrant LC3B expression patterns when compared with samples from non-IBD control patients.
The recent findings in IBD include the increasing number of IBD susceptibility genes, the demonstration that NOD2 and ATG16L1 are linked in one functional pathway and the role of IL-33/ST2 in colitis.
The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn's disease turned autophagy into the spotlight in inflammatory bowel disease (IBD).
The propensity to develop IBD has not been linked to single gene mutations in most instances, but has been linked to SNP in the NOD2 locus (which appear to create hypomorphic alleles for this bacterial response gene), the IL23R locus, the autophagy gene ATG16L1 and a wide range of other loci including the Toll-like receptors, JAK2 and STAT3, and perhaps 70 more.
The ATG16L1T300A polymorphism contributes to susceptibility to CD and UC in adults, but different in children, which implicates a role for autophagy in the pathogenesis of IBD.
Therefore we aimed to replicate these novel CD susceptibility variants in a large European cohort with inflammatory bowel disease and analyzed potential gene-gene interactions with variants in the NOD2/CARD15, IL23R, and ATG16L1 genes.
Our aims were: to replicate the ATG16L1Thr300Ala association with inflammatory bowel disease (IBD) in the Spanish population, to perform a meta-analysis to determine the risk conferred to the different IBD subgroups, and to test for the interaction with CARD15 or IL23R risk loci.