**3. The role of autophagy genes in the pathogenesis of IBD**

Autophagy is a conserved lysosome-dependent catabolic process, degrading and recycling protein aggregates or damaged organelle. Autophagy affects the pathogenesis of IBD in multiple ways, including secretion of antimicrobial materials from Paneth cells, clearance of invading pathogens, presentation of antigen, or proinflammatory cytokine production by macrophages [26].

SNPs of autophagy genes such as autophagy-related gene 16 like 1 (*ATG16L1)* and immunity-related GTPase family M (*IRGM*) have been identified to be associated with CD. *ATG16L1* and *IRGM* genes affect cellular autophagy processes and bacterial clearance in immune cells and may affect bacterial composition of the gut in patients with IBD [27].

There is some overlap in these autophagy-related genetic variants in both CD and UC, but majority of the identified variants are more associated with ileal CD. Despite this association, the positive predictive value for disease development in individuals carrying autophagy variants is low because the *ATG16L1* T300A polymorphism is linked with CD susceptibility, which is also present in a large proportion of healthy individuals who do not develop IBD [28].

However, some of the studies show that a knock-in mouse model expressing A*TG16L1* T300A does not develop spontaneous inflammation, but it exhibits morphological defects in both Paneth cells and goblet cells, and the presence of the T300A mutation in *ATG16L1* leads to aberrant functionality of Paneth cells. These findings indicate a close relationship between *ATG16L1* variants and Paneth cells [15].

Recent data GWAS identified the single-nucleotide polymorphism (SNP) rs13361189—a SNP lying immediately upstream of the autophagy gene *IRGM*, and many studies have investigated *IRGM* gene variants both in adult and pediatric and in UC, confirming its role in the IBD pathogenesis. It was shown that SNP rs13361189, the deletion allele, modulated the expression of *IRGM* in transformed cells [29].

Other study demonstrated functional effects of the synonymous SNP rs10065172 (c.313C > T). This synonymous variant rs10065172 in *IRGM* alters a binding site for certain microRNAs, miR-196, and causes deregulation of *IRGM*dependent xenophagy of bacteria in patients with CD [29].
