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Autophagy-related 16-like 1 (ATG16L1) deficiency leads to impaired cellular autophagy and bacterial degradation as well as an altered cytokine production. The single-nucleotide polymorphism rs2241880 (T300A) is associated with an increased risk for Crohn's disease (CD). ATG16L1 polymorphisms could therefore have an impact on the risk of infectious complications and disease course in CD. We examined the impact of the T300A genotype on the antibacterial response toward a panel of pathogenic bacteriain vitro, as well as clinical infectious complicationsin vivoand the disease course in a Danish cohort of patients with CD.A total of 236 CD patients were genotyped forATG16L1T300A; their clinical records were reviewed, and microbial, radiological, and surgical data were scrutinized. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and CD patients carrying the differentATG16L1genotypes, and the production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β was measured by enzyme-linked immunosorbent assay after stimulation with a panel of pathogenic bacteria of clinical relevance for the gastrointestinal tract, e.g., enteroinvasiveEscherichia coli(EIEC),Listeria monocytogenes,Salmonella typhimurium,Staphylococcus aureus, orMycobacterium avium paratuberculosis.Fifty-seven healthy controls (15, 29, 13) and 236 patients with CD (50, 108, 78) were genotyped for the T300AATG16L1polymorphism (AA homozygous, GG homozygous risk variant, AG heterozygous variant, respectively). The median duration of disease was 128 months (range, 30–175). The cumulative follow-up of this cohort was 2,366 patient-years.ATG16L1gene variations interfered with the production of IL-1β, which was significantly increased in PBMCs from GG patients in response to all tested bacteria, whereas the TNF-α production was decreased in PBMCs from GG patients stimulated with EIEC,L. monocytogenes, andS. typhimurium, but unaffected by the other bacteria tested. Moreover, the GG variant showed a nonsignificant increase in the risk of bowel resections (P=0.07) and postsurgical infections (P=0.08), whereas the risk of non-disease-related infections was unaffected by genotype in the observation period. In addition, patients with AA and AG variants had a higher frequency of complicated fistulizing disease (P=0.03) with an overall more aggravated disease course with an increased number of surgical procedures for fistulous disease from a median 6.5 operations (2.0 in GG patients;P=0.002). This risk was independent on disease phenotype (penetrating vs. non-penetrating) and immunomodulating medication.The T300A variant in patients with CD strongly increases the risk for complicated fistulizing disease, and significantly affects antibacterial responsesin vitro, but the latter effect seems to have a minor role for the infectious risk in CD.