Background:The role of autophagy in colonic homeostasis is not clear. Results: Colonic epithelial cell-specific and autophagy-deficient mice showed exacerbation of colitis and abnormal gut microflora with less abundant antimicrobial peptide production and secretion of mucus. Conclusion: Autophagy protects against colitis by the maintenance of normal gut microflora and secretion of mucus. Significance: These findings may ultimately lead to an efficient intervention for inflammatory bowel diseases.