Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the Immunity Related GTPase (IRG) M. IRGs are a family of proteins known to confer resistance to intracellular infections through various mechanisms, including the regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. In the present study, we investigated the involvement of Irgm1, an orthologue of IRGM, in the genesis of murine intestinal inflammation. After DSS exposure, Irgm1^-/- mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1^-/- mice, even without DSS exposure, and were associated with impaired mitophagy and autophagy in Irgm1^-/- intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria, and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes that may be pivotal for proper Paneth cell functioning.