The core autophagy protein Atg16L1 has been identified as a genetic risk factor in inflammatory bowel disease, but how it plays this role has remained unclear. On p. 3990, Gábor Juhász and colleagues interrogate the role of Atg16, the Drosophila orthologue of human ATG16L1, in intestinal homeostasis and inflammation. Using mutants that affect either the N-terminal autophagic domain or the C-terminal WD40 domain, they observe defects in intestinal morphology and an impaired stress response in Atg16 WD40 mutants. In Atg16 WD40 mutant intestines, the differentiation of enteroendocrine (EE) cells is impaired, leading to an accumulation of pre-EE cells, and this results from reduced Slit/Robo signalling (a pathway known to regulate EE cell number). The failure of EE differentiation is accompanied by an inflammatory response, but appears to be independent of autophagy: autophagy is not altered in Atg16 WD40 mutants, and mutants affecting the autophagy domain alter neither Slit/Robo signalling nor EE differentiation. Finally, the authors show that Atg16 binds to the GTPase Rab19 – also a genetic risk factor for inflammatory bowel disease – and the two cooperate in regulating intestinal homeostasis. This work provides insight into the molecular control of intestinal homeostasis and implies a link between impaired cell differentiation and intestinal pathologies in humans.