Abstract A high prevalence of adherent-invasive E. coli (AIEC) in the intestinal mucosa of Crohn’s disease patients has been shown. AIEC colonize the intestine and induce inflammation in genetically predisposed mouse models including CEABAC10 transgenic (Tg) mice expressing human CEACAM6-receptor for AIEC and eif2ak4 −/− mice exhibiting autophagy defect in response to AIEC infection. Here, we aimed at investigating whether gut microbiota modification contributes to AIEC-induced intestinal inflammation in these mouse models. For this, eif2ak4 +/+ and eif2ak4 −/− mice or CEABAC10 Tg mice invalidated for Eif2ak4 gene (Tg/eif2ak4 −/−) or not (Tg/eif2ak4 +/+) were infected with the AIEC reference strain LF82 or the non-pathogenic E. coli K12 MG1655 strain. In all mouse groups, LF82 colonized the gut better and longer than MG1655. No difference in fecal microbiota composition was observed in eif2ak4 +/+ and eif2ak4 −/− mice before infection and at day 1 and 4 post-infection. LF82-infected eif2ak4 −/− mice exhibited altered fecal microbiota composition at day 14 and 21 post-infection and increased fecal lipocalin-2 level at day 21 post-infection compared to other groups, indicating that intestinal inflammation developed after microbiota modification. Similar results were obtained for LF82-infected Tg/eif2ak4 −/− mice. These results suggest that in genetically predisposed hosts, AIEC colonization might induce chronic intestinal inflammation by altering the gut microbiota composition.