ALBERT

Description: Background: Inflammatory bowel diseases are associated with increased expression of zinc-dependentMatrix Metalloproteinase 9 (MMP-9). A stark dysregulation of intestinal mucosalhomeostasis has been observed in patients with chronic inflammatory bowel diseases. Wetherefore sought to determine the contribution of MMP-9 to the pathogenesis of Citrobacterrodentium-induced colitis and its effects on gut microbiome homeostasis. Results: Wild-type and MMP-9/ mice aged 5-6 weeks were challenged with C. rodentium byorogastric gavage and sacrificed either 10 or 30 days post-infection. Disease severity wasassessed by histological analysis of colonic epithelial hyperplasia and by using an in vivointestinal permeability assay. Changes in the inflammatory responses were measured by usingqPCR, and the composition of the fecal microbiome evaluated with both qPCR and terminalrestriction fragment length polymorphism. Activation and localization of MMP-9 to theapical surface of the colonic epithelium in response to C. rodentium infection wasdemonstrated by both zymography and immunocytochemistry. The pro-inflammatoryresponse to infection, including colonic epithelial cell hyperplasia and barrier dysfunction,was similar, irrespective of genotype. Nonmetric multidimensional scaling of terminalrestriction fragments revealed a different fecal microbiome composition and C. rodentiumcolonization pattern between genotypes, with MMP-9/ having elevated levels of protectivesegmented filamentous bacteria and interleukin-17, and lower levels of C. rodentium. MMP-9/ but not wild-type mice were also protected from reductions in fecal microbial diversity inresponse to the bacterial enteric infection. Conclusions: These results demonstrate that MMP-9 expression in the colon causes alterations in the fecalmicrobiome and has an impact on the pathogenesis of bacterial-induced colitis in mice.