Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis.
BACKGROUND
Inflammatory bowel diseases are associated with increased expression of zinc-dependent Matrix Metalloproteinase 9 (MMP-9). A stark dysregulation of intestinal mucosal homeostasis has been observed in patients with chronic inflammatory bowel diseases. We therefore sought to determine the contribution of MMP-9 to the pathogenesis of Citrobacter rodentium-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 by orogastric gavage and sacrificed either 10 or 30 days post-infection. Disease severity was assessed by histological analysis of colonic epithelial hyperplasia and by using an in vivo intestinal permeability assay. Changes in the inflammatory responses were measured by using qPCR, and the composition of the fecal microbiome evaluated with both qPCR and terminal restriction fragment length polymorphism. Activation and localization of MMP-9 to the apical surface of the colonic epithelium in response to C. rodentium infection was demonstrated by both zymography and immunocytochemistry. The pro-inflammatory response to infection, including colonic epithelial cell hyperplasia and barrier dysfunction, was similar, irrespective of genotype. Nonmetric multidimensional scaling of terminal restriction fragments revealed a different fecal microbiome composition and C. rodentium colonization pattern between genotypes, with MMP-9-/- having elevated levels of protective segmented 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 in response to the bacterial enteric infection.


CONCLUSIONS
These results demonstrate that MMP-9 expression in the colon causes alterations in the fecal microbiome and has an impact on the pathogenesis of bacterial-induced colitis in mice.
Department of Paediatrics, University of Toronto, 27 Kings College Circle, Toronto, Ontario, Canada. philip.sherman@sickkids.ca
David M
DM
Rodrigues
Andrew J
AJ
Sousa
Steve P
SP
Hawley
Linda
L
Vong
Melanie G
MG
Gareau
Sachin A
SA
Kumar
Kathene C
KC
Johnson-Henry
Philip M
PM
Sherman
D000818:Animals; D044822:Biodiversity; D044082:Citrobacter rodentium / Q000472:pathogenicity*; D003092:Colitis / Q000382:microbiology* / Q000473:pathology; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology* / Q000473:pathology; D006706:Homeostasis; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism*; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index
D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse