Research ArticleINFLAMMATORY BOWEL DISEASE

A specific gene-microbe interaction drives the development of Crohn’s disease–like colitis in mice

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Science Immunology  19 Apr 2019:
Vol. 4, Issue 34, eaaw4341
DOI: 10.1126/sciimmunol.aaw4341

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A mouse model for Crohn’s disease

Although several mouse models of inflammatory bowel disease exist, Crohn’s disease has been particularly difficult to model. Here, Caruso et al. report a mouse model where they can recapitulate multiple hallmarks of intestinal inflammation seen in patients with Crohn’s disease. Mice lacking nucleotide-binding oligomerization domain–containing protein 2 (NOD2) and the cytochrome b-245 beta chain (CYBB) subunit of phagocyte NADPH oxidase develop spontaneous colitis that is driven by a Gram-negative pathobiont, Mucispirillum schaedleri. NOD2/CYBB-deficient mice developed colitis only after weaning because maternal antibodies protected them from it before weaning. In addition to developing a model for studying Crohn’s disease, the study also highlights the importance of maternal antibodies in regulating immune homeostasis in early life.

Abstract

Bacterial dysbiosis is associated with Crohn’s disease (CD), a chronic intestinal inflammatory disorder thought to result from an abnormal immune response against intestinal bacteria in genetically susceptible individuals. However, it is unclear whether dysbiosis is a cause or consequence of intestinal inflammation and whether overall dysbiosis or specific bacteria trigger the disease. Here, we show that the combined deficiency of NOD2 and phagocyte NADPH oxidase, two CD susceptibility genes, triggers early-onset spontaneous TH1-type intestinal inflammation in mice with the pathological hallmarks of CD. Disease was induced by Mucispirillum schaedleri, a Gram-negative mucus-dwelling anaerobe. NOD2 and CYBB deficiencies led to marked accumulation of Mucispirillum, which was associated with impaired neutrophil recruitment and killing of the bacterium by luminal neutrophils. Maternal immunoglobulins against Mucispirillum protected mutant mice from disease during breastfeeding. Our results indicate that a specific intestinal microbe triggers CD-like disease in the presence of impaired clearance of the bacterium by innate immunity.

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