Specific host-microbial interactions required for the development of Crohn’s disease

Seminar Details
Wednesday, March 15, 2017 - 9:00am to 10:00am


Roberta Caruso, M.D., Ph.D.
Postdoctoral Fellow - Nunez Lab
Departments of Pathology and Comprehensive Cancer Center


5623 Med. Sci. II  (Wheeler Seminar Room)

Crohn's disease (CD) is a chronic relapsing intestinal inflammatory disorder that results from an abnormal mucosal immune response against intestinal bacteria in genetically susceptible individuals. Although polymorphisms in NOD2 are the strongest genetic risk factors in the development of CD, human and mouse studies have provided evidence that impaired NOD2 function is only revealed after an immune or microbial challenge. This project aims at elucidating the host-microbial interactions required for disease development in Nod2-/- mice. We used single Nod2-/- mice and generated double mutant mice harboring mutations in anti-microbial genes in addition to Nod2 deficiency. No signs of intestinal inflammation occurred in these mice housed under specific-pathogen-free conditions. However when fostered to a dam, known to harbor a diverse intestinal microbiota, they developed, at weaning, CD-like cecal and colonic inflammation, characterized by skip lesions with transmural infiltration with inflammatory cells and granuloma formation. Notably, none of the controls, neither wild type nor single mutant mice fostered to the same dam, developed intestinal inflammation, suggesting that both mutations are required for disease development. The fostered double mutant mice showed increased intestinal production of TNF-α, enhanced intestinal infiltration with Th1 cells and increased production of IFN-γ when compared to control mice. Analysis of the gut microbiota of the fostered mice led to the identification of a Gram negative commensal species that was significantly more abundant in the fostered double mutant mice as compared to control mice. In vivo challenge confirmed that this bacterium is sufficient for triggering the CD-like intestinal inflammation in the double mutant mice. Overall these results argue for a critical role for specific gut microbiota-host gene interactions in driving CD-related disease in Nod2-/-mice.

Sponsored by the Host Microbiome Initiative