P120 THE ROLE OF MICROBIOTA AND MACROPHAGES DURING COLITIS IN TUMOR NECROSIS FACTOR RECEPTOR 1 (TNFR1) AND IL-10 DEFICIENT MOUSE MODEL. (18th January 2018)

• Record Type: Journal Article
• Authors: Huang, Ying; Tam, Sharon S; Girish, Nandini; Punit, Shivesh; Liu, Cambrian Y; Washington, Kay; Polk, D Brent
• Is Part Of: Inflammatory bowel diseases. Volume 24(2018)Supplement 1
• Page Start: S42
• Page End: S42
• Publication Date: 2018-01-18
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izy019.132
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Background & Aim: Inflammatory bowel disease (IBD) remain major clinical challenges and are currently incurable. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, and TNFR1 polymorphisms have been described in IBD patients. Interleukin 10 (IL-10) receptor deficiency has been linked to early-onset human IBD and mice lacking expression of IL-10 develop spontaneous colitis from loss of immune tolerance to normal gut microbiota. We have shown that combining IL-10 deficiency with loss of TNFR1 results in severe colitis by 8 weeks. However, the potential role of the microbiota and cellular function of macrophages in disease onset remain unknown. Here, we have analyzed colitis at different ages in Il10-/-Tnfr1-/- mice and macrophage specific Tnfr1-/- mice with Il10-/- to address these questions. Method: To assess the microbial contributions, 8-week old Il10-/-Tnfr1-/- mice were treated with either antibiotics (Neomycin and Metronidazole) or water (control) for 2 weeks, and colitis was subsequently scored by colonoscopy and histology. To examine the microbial composition, co-housed litters of Il10-/- and Il10-/-Tnfr1-/- mice were collected at different age. To exam the cellular function of macrophages, macrophage specific knock out mice were collected at 8 and 12 weeks. Cecal contents were sequenced using the 16S rRNA gene. Results: Antibiotic treatment of Il10-/- Tnfr1-/-mice resulted in resolution of colitis by 8 weeks. The microbial community composition was divergence between these genotypes by 8 weeks. However, macrophage specific knock out of Tnfr1 might serve as protective role at 12 weeks. Conclusions: While microbial contents are essential for development of colitis in the Il10-/-Tnfr1-/- model, community profiling suggests that the precise species composition is not a driver of early onset disease. Dysregulated recognition of microbial patterns by the host immune system may be contributing to severe inflammation in Il10-/-Tnfr1-/-mice.