Intestinal NCoR1 Protects against Dextran Sodium Sulfate‐Induced Ulcerative Colitis

Ulcerative colitis (UC), one of the principal types of inflammatory bowel disease (IBD), is characterized as a long‐term condition that results in colon and rectum inflammation. UC affects approximately 1 in 400 people worldwide, with the highest incidence and prevalence in Northern Europe and North America. Most recently, the introduction of genetically modified mouse models and high‐throughput sequencing technology have led to key advances in identifying and characterizing genetic markers and environmental factors associated with the risk for UC. However, the precise, disease‐causing genes and their functions that link gene‐environment interactions in UC initiation have not been identified. The importance of intrinsic NCoR1 in intestinal homeostasis was first discovered in our laboratory when we generated intestinal epithelial cell (IEC) specific NCoR1 deletion mice ( NCoR1 ΔIEC ) and identified the role of NCoR1 in regulating IEC proliferation and enterocyte maturation during neonatal development. To explore NCoR1 function in the context of gastrointestinal disease, we employed dextran sodium sulfate (DSS), a standard agent used to induce experimental UC in both NCoR1 F/F (control) and NCoR1 ΔIEC mice. Eight‐week old NCoR1 F/F and NCoR1 ΔIEC mice were given 2.5% (w/v) DSS (40–50 kDa, Affymetrix) in their drinking water for six days, and body weights (BW) were monitored. It is shown that NCoR1 F/F mice were minimally affected, while NCoR1 ΔIEC mice exhibited profound body weight (BW) loss (p<0.0001, two‐way ANOVA, n=10). The BW difference was observed initially at day 5 after DSS exposure (p<0.01, student's t test, n=10). The greatest weight loss was observed on day 8 (two days after DSS withdrawal) with 18.7% weight loss in NCoR1 ΔIEC vs 8.0% in NCoR1 F/F mice. After day 8, BW began to recover but NCoR1 ΔIEC mice showed slower recovery compared to controls. In H&E staining, the water‐ NCoR1 ΔIEC mice showed no obvious histological difference from the water‐ NCoR1 F/F mice. In the DSS treated group, NCoR1 ΔIEC mice demonstrated increased disease severity as measured by the histopathological colitis score quantitated based on the presence and severity of ulcerative lesions, disrupted epithelial structure, damaged crypt architecture, and increased inflammatory cell infiltration. Consistently, RT‐qPCR also demonstrated increased mRNA expression of pro‐inflammatory cytokines TNFα , IL‐1β , IL‐6 , and IL‐8 in NCoR1 ΔIEC mice. To further explore the potential mechanisms, we have carried out BrdU cell proliferation assays. Results demonstrated that BrdU‐positive (BrdU+) cells had increased by approximately 70% in water‐ NCoR1 ΔIEC mice (n = 5, p<0.05). Following DSS exposure for two days, no significant changes were observed in DSS‐ NCoR1 F/F mice. However, BrdU+ cells were significantly decreased in NCoR1 ΔIEC mice, which maintained approximately 35% BrdU+ cells in comparison to DSS‐ NCoR1 F/F mice. These results suggest that intrinsic NCoR1 plays an important role in protecting against DSS‐induced UC, particularly the intestinal proliferative cells in mice. Support or Funding Information Supported by ES024818 and AI135677. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .