Critical Roles of Notch and Wnt/β-Catenin Pathways in the Regulation of Hyperplasia and/or Colitis in Response to Bacterial Infection

Abstract

Notch and Wnt/␤-catenin signals play essential roles in intestinal development and homeostasis. Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and various degrees of inflammation, depending upon the genetic background. We aimed at delineating the role of the Notch and Wnt/␤-catenin pathways in the regulation of colonic crypt hyperplasia and/or colitis following C. rodentium infection. During TMCH, relative levels of the Notch intracellular domain (NICD) increased significantly, along with increases in Jagged-1 and Hes-1 coinciding with the progression and regression phases of hyperplasia. Blocking of Notch signaling with dibenzazepine (DBZ) for 5 days before the onset of hyperplasia also blocked Wnt/ ␤-catenin signaling. Targeting the Notch pathway for 5 days after the onset of hyperplasia failed to inhibit Wnt/␤-catenin-regulated crypt hyperplasia. Chronic DBZ administration for 10 days blocked both Notch and Wnt signaling, disrupted the intestinal barrier, and induced colitis. Core-3 ؊/؊ mice, which are defective in mucin secretion and are susceptible to experimental triggers of colitis, also exhibited significant colitis in response to C. rodentium plus DBZ. Chronic DBZ administration in these mice did not result in depletion of the putative stem cell marker doublecortin-like kinase-1 (DCLK1) in the crypts. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored signaling via the Notch and Wnt/␤-catenin pathways, thereby promoting crypt regeneration, and also replenished the mucus layer, leading to amelioration of C. rodentium-and DBZ-induced colitis in NIH:Swiss mice. Thus, the balancing act between cell proliferation and mucus production to restore barrier integrity seems to depend upon the interplay between the Wnt/␤-catenin and Notch pathways in the TMCH model.

Chemoprevention in Gastrointestinal Physiology and Disease. Natural products and microbiome

“…We and other investigators have also demonstrated that curcumin inhibits several important signaling pathways including Notch and Wnt signaling (4,132). Interestingly, it was found that curcumin could inhibit mammosphere formation and could also decrease the amount of aldehyde dehydrogenase-positive cells in normal and malignant breast cancer cells through the inhibition of Wnt signaling (23), suggesting the inhibitory effects of curcumin on breast cancer stem cells (23).…”

Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration

“…C. rodentium infection induces epithelial regeneration and repair mechanisms, which drives a marked expansion of undifferentiated colonocytes, resulting in crypt elongation and the presence of undifferentiated colonocytes at the luminal surface (31, 32)(Fig. S1).…”

Aberrant Niche Signaling in the Etiopathogenesis of Ulcerative Colitis

“…18 Several lines of evidence suggest that Wnt signaling works in tandem with Notch signaling for intestinal homeostasis and that perturbation of these pathways could lead to inflammation or cancer. 37 The concurrent abrogation of Wnt signaling target genes, such as Lgr5, Ascl2, hTert, and Msi, along with above described changes in Notch targets in the uninvolved region of patients with UC, suggests coordination between Notch and Wnt pathways in UC. These data further emphasize cooperation and hierarchical regulation of more than 1 pathway in the early pathogenesis of the disease wherein Notch primarily affects progenitors while Wnt targets stem cells in the uninvolved region of patients with UC.…”

“…37 To determine if Notch signaling is involved in the observed lower crypt defect, we next analyzed the members of Notch signaling and their downstream targets (Fig. 5F).…”