Overview of Three Proliferation Pathways (Wnt, Notch, and Hippo) in Intestine and Immune System and Their Role in Inflammatory Bowel Diseases (IBDs)

Abstract

Inflammatory bowel disease (IBD) is a disorder, which involves the gastrointestinal (GI) tract consisting Crohn's disease (CD) and ulcerative colitis (UC). The etiology of this disease is not yet clear and, hence, there are numerous medications and treatments for patients with IBD, although a definite and permanent treatment is still missing. Therefore, finding novel therapeutic approaches are vital for curing patients with IBD. In the GI tract, there are various lineages of cells with different roles that their existence is necessary for the barrier function of intestinal epithelial cells (IECs). Therefore, signaling pathways, which manage the hemostasis of cell lineages in intestine, such as Wnt, Notch, and Hippo, could have crucial roles in regulation of barrier function in the intestine. Additionally, these signaling pathways function as a governor of cell growth, tissue homeostasis, and organ size. In patients with IBD, recent studies have revealed that these signaling pathways are dysregulated that it could result in depletion or excess of a cell lineage in the intestine. Moreover, dysregulation of these signaling pathways in different cell lineages of the immune system could lead to dysregulation of the immune system's responses in IBD. In this article, we summarized the components and signaling of Wnt, Notch, and Hippo pathways and their role in the intestine and immune system. Furthermore, we reviewed latest scientific literature on the crosstalk among these three signaling pathways in IBD. An overview of these three signaling pathways and their interactions in IBD could provide a novel insight for prospective study directions into finding efficient medications or treatments.

EhrlichiaWnt short linear motif ligand mimetic deactivates the Hippo pathway to engage the anti-apoptotic Yap-GLUT1-BCL-xL axis

“…Some differences between TRP120 and Wnt5a were expected since biological functions between various Wnt ligands differ despite a highly similar amino acid sequence (49). Additionally, TRP120 also contains Notch and Hedgehog SliMs which may also influence gene expression due to the intricate crosstalk between the pathways (50, 51).…”

Using Drosophila melanogaster as a suitable platform for drug discovery from natural products in inflammatory bowel disease

“…Wnt signaling pathway regulates the stem cell proliferation, differentiation and migration in the intestinal epithelium, and participates in the pathogenesis of IBD ( Flanagan et al, 2018 ). Decreased the Paneth cell alpha-defensin is one of the factors in IBD pathogenesis ( Khoramjoo et al, 2022 ). Diminished the Wnt pathway transcription factor (Tcf-4) expression could weaken enteric antimicrobial defense by reducing the Paneth cell alpha-defensin ( Pu et al, 2021 ; Khoramjoo et al, 2022 ).…”

“…Decreased the Paneth cell alpha-defensin is one of the factors in IBD pathogenesis ( Khoramjoo et al, 2022 ). Diminished the Wnt pathway transcription factor (Tcf-4) expression could weaken enteric antimicrobial defense by reducing the Paneth cell alpha-defensin ( Pu et al, 2021 ; Khoramjoo et al, 2022 ). In addition, studies have shown that in Tcf-4 knockout mice, reduced level of Paneth cell alpha-defensin in intestine permitted bacteria to invade the epithelium and result in colitis ( Wehkamp et al, 2007 ).…”

Molecular regulation after mucosal injury and regeneration in ulcerative colitis

“…Another researcher studied 44 patients with UC and found that 41 (93%) presented with Paneth cell metaplasia (PCM) in the colon or rectum ( Tanaka et al, 2001 ). In addition, PCM was positively correlated with crypt distortion and monocyte infiltration but not with crypt atrophy or mucin deficiency, suggesting that the hyperplasia and repair of intestinal mucosa may be important in PCM ( Khoramjoo et al, 2022 ). The intestinal flora of patients with UC is significantly different from that of healthy people.…”

“…Although no direct evidence has shown that the intestinal flora induces the differentiation of stem cells into Paneth cells through a direct mechanism, we propose that a change in the intestinal flora may cause PCM. The mild Paneth cytogenesis in individuals with UC plays a positive role in maintaining the growth and developmental environment of crypt ISCs and promotes the repair of the injured intestinal mucosa ( Khoramjoo et al, 2022 ). However, because metaplastic cells are derived from crypt stem cells, excessive metaplastic cell differentiation inevitably causes the excessive consumption of crypt stem cells, reducing the number of stem cells available to differentiate into other types of cells and delaying the mucosal repair process.…”