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Review
. 2024 Jan 5:10:1333531.
doi: 10.3389/fmed.2023.1333531. eCollection 2023.

The role of the Notch signalling pathway in the pathogenesis of ulcerative colitis: from the perspective of intestinal mucosal barrier

Affiliations
Review

The role of the Notch signalling pathway in the pathogenesis of ulcerative colitis: from the perspective of intestinal mucosal barrier

Hang Ning et al. Front Med (Lausanne). .

Abstract

Ulcerative colitis is a common digestive disorder worldwide, with increasing incidence in recent years. It is an urgent problem to be solved, as it seriously affects and threatens the health and life of the global population. Studies have shown that dysfunction of the intestinal mucosal barrier is a critical pathogenic factor and molecular basis of ulcerative colitis, and some scholars have described it as a "barrier organ disease." While the Notch signalling pathway affects a series of cellular processes, including proliferation, differentiation, development, migration, and apoptosis. Therefore, it can regulate intestinal stem cells, CD4+ T cells, innate lymphoid cells, macrophages, and intestinal microbiota and intervene in the chemical, physical, immune, and biological mucosal barriers in cases of ulcerative colitis. The Notch signalling pathway associated with the pathogenesis of ulcerative colitis has distinct characteristics, with good regulatory effects on the mucosal barrier. However, research on ulcerative colitis has mainly focused on immune regulation, anti-inflammatory activity, and antioxidant stress; therefore, the study of the Notch signalling pathway suggests the possibility of understanding the pathogenesis of ulcerative colitis from another perspective. In this article we explore the role and mechanism of the Notch signalling pathway in the pathogenesis of ulcerative colitis from the perspective of the intestinal mucosal barrier to provide new targets and theoretical support for further research on the pathogenesis and clinical treatment of ulcerative colitis.

Keywords: Notch; mucosal barrier; review; signalling pathway; ulcerative colitis.

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Conflict of interest statement

HN received the grant from Hunan Province College Students’ Innovation and Entrepreneurship Training Program. JL received the grant from the National Natural Science Foundation of China and the High-Level Innovative Talents Project of Guizhou Province. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The Notch signalling pathway comprises Notch receptors and ligands, DNA-binding proteins (such as RBP-Jk), regulatory factors, and downstream target genes (such as Hes1 and Math1). The classical RBP-Jk-dependent activation of Notch signalling pathway including three key steps, and Notch receptors were turned into NICD in this process. Then NICD forms a trimeric transcription complex with RBP-Jk and recruits mastermind-like transcriptional co-activators in the cell nucleus, finally activates the transcription of downstream target genes of Notch.
Figure 2
Figure 2
Notch signalling pathway regulates intestinal stem cell differentiation, BESTs, DCLK1 and GABA to affect the development of UC. Activation of the GABAergic signalling system in the colonic epithelium can activate the Notch signalling pathway, thereby disrupting the intestinal epithelial mucosal barrier, this suggests that the brain-gut axis may mediate the involvement of the Notch signalling pathway in UC pathogenesis. In cases of UC, the Notch signalling pathway exhibits abnormally high activity, inhibiting differentiation into the secretory lineage, down regulating the expression of BEST2, up regulating the expression of BEST4, finally weakening the mucous barrier. And there is a self-protection mechanism, activation of the Notch signalling pathway can promote the expression of DCLK1, benefit to crypt repair and suppression of inflammation in patients with UC.
Figure 3
Figure 3
Olfm4 exhibit antimicrobial activity and show cell-protective effect against apoptosis. Activation of the Notch signalling pathway can promote the expression of Olfm4. At the same time, it is also showing anti-inflammatory activity and can inhibit NF-κB activation.
Figure 4
Figure 4
Intestinal stem cells expressing LGR5+ exhibit self-renewal and high differentiation potentials, playing an important role in the repair of intestinal mucosal damage. The Wnt/β-catenin and Notch signalling pathways collectively maintain the function of intestinal stem cells expressing LGR5+. Both pathways exhibit opposing activities in regulating intestinal stem cell differentiation. Therefore, the interaction between the Wnt/β-catenin and Notch signalling pathways is considered to influence intestinal stem cell differentiation and mucosal barrier repair. The signals of Wnt/β-catenin and Notch1 can be integrated by NOX1.
Figure 5
Figure 5
In active UC intestines, both TJ and AJ proteins exhibit pathological changes, in expression, distribution, and alignment. Claudin1, 2, and 4 are upregulated, whereas occludin, claudin5, and claudin8 are downregulated. Blocking the Notch signalling pathway, can improve the barrier function of the mucosal mechanical barrier by upregulating the expression of Zonula occludens-1 and occludin and downregulating claudin2 expression.
Figure 6
Figure 6
The Notch1 signalling pathway as a regulator of Th17/regulatory T cell balance; however, there is still no consensus on its exact mechanism. Th1 and 2 have their specific roles, with Delta inducing Th1 and Jagged inducing Th2. The intervention of Notch ligands in Th1 or 2 differentiation cannot occur independently of cytokines and cannot reset cytokine-driven Th1 or 2 differentiation.
Figure 7
Figure 7
ILC3 plays an important role in the pathogenesis of UC. And the Notch signalling pathway plays a crucial role in development and lineage classification of ILCs. Notch signalling can silencing the early B cell factor 1 and paired box 5 in common lymphoid progenitor cell to form a population of ILC/T progenitor cells. Then, inhibiting the differentiation towards T cells by suppressing the expression of E-box family transcription factors, thereby promoting the differentiation of ILC/T progenitor cells towards ChILPs. ChILPs can be divided into Promyelocytic leukaemia zinc finger (PLZF) + ChILPs and PLZF − ChILPs. PLZF + ChILPs can differentiate into NCR − ILC3 under the influence of Notch signalling pathway.
Figure 8
Figure 8
In patients with UC, increased M1 and decreased M2 polarisation occur with high transmission of the Notch1 signalling pathway. Inhibiting Notch1 significantly reduces M1 polarisation, increases M2 polarisation and anti-inflammatory markers, and restores the M1/M2 balance. Furthermore, Notch signalling exhibits partial anti-inflammatory effects.
Figure 9
Figure 9
The interaction between the Notch signalling pathway and gut microbiota is an important research direction for regulating host life activities and immune responses. Currently, there are two research approaches, one is focuses on the influence of gut microbiota on Notch signalling transduction, another one is the intervention of gut microbiota metabolites in the Notch signalling pathway and their effects on UC.

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