Why Are Goblet Cells Necessary For Gi Tract Function – Throughout the gastrointestinal (GI) tract, a distinct mucosal layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for food passage, participating in cell signaling pathways, and protecting the host epithelium against commensal microorganisms and pathogens. Plays. Also toxins and other environmental triggers. These mucins can be broadly classified into two categories: secreted gel-forming mucins, those that provide the structural backbone of the mucosal barrier, or transmembrane mucins, those that form the glycocalyx layer that covers the underlying epithelial cells. Goblet cells scattered among the intestinal epithelial cells are mainly responsible for the synthesis and secretion of mucin in the intestine and are strongly influenced by interactions with the immune system. Evidence from clinical and animal studies has shown that several gastrointestinal diseases, including inflammatory bowel disease (IBD), colorectal cancer, and multiple intestinal infections are associated with significant changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, impaired synthesis, and altered post-translational modifications. The aim of the present review is to highlight the structural and functional features as well as the production and immune regulation of mucins and the impact of these key elements in the context of barrier function and host defense in intestinal inflammation.

The mammalian gastrointestinal tract has a dynamic and complex ecosystem with gut microbes, food particles, foreign substances, and host cells engaging in constant interaction. As such, the host requires relentless monitoring and constant protection to maintain a strict homeostatic condition. As the bridge between the internal and external environment, it is not surprising that approximately 70% of the immune system resides within the gastrointestinal tract (1). Although these essential defense mechanisms mask basic innate responses to more complex adaptive pathways, the physical aspects of protection should not be overlooked. One of these physical aspects is the mucosal layer of the gastrointestinal tract, which acts as a lubricant for the passage of food, protects the underlying epithelium from normal microbes, and creates a physical barrier against invading pathogens, as well as toxins and other environmental stimuli. , 3). The mucosal layer, particularly through its transmembrane components, also affects several cell signaling pathways that can modulate inflammatory responses, influence cell-cell interactions, and regulate proliferation, differentiation, and apoptosis (4- 6).

Why Are Goblet Cells Necessary For Gi Tract Function

Why Are Goblet Cells Necessary For Gi Tract Function

The intestinal mucous layer is mainly composed of a subset of high molecular weight glycoproteins called mucins, which play an important role in physical protection as well as in regulating the concentration and passage of water, ions and other immune mediators such as antimicrobial peptides (AMPs). . and immunoglobulin-A (IgA) in the intestine (2, 3, 7). The stomach and large intestine contain a mucosal bilayer composed of polymeric sheets of these highly glycosylated mucins (Figure 1). These two layers can be classified into the dense inner layer, which is firmly attached to the underlying epithelial cells and impermeable to bacteria, versus the outer layer, which is loosely attached to and easily detached from the underlying dense layer (8, 9). . . This outer layer can also be penetrated by bacteria. In contrast, the small intestine contains only a loose layer of mucus that is permeable to bacteria [Figure 1; (8, 9)].

Structure Of The Gi Tract Wall. A Histological Presentation, Stained…

Figure 1. The mucosal layer of the small intestine and colon. (a) In the small intestine, only one layer of mucus is loosely attached and permeable to resident microbes. (b) Colonic mucus, produced mainly by goblet cells, consists of two layers: an outer layer permeable to bacteria and a tightly adherent inner layer impermeable to bacteria. Here, secreted gel-forming mucins, mainly MUC2, are the main components of this mucus layer and provide its viscoelastic properties. Transmembrane mucins, including MUC3A/B, MUC12, MUC13, MUC15, and MUC17, form a carbohydrate-rich layer called the glycocalyx, which lies between the secreted mucins and the underlying epithelial cells in the small and large intestine. Simplified structures of transmembrane mucins and gel-forming mucins can be seen in magnified sections. Transmembrane mucins are usually composed of two subunits. The extracellular subunit is highly glycosylated and the larger and shorter subunit are composed of a small extracellular domain, a transmembrane domain, and a cytosolic portion. The extracellular protein backbone consists of tandem repeat units of varying lengths composed of the amino acids proline, serine, and threonine that provide binding sites for O-link oligosaccharides. This protein backbone and O-linked glycan structure is also present in secretory/gel-forming mucins.

Goblet cells, as well as the other three main cells (enterocytes, enteroendocrine cells, and Paneth cells) of the intestinal mucosa arise from pluripotent stem cells at the base of the crypts of Lieberkühn (10). Among these unique cell types, goblet cells are mainly responsible for the production and maintenance of the mucosal lining through mucin production and are strongly influenced by interactions with the immune system (3). Enterocytes also play a minor role in the production of secreted mucins (11-13). It should also be noted that the distribution and density of goblet cells inside the digestive tract is different. Distal numbers increase and peak in the distal ileum and rectum (14). In the stomach, mucus production is critical to protect the gastric mucosa from digestive enzymes and the harsh acidic environment of the lumen. Of the five main cell types that contribute to the biochemical environment of the gastrointestinal tract (including parietal cells, chief cells, and enterochromaffin-like cells), surface mucosal cells or foveolar cells, and cervical mucus cells, as the names suggest , the main producers of gastric mucus (15-18). In different areas of the stomach, the organization of the invaginal cells that contain these cells is different. In the proximal body, the stem cells are largely located within the isthmus and are limited to the upper third of the gastric cavities. In contrast, stem cells in the distal antrum are typically located in the lower third of the intussusception. However, these pluripotent progenitor cells can migrate bidirectionally to the mucosal surface or the base of gastric cavities and, in doing so, differentiate and mature into primary gastric epithelial cells (19). During migration, those cells destined to become surface mucus and cervical mucosal cells differentiate and gradually release mucin glycoproteins into the lumen (15).

Due to the primary role of the mucosal layer in physical defense, the effect it has on inflammatory pathologies of the gastrointestinal tract is of increasing interest. Most of these pathologies are associated with dysfunction of goblet cells as well as disordered mucin biosynthesis with significant qualitative and quantitative changes (20, 21). A group of diseases strongly affected by the proper function of goblet cells and their secreted mucin is inflammatory bowel disease (IBD), which is broadly classified into Crohn’s disease (CD) and ulcerative colitis (UC) (22). These conditions are characterized by chronic inflammation of the gastrointestinal tract and are increasing in prevalence, especially as newly industrialized countries become progressively more “westernized” (23). Unfortunately, both the cause and the cure are elusive. Colorectal cancer also causes changes in the production and function of gastrointestinal mucin. Finally, bacterial and parasitic infections, which are more common in developing countries, are also associated with mucin dysfunction and gastrointestinal inflammation (3, 24). The present review aims to highlight the structural and functional features as well as the production and immune regulation of mucins and the impact of these key elements in the context of barrier function and host defense in intestinal inflammation.

So far, more than 20 mucin genes have been identified (25). Although the glycoproteins corresponding to each of these genes have distinct differences, in general mucins have conserved structural features. The protein backbone contains tandem repeat units of varying lengths consisting of the amino acids proline, serine, and threonine, which provide sites for O-glycosylation by O-link oligosaccharides (26). Most of these O-linked oligosaccharides are composed of N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), galactose (Gal), and fucose (Fuc) and are often terminated by sialic acids (2, 26, 27). . ).

A Bioengineering Perspective On Modelling The Intestinal Epithelial Physiology In Vitro

The process of O-glycosylation is initiated by binding of GalNAc to serine or threonine residues in the protein backbone, which can then be further enhanced by additional carbohydrate residues. These primary adducts can be classified as one of six common “core” regions that encompass the GalNAc-peptide binding site and any sugars directly linked to this GalNAc. This core region is either terminated by a sialic acid residue or extended to form the backbone and ultimately the peripheral regions of the glycan, the addition of which marks the end of O -glycosylation ( 28 ). Variation in the number and type of added residues, as well as substrate availability and competition between transferases, creates a great deal of structural diversity in mucin glycoproteins, resulting in a range from short linear structures to more complex branched forms (28 ). In the structure of mucin, O-linked oligosaccharides can be added as many times as one of the three amino acids, which can significantly increase the molecular weight of mucin and help absorb water into the mucous layer. O-glycosylation of mucins also provides resistance to these proteins against the activity of proteases and helps prevent degradation (28, 29).

Mucins can be broadly classified into gelling agents

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