Inflammatory bowel disease (IBD) is a digestive disorder in which chronic inflammation repeats exacerbation and improvement. The two main types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). IBD is a multifactorial disease, with both genetic and environmental factors contributing to the disease. In particular, loss of intestinal epithelium completeness plays a very important role in IBD (1, 2). Dysfunction of the innate immune system due to abnormal signal transduction caused by pathogens, excessive leakage of bacterial antigens into the mucosa, or inappropriate immune responses due to changes in the composition of the intestinal microflora induce an inflammatory response that progressively degrades the intestinal epithelium. This allows more antigen to leak and worsens inflammation, further damaging the barrier, so the integrity of the mucosal barrier is a key factor in determining the status of IBD (3, 4).

Given the role of the mucus layer, there is growing interest in it because loss of intestinal barrier integrity can cause or exacerbate the progression of inflammatory diseases of the gastrointestinal tract, such as IBD. Although the prevalence is continuously increasing, the cause and treatment are still difficult to identify (5). In particular, IBD onset during childhood and adolescence affects more than 70,000 children in the United States, accounting for 25% of all patients with IBD cases (6–11). About 20–30% of pediatric patients with IBD require surgery within 10 years of diagnosis, so they are more severe than adults, and many receive additional surgical intervention in consideration of recurrence and complications (12–16).

Early diagnosis and treatment of pediatric patients with IBD is very important because children and adolescents are often accompanied by symptoms such as growth retardation and depression due to the characteristics of growth and puberty. In addition, since it requires active treatment from the early stage of diagnosis, high medical costs cannot be ignored. Therefore, to identify differences between adult and pediatric patients with IBD and to enable them to be applied to treatment and prevention, this review highlights the characteristics of MUC2 mucin and its role in IBD, factors affecting MUC2, and differences between IBD in adults and children.

From MUC1 to MUC22, up to 22 distinct mucin genes have been identified in the sequence of discovery. They are expressed according to tissues and cell types and they are broadly categorized into two types: secretory and membrane related (17–23). MUC2, MUC5AC, MUC5B, and MUC6 are gel-forming secretory mucins found on the mucosal surface. However, MUC1, MUC3, MUC4, MUC13, and MUC17 are membrane-associated mucins found in the apical membranes of epithelial cells (Figure 1). MUC1, MUC2, MUC3, and MUC4 are the predominant mucus detected in colorectum, with MUC2 being produced specifically in goblet cells (21, 24, 25). MUC2 exhibits similar structural and physicochemical properties to other secreted mucins expressed in the gastric and respiratory glandular epithelium, such as MUC5AC, MUC5B, and MUC6. MUC2 monomer contains over 5,000 amino acids and is rich in proline, serine, and threonine (19, 26, 27). MUC2 consists of five distinct regions, including an N-terminal domain comprising von Willebrand D4 domain and CysD domain, a small PTS domain, another CysD domain, a large PTS domain, and a C-terminal part containing von Willebrand D4-C domains, and a cystine knot domain (28).

MUC2 is expressed early in fetal development and is detected in the colon at 12 weeks of gestation and is expressed by individual cells that are goblet cell precursors (29). And most of these cells are localized in the crypt region (30). In the normal colon, MUC2 is expressed in goblet cells (31). Several bioactive factors that enhance mucin secretion regulate mucin synthesis. According to numerous research, mucin expression is regulated by transcriptional or epigenetic regulation (18, 32, 33). MUC2 transcription is regulated by signal transduction pathways, which target transcription factors binding to specific regions of the promoter. Activation of nuclear factor (NF)-κB, a transcription factor, is common during inflammation of the gastrointestinal tract, and the promoter of MUC2 contains an NF-κB binding site. Several pathways activate NF-κB, and the representative pathways are the Ras-mitogen-activated protein kinase (MAPK) pathway through lipopolysaccharide (LPS) and the phosphoinositide 3-kinase (PI3K)/Akt pathway by tumor necrosis factor (TNF)-α. Interleukin (IL)-4 and IL-13 also activate NF-κB through MAPK and upregulate MUC2 transcription (34–36). In contrast, the neuropeptide hormone vasoactive intestinal peptide upregulates MUC2 transcription by activating the transcription factor cAMP response element-binding protein (CREB)/cyclic AMP-dependent transcription factor (ATF)-1, whereas prostaglandin PGE2 also induces MUC2 transcription by activating CREB/ATF1 (37). A recent study reported that the transcription factor SAM pointed a domain-containing Ets (SPDEF) can upregulate MUC2 production by stimulating the differentiation of secretory progenitors into Paneth and goblet cells (38). Epigenetic studies have revealed that MUC2 expression can be downregulated by methylation of CpG islands in specific regions of the MUC2 promoter. Additionally, we reported that MUC2 gene expression is regulated by epigenetic mechanisms of DNA methylation and histone modification of specific regions of the MUC2 promoter (39, 40).

Absorption of nutrition is an important function of the small intestine, and the mucous system facilitates this by lubricating and protecting against endogenous enzymes and microorganisms. Mucus entirely covers the surface of the epithelium (20). The intestinal mucus layer consists of a dense mesh-like network of MUC2 secreted by goblet cells, which serve as host defense against endogenous and exogenous irritants and microbial adhesion and invasion but permit the transport of nutrients. The mucus layer is primarily composed of MUC2, but also contains other goblet cell products, such as trefoil factor (TFF)-3, resistin-like molecule (RELM)-β, and Fc fragment of IgG binding protein (Fcgbp) (41–44). The mucous membrane has two mucus layers, which are densely and firmly attached to the interior and loosely attached to the exterior compared to the interior. The thickness of the inner and outer mucus layers was similar in the stomach and jejunum, increased significantly in the ileum, and was thickest in the colon. The thickness of the entire mucus layer exhibited a similar trend. The thickness of the mucus layer is maintained by a balance of synthesis, secretion, and degradation, which is regulated by glycosidases, proteases, and other enzymes (45, 46) (Figure 1).

Mucin acts as an innate host defense mechanism by forming a mucus layer that protects the host from pathogenic microflora invasion and is vital for intestinal microflora formation. Defects in the mucosal barrier result in abnormal bacterial symbiosis and defects in the host's innate and adaptive immune responses, resulting in intestinal inflammatory responses and damage (Figure 1). Therefore, in order to maintain the integrity of the mucosal barrier, the quantity and quality of mucus are also important, and MUC, which is a component of mucus, is inevitably important.

Mucin genes were identified from MUC1 to MUC22 in the order of discovery, and are largely divided into secretory and membrane-related types. Among them, MUC1, 2, 3 and 4 are mucins detected in the colorectal, and MUC2 is the main mucin produced specifically in goblet cells. MUC2 is expressed in colon goblet cells of UC and CD patients as well as healthy individuals. When the colon is depleted of goblet cells due to IBD and other inflammatory conditions, the expression of MUC2 is also reduced and remains in a relatively immature state. This mucus loses its barrier function and exposes the mucous membrane to inflammatory substances. The factors that cause IBD and inflammatory disease are very diverse, but when the integrity of the mucus barrier is lost, it can be a key factor in exacerbating the disease state.

When reviewing the results of various researchers, there are not many studies targeting pediatric IBD patients and many contradictory results have been reported in adult IBD patients, so it is difficult to clearly conclude that the pattern between adults and children is the same. However, at least according to our investigation, it can be suggested that MUC2 expression is decreased and goblet cell decrease is the same in both adults and children in CD and UC in acute inflammatory state. In addition, in the tissues of CD or UC patients, the opposite expression levels may be observed depending on the state of the tissue with or without inflammation or the degree of remission of inflammation, and these results can be considered as a compensatory repair mechanism for mucosal barrier healing and regeneration.

When IBD occurs, pediatric patients need active treatment with biological agents from the beginning, unlike adult patients. As such, pediatric patients have different symptoms or treatment methods from adult patients, but the level of MUC expression is similar. Most of the experimental systems show reproducible results, but for patients, some studies have weak correlations. This is because the factors involved are very diverse and complex. In addition, MUC expression patterns may vary depending on the presence or absence of inflammation and the degree of inflammation in the tissue sample.

Overall, the complexity and heterogeneity of both MUC and TFF makes it difficult to decipher their diverse roles in the pathophysiological process as either a cause or a consequence of IBD. Although many researchers analyzed the results of IBD patient samples, many were excluded when they attempted to draw conclusions by comparing them to each other under similar conditions. Although some studies have documented detailed conditions, many studies have been conducted under relatively broad conditions. In the case of pediatric IBD patients, the number of studies is very limited, regardless of study comparison conditions. This is probably because the patient's age is very young or the sample volume is small, making it very difficult to obtain sufficient samples for the study. To overcome these problems, it is necessary to analyze the sample by subdividing it under more various conditions, and accordingly, it is believed that more consistent results can be derived. In addition, if the criteria for comparative conditions are established and shared, clinical results will be much richer and comparative analysis will be possible for each researcher under the conditions they want. More clinical findings and further studies in pediatric IBD and other inflammatory diseases continue to be needed in the future to determine immune function and potential interaction partners.

YK and HP contributed in the acquisition, analysis and interpretation of data, and drafting of the initial manuscript. B-HC contributed in the acquisition, analysis and interpretation of data, and critical revision for important intellectual content. BK contributed in the conception of the study, acquisition, analysis and interpretation of data, and critical revision for important intellectual content. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

This work was supported by the following grants: National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIT) (No. 2021R1C1C2005429).

The 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.

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