Anthony P. Corfield

Bio: Anthony P. Corfield is an academic researcher from Bristol Royal Infirmary. The author has contributed to research in topics: Mucin & Mucus. The author has an hindex of 41, co-authored 132 publications receiving 5599 citations.

Mucins and mucosal protection in the gastrointestinal tract: new prospects for mucins in the pathology of gastrointestinal disease

Abstract: The luminal surface of the gastrointestinal tract is covered by a viscoelastic mucous gel layer that acts as a protective barrier against the harsh luminal environment. The structural characteristics of this barrier are primary indicators of its physiological function and changes to its composition have long been identified in gastrointestinal pathologies. During the past decade significant improvements in analytical techniques coupled with detailed knowledge of the genes coding for the mucin proteins have provided exciting new insights into the role of the mucous layer and its relevance to gastrointestinal disease. The high molecular weight mucins are responsible for the viscoelastic properties of the mucous barrier. They are widely expressed in epithelial tissues and are characterised by variable number tandem repeat peptide sequences rich in serine, threonine, and proline which carry large numbers of O -linked oligosaccharide chains.1 2 At present, 12 genes have been described, shown in table 1.1 3 Secreted and membrane associated forms have been found based on their function as extracellular viscous secretions or viscoelastic polymer gels or location as membrane anchored molecules in the glycocalyx.3 4 Two clusters have been reported, the secretory mucin genes MUC2, MUC5AC, MUC5B, and MUC6 on chromosome 11p15.5, and MUC3, MUC11, and MUC12 on chromosome 7q22.3 View this table: Table 1 Mucin genes and their location in the human gastrointestinal tract Histochemical techniques for mucin detection rely on the ability to detect carbohydrate or negative charge and were widely used for classification of changes in disease.5 6 The use of lectins and anticarbohydrate antibodies has greatly improved the specific detection of mucins histochemically and biochemically.5 6 A group of mucin oligosaccharide antigens, including Tn, sialyl-Tn, T, Lewisx and Lewisy, sialyl and sulpho-Lewisx and -Lewisa, and the blood group ABH antigens, have been identified …

Mucins in the gastrointestinal tract in health and disease.

Abstract: Mucins form part of the dynamic, interactive mucosal defensive system active at the mucosal surface of the gastrointestinal tract. They are carbohydrate rich glycoproteins with unique molecular structure and chemical properties. The family of mucin (MUC) genes has 13 members that can be divided into secreted and membrane-associated forms each with characteristic protein domains and tissue specific glycosylation. Biosynthetic pathways have been described for the secreted and membrane-associated mucins and their eventual degradation and turnover. Mucins are present at all mucosal surfaces throughout the body in typical combinations and relate to the demands of organ function. Patterns of MUC gene expression with gastrointestinal site specific glycosylation are clearly important but are not yet well defined. Mucin production during fetal development shows distinct patterns that may correlate in many cases with neoplastic expression in adult life. An increasing number of protective proteins have been identified that appear in the adherent mucus layer at the mucosal surface. These proteins are co-secreted with mucins in some cases, interact with mucins at a molecular level through peptide and carbohydrate sites or benefit from the viscoelastic, aqueous environment afforded by the mucus gel to effect their defensive roles. The mechanism of many of these interaction remains to be elucidated but is clearly part of an integrated innate and adaptive mucosal defensive system relying on the mucins as an integral component to provide a mucus gel. Recent improvements in the description of MUC gene expression and mature mucin synthesis in the healthy gastrointestinal tract has formed a basis for assessment of mucosal disease at sites throughout the tract. Pathological patterns of mucin expression in disease appear to follow tissue phenotype, so that gastric and intestinal types can be defined and appear in metaplasia in e.g. esophagus and stomach. Adaptation of previous mucin based, histochemical classification of intestinal metaplasia to assess MUC gene expression has proved helpful and promises greater value if reliably combined with mucin linked glycosylation markers. Few changes in MUC gene expression or polymorphism have been detected in inflammatory bowel diseases in contrast to malignant transformation. Glycosylation changes however, are evident in both types of disease and appear to be early events in disease pathogenesis. Review of the major mucosal diseases affecting the gastrointestinal tract in childhood reveals parallel patterns to those found in adult pathology, but with some novel conditions arising through the developmental stages at lactation and weaning. The impact of bacterial colonization and nutrition at these stages of life are important in the evaluation of mucosal responses in pediatric disease.

Mucins and inflammatory bowel disease

Abstract: There is a layer of mucus lining the gastrointestinal tract, which acts as both a lubricant and as a physical barrier between luminal contents and the mucosal surface. The mucins that make up this layer consist of a protein backbone with oligosaccharides attached to specific areas of the protein core. These areas are called the variable number tandem repeat regions. The degree of glycosylation of the mucins is central to their role in the mucus barrier. The oligosaccharides are variable and complex. It has been demonstrated that the degree of sulphation and sialylation and the length of the oligosaccharide chains all vary in inflammatory bowel disease. These changes can alter the function of the mucins. Mucins are broadly divided into two groups, those that are secreted and those that are membrane bound. The major mucins present in the colorectum are MUC1, MUC2, MUC3, and MUC4. Trefoils are a group of small peptides that have an important role in the mucus layer. Three trefoils have been demonstrated so far. They seem to play a part in mucosal protection and in mucosal repair. They may help to stabilise the mucus layer by cross linking with mucins to aid formation of stable gels. Trefoils can be expressed in the ulcer associated cell lineage, a glandular structure that can occur in the inflamed mucosa. There seem to be differences in the expression of trefoils in the colon and the small bowel, which may imply different method of mucosal repair. Keywords: mucins; trefoil; Crohn's disease; colitis

Mucin degradation in the human colon: production of sialidase, sialate O-acetylesterase, N-acetylneuraminate lyase, arylesterase, and glycosulfatase activities by strains of fecal bacteria.

Abstract: Oligosaccharide side chains of human colonic mucins contain O-acetylated sialic acids and glycosulfate esters. Although these substituents are considered to protect the chains against degradation by bacterial glycosidases, sialate O-acetylesterase, N-acetylneuraminate lyase, and glycosulfatase activities have been found in fecal extracts. To better define the source of these activities, we measured extracellular and cell-bound sialidase, sialate O-acetylesterase, N-acetylneuraminate lyase, arylesterase, and glycosulfatase activities produced by 23 isolates of human fecal bacteria grown anaerobically in a hog gastric mucin culture medium; these represented dominant populations of fecal anaerobes, facultative anaerobes, and the subset of mucin oligosaccharide-degrading bacteria. Every strain produced sialidase and high levels of arylesterase, and all but five facultative anaerobes produced sialate O-acetylesterase. Sialic acids containing 2 mol or more of O-acetyl ester per mol of sialic acid were cleaved from mucin glycoproteins more slowly by sialidases of mucin oligosaccharide-degrading stains than were sialic acids containing 1 or 0 mol, and only N-acetyl- and mono-O-acetylated sialic acids were recovered from enzyme digests of a mucin containing di-O-acetylated sialic acids. No detectable N-acetylneuraminate lyase activity was produced by any strain, but low activity was induced by increasing the glycoprotein-bound sialic acid concentration in the culture medium of six Escherichia coli strains. Using lactitol-6-sulfate as a substrate, we found weak glycosulfatase activity in the partially purified, concentrated enzyme mixture in the culture supernatants of four mucin oligosaccharide-degrading strains but in none of the unconcentrated culture fractions. We conclude that the presence of two or more O-acetyl groups on sialic acids inhibits enteric bacterial sialidases but that production of sialate O-acetylesterases by several populations of enteric bacteria lessens the likelihood that mucin oligosaccharide chains terminating in O-acetylated sialic acids are protected from degradation. Sialate O-acetylesterases have a role in bacterial degradation of mucin glycoproteins in the human colon. Images

Gut Microbiota in Health and Disease

Abstract: Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.

Mucins in cancer: Protection and control of the cell surface

Abstract: Mucins — large extracellular proteins that are heavily glycosylated with complex oligosaccharides — establish a selective molecular barrier at the epithelial surface and engage in morphogenetic signal transduction. Alterations in mucin expression or glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion and immune surveillance. Mucins are used as diagnostic markers in cancer, and are under investigation as therapeutic targets for cancer.