Mucus barrier, mucins and gut microbiota: the expected slimy partners?

Abstract

The gastrointestinal tract is often considered as a key organ involved in the digestion of food and providing nutrients to the body for proper maintenance. However, this system is composed of organs that are extremely complex. Among the different parts, the intestine is viewed as an incredible surface of contact with the environment and is colonised by hundreds of trillions of gut microbes. The role of the gut barrier has been studied for decades, but the exact mechanisms involved in the protection of the gut barrier are various and complementary. Among them, the integrity of the mucus barrier is one of the first lines of protection of the gastrointestinal tract. In the past, this 'slimy' partner was mostly considered a simple lubricant for facilitating the progression of the food bolus and the stools in the gut. Since then, different researchers have made important progress, and currently, the regulation of this mucus barrier is gaining increasing attention from the scientific community. Among the factors influencing the mucus barrier, the microbiome plays a major role in driving mucus changes. Additionally, our dietary habits (ie, high-fat diet, low-fibre/high-fibre diet, food additives, pre- probiotics) influence the mucus at different levels. Given that the mucus layer has been linked with the appearance of diseases, proper knowledge is highly warranted. Here, we debate different aspects of the mucus layer by focusing on its chemical composition, regulation of synthesis and degradation by the microbiota as well as some characteristics of the mucus layer in both physiological and pathological situations.

Keywords: glycobiology; intestinal microbiology; intestinal permeability; mucins; mucus.

Figure 1

Chemical structure of MUC2 and synthesis of the mucus in the intestine. Specific structure of MUC2 including the different steps involved in the addition of the first-glycosylation made by the peptidyl-GalNAc transferases, that add the first sugar, the N-acetylgalactosamine (GalNAc) residue, to the Ser and Thr of the PTS sequences. Subsequent elongation and branching of the O-glycan chains with for instance GalNAc, galactose, N-acetylglucosamine (GlcNAc), N-acetylneuraminic acid (NeuAc), and sulfate groups. Illustration of the transmembrane mucins on the surface of the enterocytes. Pro, proline; Ser, serine; Thr, threonine.

Figure 2

Production and distribution of the mucus in the small and the large intestine. Representation of the type of mucus layers in the small and the large intestine (inner and outer mucus layer). Identification of the steps involved in mucus production in the goblet cells and its secretion and expansion in the lumen (from 1 to 7). First, MUC2 monomers form dimers in the endoplasmic reticulum (ER), that are then O-glycosylated in the Golgi apparatus and, in the trans-Golgi network (TGN), the MUC2 mucin dimers form trimers that are packed inside the secretory vesicles. The mucus secretion is a complex process; the goblet cells fill their secretory vesicles with Muc2 while migrating from the crypt bottom and contain other components, such as the Fc fragment of IgG-binding protein (FCGBP), chloride channel accessory 1 (CLCA1), zymogen granule protein 16 (ZG16) and anterior gradient homolog 2 (AGR2). The secretory vesicles extrude their content after their fusion with the apical membrane of the goblet cells, by exocytosis, allowing mucus secretion. Finally, the packed mucins must be exposed to several factors to expand, such as changes in pH, Ca⁺² concentration and bicarbonate ions (HCO₃ ^-) thanks to the cystic fibrosis transmembrane conductance regulator (CFTR) channel that will allow the mucins to form a net-like structure by expanding 100–1000 times in volume and binding water.

Figure 3

Mucus thickness and type of mucins in the intestinal tract in mice and humans. Description of the type of mucins and mucus thickness in the different parts of the GI tract in both mice and humans, and their specific roles.

Figure 4

Major effectors regulating the expression and the secretion of mucus. Principal effectors (ie, gut bacteria, cytokine and inflammatory markers, hormones, neurotransmitters and bioactive lipids acting on specific external (extracellular) and internal (intracellular signal transduction) signalling pathways influencing the expression (ie, gene expression and synthesis) and the secretion of the major mucin MUC2, and its impact on host. CREB, cAMP-response element (CRE)-binding protein; DCA, deoxycholic acid; EGF, epidermal growth factor; FXR, farnesoid receptor X; IL, interleukin; JAK, Janus kinase; JNK, c-Jun-N-terminal kinase; LP, lipopeptide; LPA, lipoteichoic acid; LPS, lipopolysaccharides; MAPK, mitogen-activated protein kinases; SAA, serum amyloid A; STAT, signal transducer and activator of transcription; TGF-alpha, transforming growth factor alpha; TLR, prostaglandin E2 (PGE2) Toll-like receptors; TNF, tumour necrosis factor; VIP, vasoactive intestinal peptide.

Figure 5

Mucus regulation by specific micro-organisms and microbial metabolites. Overview of the impact of different microbial species, parasites and short chain fatty acids (SCFAs) on mucus properties, composition or functions.