Intestinal mucus components and secretion mechanisms: what we do and do not know

Abstract

Damage to the colon mucus barrier, the first line of defense against microorganisms, is an important determinant of intestinal diseases such as inflammatory bowel disease and colorectal cancer, and disorder in extraintestinal organs. The mucus layer has attracted the attention of the scientific community in recent years, and with the discovery of new mucosal components, it has become increasingly clear that the mucosal barrier is a complex system composed of many components. Moreover, certain components are jointly involved in regulating the structure and function of the mucus barrier. Therefore, a comprehensive and systematic understanding of the functional components of the mucus layer is clearly warranted. In this review, we summarize the various functional components of the mucus layer identified thus far and describe their unique roles in shaping mucosal structure and function. Furthermore, we detail the mechanisms underlying mucus secretion, including baseline and stimulated secretion. In our opinion, baseline secretion can be categorized into spontaneous Ca²⁺ oscillation-mediated slow and continuous secretion and stimulated secretion, which is mediated by massive Ca²⁺ influx induced by exogenous stimuli. This review extends the current understanding of the intestinal mucus barrier, with an emphasis on host defense strategies based on fortification of the mucus layer.

Fig. 1. Main components of the intestinal mucus layer.

The colonic mucus layer consists of a dense inner layer and a loose outer layer. Multiple components are involved in the maintenance of the structure and function of the mucus barrier in addition to MUC2, which composes the skeleton of the mucus layer. FCGBP and TFF3 act synergistically to enhance the mucus barrier and exert antibacterial effects, while the metalloenzyme CLCA1 is involved mainly in the stratification and expansion of mucus. ZG16, RELMβ, Lypd8, sIgA, and AMP exert bacteriostatic or bactericidal effects under different conditions.

Fig. 2. Baseline mucus secretion and SNARE assembly.

Baseline mucus secretion is the continuous release of mucins at a low rate. a The Golgi apparatus releases mature, primed mucin secretory vesicles filled with MUC2. The high-affinity Ca²⁺ sensor KChIP3, which senses Ca²⁺ concentrations <1 μM, binds to secretory vesicles and prevents them from fusing with the cell membrane in the absence of intracellular Ca²⁺ oscillations as a tonic brake. b Intracellular Ca²⁺ oscillation plays an important role in baseline mucin secretion. Spontaneous oscillations in Ca²⁺ from internal stores (mainly in the ER) initiate steady, moderated mucus release in a ryanodine receptor 2 (RYR2)-dependent manner.

Fig. 3. The underlying mechanism for stimulated mucus secretion.

Several physiological or pathological stimuli result in a marked increase in intracellular Ca²⁺-triggered stimulated mucus secretion. Intracellular Ca²⁺ levels are increased through two mechanisms. After stimulation with an exogenous stimulus, TRPM4/5 are activated and cooperate with NCX2 to enhance Ca²⁺ influx. LPS and flagella in bacteria induce TLR-mediated ROS production and activate NLRP6, which in turn promotes Ca²⁺ release from the ER. Protein kinase C induces detachment from the membrane and subsequent recruitment of MARCKS onto mucus vesicles, and MARCKS-bound mucus vesicles then migrate to the apical side of cells under the action of Hsp70 and CSP. The low-affinity Ca²⁺ sensor Syt2, which can only sense calcium concentrations greater than 10 μM, senses elevated Ca²⁺ levels and drives the fusion of mucus vesicles with the cell membrane.