Epithelial Barrier Integrity / Mucosal Barrier Integrity

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The intestinal epithelium, despite being only a single layer of cells, plays a crucial role in controlling the access of potential antigens and pathogens while simultaneously facilitating the digestive absorption of dietary nutrients. It is aided this dual role by intercellular tight junctions (i.e., adhesive plasma membrane structures) between enterocytes that restrict the passage of even very small (2-kDa) molecules while simultaneously walling the lamina propria from the lumen (7).

Structure

A healthy intestinal epithelium is characterized by an outer and inner Intestinal Epithelial Barrier / Mucosal Barrier / Mucus Layer, which acts as a physical barrier and hosts a diverse gut microbiota. This microbiota supports the functions of mucus and the trophism of epithelial cells (ECs) (1)

The intercellular junctions of the intestinal epithelium, from top to base, include:

1. Tight Junctions (TJs)


2. Adherens Junctions (AJs)


3. Desmosomes

Occludin, important for the formation and disassembly of the Tight Junction proteins, is vital for regulating interactions with Zonula Occludens Protein-1 (ZO-1), essential for maintaining a complete TJ complex and ensuring the paracellular barrier function. Research indicates that short-chain fatty acids (SCFAs) enhance the intestinal barrier by increasing the expression of claudin. Junctional adhesion molecules (JAMs) recruit scaffolding and polarity complex proteins, aiding in establishing basolateral and apical polarity of cell-cell junctions. The engagement of both cadherin and nectin significantly influences the stability of these junctions.

Mucus Barrier and Microbiota

The formation of the protective mucus barrier on the intestinal lumen lining creates a physical space for host-microbe exchange of nutrients and metabolites (2). The response of MUCIN-2 (MUC2) to bacterial toll-like receptor (TLR) ligands can disrupt cytokine transcription, affecting Interleukin-12 (IL-12), Interleukin-6 (IL-6), Chemokine (C-X-C motif) ligand 8 (CXCL8) / Interleukin-8 (IL-8), and Tumor Necrosis Factor alfa (TNF-alfa).

Specialized Cells and Functions

In the small intestine, specialized Microfold cells (M cells) efficiently sample luminal antigens and microbiota. These are then transcytosed through M cells and presented to dendritic cells (DCs) (3)

Factors Affecting Intestinal Health

Secondary fatty acids and toxic metabolites can cause intestinal damage in various ways (4). An intact and functional gut epithelium is essential for maintaining a healthy body (5).

Prostacyclin and Prostaglandin E2 (PGE2) synergistically restore barrier function in the ileum through intracellular Ca²⁺ and cAMP signaling-dependent mechanisms (6).

Microbial associated molecular patterns (MAMPs)

The MAMPs that stimulate the pattern recognition receptors (PRRs) (e.g., Toll-like receptors Toll-like receptor 2 (TLR-2), CD284 (Toll-Like Receptor 4 (TLR-4)), Toll-like receptor 5 (TLR-5), Nucleotide Oligomerization Domain-like receptors 1 and 2 (NLRC1 / NOD1 (NOD-like receptor family CARD Domain-Containing Protein 1) / NLRC2 / NOD2 (NOD-like receptor family CARD Domain-Containing Protein 2)) on the enterocytes lead to their proliferation, which serves to maintain the epithelial cell homeostasis or repair the mucosal barrier.

Secondary bile salts / Secondary bile acids (SBAs)

Secondary bile acids, metabolites of the intestinal microbiota, are also involved in maintaining the barrier's integrity or in its repair. They use various mechanisms:
Via its receptor, the farnesoid receptor (FXR), DCA inhibits the enzyme cPLA2, responsible for PGE2 synthesis. High local DCA and low PGE2 concentrations lead to epithelial cell proliferation and crypt regeneration (8, 9).

Also, Prostaglandin E2 (PGE2) and PGI2 lead synergistically to an increase in intracellular cAMP and Ca^2+^. This leads to a cytoskeleton-mediated closure of tight junctions. These are dynamic structures that are regulated by various mediators, including cAMP and Ca^2+^. They control the passage of solutes through the paracellular gap, the main route of the transepithelial passage (6, 7).

References

(1) Petito et al. 2021
(2) Johansson & Hansson 2016 Nat. Rev. Immunol. 16: 639-649
(3) Li et al. 2020s
(4) Meng et al. 2020 J Appl Microbiol 129(4): 787-805
(5) Roy & Trinchieri 2017
(6) Blikslager et al. 1997 J. Clin. Invest. 100: 1928–1933
(7) Madara 1989 J. Clin. Invest. 83:1089–1094
(8) Jain et al. 2018 Cell Host Microbe 24: 353–363
(9) Kayama & Takeda 2020

see also:
Adherens Junctions
Bile acids / Bile salts & Epithelial barrier integrity / Mucosal barrier integrity
CD284 (Toll-Like Receptor 4 (TLR-4)) & Enterocytes / Intestinal Epithelial Cells (IECs)
Enterocytes / Intestinal epithelial cells (IECs) & Toll-like receptor 2 (TLR-2)
Intestinal mucosal barrier / Mucus layer & Short-chain fatty acids (SCFAs)
Leaky gut syndrome / Leaky gut