Intestinal epithelium

Seven different cell types are produced by the stem cells that reside at the base of the crypts.[6] Each type matures according to its specific differentiation program as it migrates up and out of the crypt. Many of the genes necessary for differentiation into the different epithelial cell types have been identified and characterized (see this table). The cell types produced are: enterocytes, Goblet cells, enteroendocrine cells, Paneth cells, microfold cells, cup cells and tuft cells. Their functions are listed here:[7]

• Enterocytes are the most numerous and function primarily for nutrient absorption. Enterocytes express many catabolic enzymes on their exterior luminal surface to break down molecules to sizes appropriate for uptake into the cell. Examples of molecules taken up by enterocytes are: ions, water, simple sugars, vitamins, lipids, peptides and amino acids.
• Goblet cells secrete the mucus layer which protects the epithelium from the lumenal contents.
• Enteroendocrine cells secrete various gastrointestinal hormones including secretin, pancreozymin, enteroglucagon among others. Subsets of sensory intestinal epithelial cells synapse with nerves,[8] and are known as neuropod cells.[9]
• Paneth cells produce antimicrobial peptides such as human alpha-defensin.[10][11]
• Microfold cells (commonly referred to as M cells) sample antigens from the lumen and deliver them to the lymphoid tissue associated with the mucosa (MALT). In the small intestine, M cells are associated with Peyer's patches.
• Cup cells are a distinct cell type but with no known function.
• Tuft cells play a part in the immune response.[12]

Throughout the digestive tract, the distribution of the different types of epithelial cells varies according to the function of that region.[3]

Types of cell junctions (click to enlarge).

Important for the barrier function of intestinal epithelium, its cells are joined securely together by four types of junctions (cell junctions),[13] which can be identified at the ultrastructural level:[14]

• Gap junctions
• Desmosomes
• Adherens junctions
• Tight junctions

Gap junctions bring the adjacent cells within 2 nanometers of each other. They are formed by several homologous proteins encoded by the connexin gene family coming together to form a multiprotein complex. The molecular structure of this complex is in the form of a hexamer. The complex, which is embedded in the cell membranes of the two joined cells, forms a gap or channel in the middle of the six proteins. This channel allows various molecules, ions and electrical impulses to pass between the two cells.[15]

These complexes, consisting of transmembrane adhesion proteins of the cadherin family, link adjacent cells together through their cytoskeletons.[16] Desmosomes leave a gap of 30 nanometers between cells.[15]

Adherens junctions, also called zonula adherens, are multiprotein complexes formed by proteins of the catenin and cadherin families. They are located in the membrane at the contact points between the cells. They are formed by interactions between intracellular adapter proteins, transmembrane proteins and the actin cytoskeletons of the cells . Besides their role in linking adjacent cells, these complexes are important for regulating epithelial migration, cell polarity, and the formation of other cell junction complexes.[14]

Tight junctions, also called zonula occludens, are the most important components of the intestinal epithelium for its barrier function.[17] These complexes, formed primarily of members of the claudin and the occludin families, consist of about 35 different proteins,[13] form a ring shaped continuous ribbon around the cells, and are located near the borders of the lateral and apical membranes.[14]

The extracellular domains of the transmembrane proteins in adjacent cells cross connect to form a tight seal. These interactions include those between proteins in the same membrane ("cis") and proteins in adjacent cells ("trans"). In addition, interactions can be homophilic (between identical proteins) or heterophilic (between different proteins).[14]

Similar to adherens junctions, the intracellular domains of tight junctions interact with different scaffold proteins, adapter proteins and signaling complexes to regulate cytoskeletal linking, cell polarity, cell signaling and vesical trafficking.[14]

Tight junctions provide a narrow but modifiable seal between adjacent cells in the epithelial layer and thereby provide selective paracellular transport of solutes.[14] While previously thought to be static structures, tight junctions are now known to be dynamic and can change the size of the opening between cells and thereby adapt to the different states of development, physiologies and pathologies.[17] They function as a selective and semipermeable paracellular barrier between apical and basolateral compartments of the epithelial layer. They function to facilitate the passage of small ions and water-soluble solutes through the paracellular space while preventing the passage of luminal antigens, microorganisms and their toxins.[14]

Overlaying the brush border of the apical surface of the enterocytes is the glycocalyx, which is a loose network composed of the oligosaccharide side chains of integral membrane hydrolases and other enzymes essential for the digestion of proteins and carbohydrates. These glycoproteins, glycolipids, and enzymes catalyze the final digestive stages of luminal carbohydrates and proteins. The monosaccharides and amino acids thus produced are subsequently transported across the intestinal epithelium and eventually into the bloodstream.[5]

The absorption of electrolytes and water is one of the most important functions of the digestive tract. Water absorption is passive and isotonic - depending on the speed and direction of solute flow. Other factors influencing fluid absorption are osmolarity and the specific intestinal region.[18] Regulated selective permeability is performed through two major routes: the transcellular (transepithelial) route and the paracellular route.[14]

Scheme of selective permeability routes of epithelial cells (red arrows). The transcellular (through the cells) and paracellular (between the cells) routes control the passage of substances between the intestinal lumen and blood.

This consists of specific transport of solutes across the epithelial cells. It is predominantly regulated by the activities of specialised transporters that translocate specific electrolytes, amino acids, sugars, short chain fatty acids and other molecules into or out of the cell.[14]

Paracellular permeability depends on transport through the spaces that exist between epithelial cells. It is regulated by cellular junctions that are localized in the laminal membranes of the cells.[14] This is the main route of passive flow of water and solutes across the intestinal epithelium. Regulation depends on the intercellular tight junctions which have the most influence on paracellular transport.[22] Studies using the electron microscope showed that the electrical resistance of epithelial layers depends on the complexity and number of filaments within the tight junction transmembrane protein complexes.[18] Also, the plasma membrane resistance and variable transmembrane conductance of the epithelial cells can also modulate paracellular pathway function.[18]