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ENTEROCYTE

Enterocytes are columnar cells that form most of the epithelium of the gut intestine (Figures 1 and 2). They are more abundant in the small intestine than in the large intestine and appendix. In the small intestine, the amount of enterocytes is about 80 % of the total gut enterocytes. The main function of enterocytes is absorbing molecules from the gut lumen and transport them to inner connective tissue and blood vessels. It is of notice that the gut epithelium is the larger surface of the body in contact with the external environment (the lumen of gut is external to body tissues).

Enterocitos
Figure 1. Small intestine of a rat showing that enterocytes are abundant in the epithelium. Purple cells are globet cells.
Enterocitos
Figure 2. Scanning electron microscopy image of intestinal villi (on the left) and enterocytes (on the right).

1. Morphology

Enterocytes have microvilli in the apical (free) surface (Figure 3), many mitochondria in the basal part, and well-developed Golgi apparatus and endoplasmic reticulum. The mechanical integrity of the intestine epithelium, that is, the cohesion between enterocytes and the lack of intercelular passages, depends on the cell adhesion complexes between adjacent enterocytes. There are tight junctions and adherent junctions close to the apical domain of the enterocyte. Desmosomes are found in the latero-basal membranes. Gap junctions are observed in the latero-basal membranes as well. Hemidesmosomes are found in the basal membrane of enterocytes anchoring the cell to the basal membrane.

Enterocytes
Figure 3. Small intestine of a rat. On the left, ligth microscopy image. On the right, electron microscopy image. Microvilli are observed in the free or apical surface of enterocites.

Enterocytes have two domains: apical and basolateral. That is why they are polarized cells. Polarization is produced by the activity of a well-arranged cytoskeleton and well-developed vesicular traffic that distributed molecules differentialy between both domains. Tight junctions prevent lateral diffusion of molecules between both domains, thus helping to maintain the polarity. Enterocytes show a highly packaged microvilly in the apical domain, that increase the membrane surface about 100 times (Figure 3). In the apical membranes, there area many transporters that are the gates for molecules resulting from digestion to come in the enterocyte. In the basolateal membranes there are other transporters for these molecules to exit the enterocyte and reach the blood vessels. This segregated distribution of receptors is generated by vesicular trafficking.

2. Life cycle

The intestine lumen is full of molecules potentially toxic for enterocytes. Instead of repairing every insult, damaged and old enterocytes die by apoptosis,are then extruded from the epithelial layer, and continuously replaced by new ones. Small intestine mucosa is highly folded and forms many evaginations or villi and invaginations or glands, known as Lieberkühn crypts. In the large intestine, there are Lieberkühn crypts. The life cycle of enterocytes begins in the bottom part of the Lieberkühn glands and ends in the tips of the villi of the small intestine or in the epithelial surface of the large intestine. The life of an enterocyte about 2 to 5 days long. In humans the intestinal epithelium is renewed every 4 to 5 days.

Enterocytes differentiate from adult stem cells that are found in the bottom of the Lieberkühn glands (Figure 4). Initially, adult stem cells become transient amplifying cells (progenitor cells), which are located a bit further from the adult stem cell niche. Transient amplifying cells divide 4 to 6 times to increase the progenitor population and then differentiate in the variety of cell types found in the intestinal epithelium. Most of them become enterocytes, but also globet cells, M cells, and the other cell types. New enterocytes move progressively toward the tips of the villi or to the luminal epithelial surface. Once they reach these positions they die and are extruded from the epithelium. Extrusion involves both mechanical pressure and lost of adhesion connection with neighbor cells. Some cells die by apoptosis and then are expelled from the epithelium. It is not known what is the mechanism for moving enterocytes from the glands to the epithelial surface. Molecular components of the basal lamina are different along the enterocyte path, and it is thought that it can contribute to the movement. The diet has also been thought to be involved in the dynamic of the life of enterocytes.

Enterocytes lineages
Figure 4. Drawing of the main cell lineages of the small intestine (upper part) and large intestine (bottom part). Thick arrows indicate a larger population. (Adapted from Baker, 2014).

3. Functions

Digestion

The main function of enterocites is to absorb nutrients after stomach and enzymatic digestion of food. Enterocytes may use glutamate and glutamine, as well as fatty acids and glucose, as their energy supply. This is curious because all type of nutrients go through enterocytes. They also help with digestion by secreting enzymes that degrade peptides and disacararides. The glycocalyx of the enterocyte apical domain forms a layer of about 400 to 500 nm thick, sometimes even 1 µm thick. Some enzymes that participate in digestion are anchored to this glycocalyx. Thus, enterocytes not only select and catch substances from digestion, but they also process some of them. Actually, it is said that there are two digestion phases, one happening in the lumen of the intestine, carry out by pancreatic enzymes, and the other in the surface of the enterocytes, performed by other digestive enzymes. Most of the nutrient absorption is accomplished by the small intestine enterocytes, whereas large intestine enterocytes mainly absorb water. In addition, small vesicles are released from the tips of the microvilli containing enzymes like phosphatases, which may have a defense function against pathogens.

Substances resulting from digestion have to cross the intestinal epithelium to reach the blood stream. It can be done by several pathways: transcellular, endocytosis/transcytosis and paracellular.

Transcelullar. Most molecules cross the epithelial layer of the intestine going through enterocytes. First crossing the apical membrane and then the basolateral one. Molecules may be moved by free passive diffusion, facilitated passive diffusion, or active transport. In the free passive diffusion, molecules cross membranes without any help, whereas in facilitated and active transport, molecules need to be recognized by specific transporters inserted in the membranes. Water, ethanol and many lipids cross through enterocytes by free passive diffusion. Glucose, some lipids, and amino acids enter enterocytes by facilitated passive transport or by active transport.

The apical domain of the cell bears a set of proteins for absorption substances, whereas the latero-basal membranes have another transmembrane transporters for getting molecules out of the enterocyte.

The absorption capability depends on differentiation stage of the enterocyte, which means a number of sodium membrane pumps, more abundant as enterocytes move further away from the deep of the crypts. Thus, most absorption of sugars and amino acids is done in the upper third of the villi of the small intestine and near the surface of the large intestine. For example, hydrolase activity increases as enterocytes move away from the stem cell niches (deep parts of the crypts).

The absorption of glucose is an example of typical absorption mechanism. Glucose crosses the apical membrane of the enterocyte by co-transport coupled to a sodium gradient. This gradient is generated by sodium/potassium pumps, and can enter glucose in the enterocyte against glucose concentration gradient. The sodium glucose transporter (SGLT) allows this co-transport. On the other hand, the GLUT2 transporter is found in the laterobasal membranes, which translocate glucose from the cytoplasm to the intercellular space. Thus, SGLT increases glucose concentration in the enterocyte cytoplasm and GLUT2 allows glucose to escape toward the blood vessels. The precise location of the two transporters produces a flux of glucose through enterocytes, from the intestine lumen to the blood vessels.

Fat is among the most energetic substances, besides being necessary for cell membranes. The majority of meal fat which is incorporate from the intestine is in triacylglycerol form, although other types can be absorbed too, such as cholesterol. First, pancreatic enzymes degrade meal fat in the intestine lumen and triacylglycerols are converted in fatty acids and monoacylglycerols (Figure 5). These molecules, together with cholesterol, fat soluble vitamins, and phospholipids, form micelas, which are small lipid droplets which are soluble in water thanks to the biliary acids. Micelles cross freely the enterocyte apical membrane. CD36 y FABP (fatty acid binding protein) transporters s 3make possible for some fatty substances to cross the enterocyte apical membrane by facilitated passive transport. The bulk of the fat transport is as micelles, whereas the membrane transporters look like a sensory system to detect fatty acids s 3with long chains in the intestine. Cholesterol, as individual molecule, can be also transported by NPC1L1 (Niemann-Pick C1-like 1) transporter, which transfers cholesterol from the intestine lumen to the enterocyte cytoplasm.

Fat absorption
Figure 5. Fat absorption by enterocytes.

Once in the enterocyte, fats are joined to some proteins and moved to the endoplasmic reticulum, where triacylglycerols are synthesized again. They are combined with some proteins to form pre-chylomicrons. ApoB protein is synthesized in the endoplasmic reticulum. ApoB, together with MTP (microsome tranfer protein) and fatty acids form the lipoprotein primordial particle. In the smooth endoplasmic reticulum, ApoB is substituted by Apo A-IV protein. All these components constitute pre-chylomicrons, which are included in vesicles and moved to the Golgi apparatus. Here, pre-chylomicrons are joined together to form chylomicrons, which are included in exocytic vesicles and released at the laterobasal domain of the enterocyte. In this way, chylomicrons can reach blood and lymphatic vessels. Chylomicrons are lipoproteins with a body mainly compose of triacylglycerols and coat of phospholipds, cholesterol and apolipoproteins. They play a major role transporting triacylglycerols and liposoluble vitamins.

Outside the enterocyte, chylomicrons enter lymphatic vessels of the intestinal villi, and then in the lymphatic myenteric plexuses from which they pass to the blood vessels. Besides chylomicrons, fat is also packed into very low density lipoproteins (VLDL), which are also exocyted from enterocytes. Fat can be stored in enterocyte lipid droplets as well.

Enterocytes also get the iron after digestion. Iron is important for many proteins, such as hemoglobin, and it can be found in food as part of hemo groups or bound to ferritin (in animal meat) (Figure 6). Iron from digestion enters the body through DMT1 transporter (divalent metal transporter 1) found in the apical membranes of enterocytes. Transgenic mice lacking this transporter develop severe anemia. DMT1 is a co-transporter coupled to a proton gradient. The proton gradient is generated by Na+/K+ pump, also found in the apical membrane of enterocytes. DMT1 transport Fe2+ but most irons from meal is Fe3+ form. Iron reduction (Fe3+ to Fe2+) is carried out by a reductase enzyme located in the apical surface of the enterocyte. The iron bound to hemo groups appears to be incorporated by receptor mediated endocytosis. Once inside the enterocyte, the hemo group is degraded and the iron can get into the cytosol.

Iron absorption
Figure 6. Absorption of iron by enterocytes (adapted from Knutson 2017)

Whatever the entry pathway, once in the cytosol, the movement of iron toward the basolateral membranes appears to be mediated by metallochaperone proteins. In the basolateral membranes, iron is translocated to the extracellular space by ferroportin transporter. Ferroportin takes out Fe2+ form. However, ferritin is the protein that transports iron to the portal vein system and iron must be in Fe3+ form. There are ferro-oxidases in the basolateral membranes of the enterocyte that make possible the conversion from Fe2+ to Fe3+. Iron can be stored in the enterocyte cytosol bound to ferritin.

Endocytosis/transcytosis. Molecules like immunoglobulins are endocyted by receptor mediated endocytosis and transported to other membrane domains by transcytosis. Vesicles are formed at the base of the microvilli, and they fuse later with endosomes. Immunoglobulins are then enclosed in vesicles generated in endosomes and targeted to the basolateral domain membranes. In this way, immunoglobulins escape the lysosomal degradation pathway.

Paracellular. Water and ions cross the epithelim by paracellular pathway.

Protection

Enterocytes form a barrier rejecting antigens, toxic molecules and microorganisms, and at the same time let cross nutritive substances. Enterocytes are in contact with many microorganisms. Those that are resident microorganisms in the intestine, but can be dangerous if they reach the internal tissues, and those non-resident pathogens that come with the meal. The apical surface of the enterocytes is covered with a layer of mucous substances released by globet cells. This layer is composed of carbohydrates and has a dense viscosity that allows the diffusion of molecules, but rejects cells and the largest molecules. In addition, enterocyte microvilli show a well-developed glycocalyx in the apical tips of each microvillus, which acts as physical and electrical barrier since it is full of negative charges. These microvilli make difficult a direct physical contact between microorganisms and enterocyte membrane. However, even if the pass these two barriers, microorganisms should overcome the transport mechanism of the microvilli.

Mucins are highly glycosylated proteins found in the apical membrane of enterocytes. They contribute to the well-developed glycocalyx. Mucines are transmembrane proteins linked to the cytoskeleton by their cytosolic domain. MUC3, MUC12 and MUC17 are the most abundant mucins. They contain about 5000 amino acids and their carbohydrate component can extend up to 1 µm from the cell surface. Mucins form a physical barrier hard to cross by bacteria.

Enterocytes are able to start and regulate inflammatory processes by releasing several chimocines and cytokines. They also have receptors for these molecules. Enterocytes release pro-inflammatory molecules that influence immune cells found in the intestinal mucosa.

Another less known protection mechanism is the release of vesicles from the apical surface of enterocytes. Actin and myosin, the motor apparatus of microvilli, produce mechanical forces that drag membranes toward the tip of each microvillus. The membrane accumulation ends up as vesicles, which are released into the intestinal lumen. These vesicles contain a high amount of alkaline phosphatase that is a powerful anti-pathogen agent by reducing lipopolysacharide toxicity and intestinal inflammation. It also hinders the attachment of bacteria to the instestinal epithelium and decreases the proliferation of bacteria. The vesicles released by enterocyte are a way of sending anti-microbe molecules to areas far away from the epithelium.

Bibliography

Barker N. 2014. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nature. 15: 19-33.

Giammanco A, Cefalù AB, Noto D, Averna MR. 2015. The pathophysiology of intestinal lipoprotein production. Frontiers in physiology. 6: 61. Read the article

Knutson MD. 2014. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nature review in molecular cell biology. 15:19-33.

Knutson MD. 2017. Iron transport proteins: gateways of cellular and systemic iron homeostasis. Journal of biological chemistry Nature review in molecular cell biology. 292: 12735-12743.

Shifrin DA, McConell RE, Nambiar R, Higginbotham JN, Coffey RJ, Tyska MJ. 2012. Enterocyte microvillus-derived vesicles detoxify bacterial products and regulate epithelial-microbial interactions. Current biology. 22: 627-631.

Snoeck V, Goddeeries B, Cox E. 2005. The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes and infection. 7: 997-1004.

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