The small intestine

3.2.3.1 General description

The small intestine is often said to be about 6 m (20 feet) long and about 2.5 cm (one inch) in diameter. This is a generalisation and its length actually differs in life and after death; in life, it is somewhat contracted by virtue of the 'tone' of its muscular walls. Measurements made by passing tubes through the small intestine in adult, living humans show the length to vary between about 3 and 4.5 m. Of this, the first 25 cm (or so) is the duodenum, curving downwards after leaving the stomach and running roughly horizontally across the middle of the abdomen. (It gets its name from the Latin duodecim for 12, because it is about 12 inches or 12 finger-breadths long.) The jejunum begins after a sharp downward bend; it accounts for around another 2 m, and is the site of much of the absorption of the macronutrients. Finally, the ileum, about 2.5-3 m in length, leads to the large intestine at the ileo-caecal valve.

Two important glands discharge into the small intestine. The gall bladder, the storage reservoir for bile salts produced in the liver, discharges its contents via the common bile duct, and the exocrine part of the pancreas releases its secretions through the pancreatic duct; the common bile duct joins this, and they both discharge into the duodenum. The regulation, and the content, of their secretions will be covered in detail below.

The small intestine, like all parts of the intestine, has layers of smooth muscle running lengthways and around its circumference. The inner surface, or mucosal layer, is folded into finger-like projections (villi), each villus being about 1 mm long. There are 20-40 villi per mm2. This enormously increases the surface area, to a total of about 300 m2; this surface area is where absorption takes place. The surface area is increased still further by the presence of the brush border. Each cell making up the surface of a villus has its own microscopic finger-like projections, the microvilli, giving under the electron microscope a brush-like appearance. There are around 2000-4000 microvilli per cell. The presence of the microvilli increases the surface area about a further thirty-fold.

Each villus has a characteristic structure (Fig. 3.3). Within its core there is a dense network of capillaries surrounding a channel (the lacteal), which is a branch of the lymphatic system. (The name, from the latin lactis, means related to milk, because the products of fat absorption give these vessels a milky appearance.) The venous blood vessels leaving the intestinal mucosa merge and eventually form the hepatic portal vein. The lymphatic vessels also merge and

Structure Single Villus
Fig. 3.3 Structure of a villus of the small intestine. One of the absorptive cells (entero-cytes) on the surface is enlarged to illustrate the microvilli of the brush-border membrane.

form one single vessel, the thoracic duct (see Section 1.3.3), so called because it leads upwards through the thorax (chest), and finally discharges its contents into the great veins in the neck, near where they return to the heart (Fig. 3.4).

There are four important sources of digestive agents in the small intestine: the gall bladder, which provides the bile salts necessary for emulsification of fat; the exocrine pancreas, which provides bicarbonate to neutralise the acidic chyme entering through the pylorus, and a mixture of digestive enzymes; secretory cells in glands located throughout the small intestinal wall which produce an isotonic, neutral, mucus-containing juice; and the brush border membrane,

Fig. 3.4 Vessels carrying the products of digestion away from the small intestine.

Substances entering the bloodstream reach the hepatic portal vein, and are thus carried to the liver. The products of fat digestion are carried in the vessels of the lymphatic system.

Fig. 3.4 Vessels carrying the products of digestion away from the small intestine.

Substances entering the bloodstream reach the hepatic portal vein, and are thus carried to the liver. The products of fat digestion are carried in the vessels of the lymphatic system.

in which are incorporated several digestive enzymes. These, and the other digestive juices, are summarised in Table 3.2.

3.2.3.2 Regulation of digestive processes in the small intestine

The efficiency of digestion and absorption is very high. Usually the energy we excrete in faeces represents only about 5% of the energy we ingest, and even then much of the weight of faeces consists of bacteria from the colon together with material that we are unable to digest. Maintaining this efficiency requires control mechanisms. For instance, if the contents of a meal were to pass too rapidly through the gastrointestinal tract, there would not be sufficient time for digestive enzymes to act and for absorption to take place. These control mechanisms, in general, respond to the presence of food (or its components) at various points in the gastrointestinal tract and regulate movement of further food along the tract; they also control the production of digestive juices.

The presence of chyme in the duodenum activates receptors in its walls via both stretch and chemical effects. These receptors trigger the enterogastric re flex, in which the brain reduces parasympathetic activity (one of the main stimulants of gastric secretion and gastric contraction) and increases sympathetic nervous stimulation of the pyloric sphincter, which causes it to contract; these effects combine to retain food in the stomach and reduce the loading

Table 3.2 Digestive enzymes and juices.

Source

Enzyme/juice

Function

Mouth

- Salivary glands Stomach

- Gastric glands

Small intestine and associated organs

- Small intestinal wall

- Gall bladder

- Exocrine pancreas

- Brush border membrane a-Amylase HCl

Pepsin (secreted as pepsinogen) Gastric lipase

Succus entericus (intestinal juice) Bile

Bile salts Pancreatic juice

Proteases: trypsin (secreted as trypsinogen); chymotrypsin (secreted as chymotrypsinogen); carboxypeptidases A,B (secreted as procarboxypeptidase) Pancreatic lipase Disaccharidases (more detail in Table 3.3) Peptidases

Initial digestion of starch

Denaturation/swelling of proteins; acidification for pepsin action; antibacterial; activation of pepsinogen Initial digestion of proteins Lipid hydrolysis in stomach

Dilution, lubrication Neutralisation of acidic chyme

Emulsification of fats Neutralisation of acidic chyme

Digestion of protein to oligopeptides and free amino acids

Triacylglycerol hydrolysis Disaccharide hydrolysis

Hydrolysis of peptides to di-and tripeptides of the small intestine until it is ready for more. Acidity in the duodenum also causes the secretion of secretin, a 27-amino acid peptide, into the bloodstream from cells in the duodenal and jejunal mucosa. Secretin was the first hormone to be discovered, by the English physiologist W.M. Bayliss and the physician E.H. Starling in 1902. (Gastrin was the second, in 1905, by J.S. Edkins in London.) Secretin gets its name from its effects on pancreatic secretion (see below), but it has an additional effect in inhibiting gastric contractions and secretion; these effects are reinforced by other hormones, cholecystokinin and gastric inhibitory peptide, both also secreted in response to distension of the duodenum and the presence of acidic chyme. This is another example of negative feedback: the entry of chyme into the duodenum is inhibited as it accumulates there.

Two of these hormones, secretin and cholecystokinin, also have important effects on digestive enzyme secretion. Secretin stimulates the exocrine pancreas to produce a fluid which is high in bicarbonate (and is thus alkaline, to neutralise the acidic chyme) but relatively low in enzyme content. Cholecystokinin stimulates the exocrine pancreas to produce a digestive juice which is relatively lower in bicarbonate but higher in enzyme content. The name cholecystokinin, however, relates to its effect on the gall bladder: it causes the gall bladder to contract, releasing its contents via the common bile duct into the duodenum. (At one time there were thought to be two separate hormones, known as pancreozymin, responsible for stimulation of pancreatic juice secretion, and cholecystokinin, acting on the gall bladder. Now they are known to be one and the same.) Thus, the arrival of chyme in the duodenum causes the secretion of digestive juices via the release of these two hormones: this is a further example of the role of hormones in integrating events within the body. The role of hormones in integration of digestion is illustrated in Fig. 3.5.

In addition, gastrointestinal hormones modulate the secretion of other hormones, particularly of insulin secretion from the pancreas. This means that

Food entering from oesophagus

Food entering from oesophagus

Fig. 3.5 Hormonal regulation of the secretion of digestive juices. Gastrin stimulates hydrochloric acid secretion by the oxyntic cells in the gastric glands. Secretin and cholecystokinin (CCK) promote the secretion of pancreatic juices. CCK also causes the gall bladder to contract, releasing bile into the duodenum.

Fig. 3.5 Hormonal regulation of the secretion of digestive juices. Gastrin stimulates hydrochloric acid secretion by the oxyntic cells in the gastric glands. Secretin and cholecystokinin (CCK) promote the secretion of pancreatic juices. CCK also causes the gall bladder to contract, releasing bile into the duodenum.

the arrival of food in the gastrointestinal tract will amplify the secretion of insulin that is otherwise stimulated by a rise in the blood glucose concentration. This aspect of gastrointestinal hormone action will be considered more fully in Chapter 5 (Section 5.7).

And yet further, cholecystokinin, in particular, may have a role in regulation of food intake. The suggestion has been made that cholecystokinin, released in response to food in the intestine, can signal to the brain to induce satiety, the feeling that leads to termination of a meal. The same effect has also been attributed to apolipoprotein-AIV, a protein produced by small-intestinal enterocytes and secreted with chylomicron particles. The role of apolipopro-tein-AIV in lipid metabolism is not clear, and it may be that its real role is to signal to the brain that fat is being processed in the small intestine and it's time to stop eating. There is also a recently discovered peptide secreted from the stomach, ghrelin, that may play the opposite role: ghrelin secretion falls after meals and rises during fasting and it seems to stimulate appetite. These and other mechanisms for induction of hunger and satiety will be discussed in Chapter 11 (see Box 11.1).

Although most lipid absorption occurs in the jejunum (see below), some lipids may reach the later part of the small intestine, the ileum. Here a further mechanism is activated. Lipids in the ileum slow the transit of material through the earlier parts of the small intestine. This is referred to as the 'ileal brake'. The mechanism may involve a peptide known as peptide-YY (Y here is the single letter code for the amino acid tyrosine) which can act as both neurotransmitter and hormone.

3.2.3.3 Digestive processes occurring in the small intestine

The pancreatic juice contains amylases (for hydrolysis of starch), proteases and a lipase; thus, it plays a major role in luminal digestion of each of the macro-nutrients.

Starch digestion

The pancreatic juice contains two a-amylases - i.e. enzymes which hydrolyse the a-1,4 glycosidic bonds in starch. Their pH optimum is around 7.0, which is the pH of the small intestinal contents after the bicarbonate-containing pancreatic juice has neutralised its acidity. These enzymes will not hydrolyse the a-1,6 branch-point in the amylopectin molecule, nor a-1,4 links within two glucosyl units after a branch, so that a-limit dextrins, small oligosaccharides containing the a-1,6 link, are produced, along with tri- and disaccharides such as maltotri-ose and maltose (three and two a-1,4 linked glucosyl units respectively). These products, along with other disaccharides ingested in the food (such as sucrose and lactose), are then hydrolysed by the enzymes associated with the microvil-lus membrane of the absorptive cells. There are four different enzymes, which hydrolyse the various remaining bonds (including the a-1,2 linkage in sucrose), to liberate free monosaccharides (Table 3.3).

Table 3.3 Small intestinal brush-border disaccharidases.

Enzyme Hydrolyses Absorption of product

Sucrase/isomaltase Glucose a1-(2 fructose bond in Glucose: SGLT-1

sucrose (see Fig. 1.7); a1,6 bonds in Fructose: GLUT5 a-limit dextrins

Maltase/glucoamylase a1-4 bonds in maltose and isomaltose Glucose: SGLT-1

Lactase (31-4 bonds in lactose Glucose: SGLT-1

Galactose: SGLT-1

Trehalase a1-1a bonds in trehalose Glucose: SGLT-1

For more on disaccharides see Section 1.2.2.1 and text around this table.

Trehalose is D-glucose a1 -1a-D-glucose and is a disaccharide found in mushrooms and in insects (in insects, it replaces glucose as the main blood sugar).

Protein digestion

The pancreatic juice contains a number of enzymes with proteolytic activity. The most important of these are secreted as pro-enzymes or zymogens which are activated by proteolysis in the intestinal lumen, presumably to protect the pancreas from digesting itself. These proteases are trypsin (secreted as trypsino-gen), chymotrypsin (secreted as chymotrypsinogen) and carboxypeptidases (the precursor procarboxypeptidase is activated to produce carboxypeptidases A and B). The enzyme trypsin is derived from trypsinogen by the action of an 'enterokinase' associated with the brush border membrane; trypsin then catalyses the activation of the other zymogens. Each of these enzymes has its own characteristic specificity for peptide bonds, but the net result of their combined action is the liberation of some free amino acids and a mixture of oligopeptides. These may be further hydrolysed by membrane-bound enzymes to tri- and dipeptides and amino acids for absorption.

Fat digestion

This is the most complex process because, as mentioned earlier, it involves both physico-chemical and enzymatic processes. Fat digestion and absorption depend upon emulsification of triacylglycerol, and finally formation of particles even smaller than those typical of emulsions, known as micelles. The main emulsifying agents are the bile salts, amphipathic molecules secreted in the bile (Box 3.1). As fat digestion proceeds, so further amphipathic molecules are formed which may help in emulsification; these include monoacylglycerols and phospholipids, particularly lysolecithin. Emulsification is brought about by the non-polar tails of the amphipathic molecules stabilising small groups of non-polar molecules, predominantly triacylglycerol and a smaller amount of cholesterol; their polar aspects face outwards to the aqueous intestinal contents. A net repulsive action of the outward facing polar groups also tends to further split the lipid droplets, resulting in a finer and finer emulsion. These emulsified particles are typically 1 |im in diameter. It is in this form that most of the hydrolysis of triacylglycerols proceeds.

Pancreatic lipase is a member of a family of lipases which includes lipo-protein lipase, an important enzyme in fat metabolism to be discussed in later chapters. These enzymes act on the ester links in the terminal (1,3) positions in an acylglycerol, but not the central fatty acid (2-position). Thus, fatty acids are liberated and 2-monoacylglycerols remain. Both fatty acids and mono-acylglycerols have amphipathic properties. Monoacylglycerols are effective emulsifying agents and aid the action of the bile salts, as noted above. Gradually, much smaller groups of molecules are formed, the mixed micelles - mixed because they contain both bile salts (which can themselves form micelles) and other molecules, particularly fatty acids and monoacylglycerols. These micelles have a diameter of 4 - 6 nm, so small that they do not scatter light and produce an almost clear solution. They are able to move readily through the aqueous intestinal contents, and thus bring the products of triacylglycerol hydrolysis, fatty acids and monoacylglycerols, to the surface of the absorptive cells. Lipid digestion in the small intestine is summarised in Fig. 3.6.

The action of pancreatic lipase can be potently inhibited by a bacterial product called tetrahydrolipstatin (generic drug name orlistat). Orlistat is now available as a treatment for obesity: by preventing up to 30% of dietary fat digestion, nutrient (hence energy) absorption is decreased (discussed again in Section 11.5.2).

Other forms of lipid in the diet - phospholipids and cholesterol esters - are also hydrolysed by pancreatic and other lipases, and the products (fatty acids, monoacylglycerols and free cholesterol) are also incorporated into the mixed micelles.

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