Secretory, Digestive, and Absorptive Functions of Small and Large Intestines
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| DIGESTION OF PROTEIN |
The purpose of the complex enzymatic reactions to which foodstuffs are exposed within the intestinal lumen is to prepare nutrients for transfer into and assimilation within the organism. The lumen of the digestive system, which is the space encompassed by the wall of the digestive tube, belongs, fundamentally speaking, to the outside world, and the processes by which the products of digestion enter and pass through the intestinal wall into the circulation are called secretion and absorption, respectively. The mucosa of the small intestine throughout its length is lined by cells involved with both secretion and absorption: mucus-secreting cells, neuroendocrine cells, and immune active cells. The incredible efficiency of intestinal function is emphasized by the fact that of the approximately 8 L of fluid that enters the small intestine, only 100 to 200 mL is excreted from the rectum, for an efficiency rate in excess of 98%. In disease states, the large and small intestines absorb even more fluid, sometimes exceeding 25 L per day. Alternatively, in secretory disorders and infection, the volume of diarrhea lost may rapidly pose a life-threatening risk of dehydration, with the loss of many liters of fluids and their accompanying electrolytes.
The secretory product of the duodenal glands is an alkaline, pale-yellow, viscous fluid, rich in bicarbonates and also containing mucus. Its primary function is protecting the proximal duodenum against the corrosive action of the acidic gastric contents entering the intestine. While there is an increasing relative absorption to secretion as nutrients pass into the jejunum and ileum, secretion persists from epithelial cells, goblet cells, and submucosal glands. The resulting luminal contents, or succus entericus, are constantly being mixed with mucus, bile, and digestive enzyme–laden pancreatic juice. The intestinal secretion contains a wide variety of digestive enzymes, namely, peptidases, nucleases, nucleosidases, phosphatase, lipase, maltase, sucrase, and lactase. Brush-border enterokinase is essential in activating the cascade of proenzymes secreted by the pancreas, including the cascades of trypsinogen to trypsin and chymotrypsinogen to chymotrypsin. The fact that digestion can proceed even in patients who have undergone total pancreatectomy indicates that the brush-border and secreted digestive intestinal enzymes are important. Motility of the small intestinal is activated by parasympathetic nerves, enteric nerves, and a host of enteric hormones acting both locally (paraendocrine hormones) and through the systemic circulation (most notably, cholecystokinin and secretin). These neurologic and hormonal reflexes are stimulated by the presence of acids and nutrients and by distention of the stomach and small intestine. These processes are slowed when nutrients, especially fats and essential amino acids, reach the distal small bowel. There they activate the so-called ileal brake by means of neural mechanisms and release of hormones, including peptide YY and glucagon-like peptide-1. Throughout the digestive process, mucus is being secreted from the intestinal crypts and epithelial cells on the villi to ensure adequate lubrication and protection of the surface epithelial cells.
Mucus
is also secreted by colonic epithelium when it has been stimulated mechanically
or chemically. The epithelium also secretes an alkaline-rich fluid high in
potassium, which is exchanged for sodium as the fecal stream
is solidified through dehydration processes.
The
normal diet includes a variety of macronutrients composed of carbohydrates,
nucleic acids, and proteins that are soluble in water and of fats, which are
not. It also contains minerals, vitamins, and other micronutrients. Each
requires specific, distinct pathways for digestion in preparation for
absorption.
The
digestion of proteins is carried out by gastric peptidases, an array of
brush-border enzymes, and enzymes secreted by the pancreas. The primary gastric
peptidase is pepsin, but chymosin is also active in an acidic environment.
Chief cells secrete an inactive sub-stance, pepsinogen, which is activated by
acid in the stomach to become pepsin. Pancreatic juices contain a rich supply
of proteins that make up over 20 isoforms of 12 distinct enzymes and cofactors,
most of which are proteases. All proteases are secreted as inactive proenzymes
(zymogens), as are phospholipase and colipase. The proteolytic actions of each
protein-splitting enzyme have a highly specific effect. Each attacks only
certain linkages of the protein molecule or of the degradation products
resulting from the preceding effects of one or more catalytically active
compounds. According to their functions, they are typically grouped as either
exopeptidases or endopeptidases. Trypsinogen is activated by the brush-border
enzyme enterokinase to become its active form, trypsin, which in turn activates
other enzymes. Trypsin, chymotrypsin, carboxypeptidase, and the intestinal
aminopeptidases act only on polypeptides or peptides containing a free amino
group. The dipeptidases act only on dipeptides. As the peptide is digested
within the lumen, it diffuses to the epithelial surface, where a number of
membrane-bound peptidases continue the digestive process. This cascade of
proteolytic effects breaks down the original protein until it has been
fragmented into its elementary components, the 26 amino acids, dipeptides, or
tripeptides, in preparation for absorption.
For
the digestion of nucleoproteins, the pancreas supplies nucleases,
ribonuclease, desoxyribonuclease, and other substances that specifically
hydrolyze nucleosides: pentose or deoxypentose is conjugated to purines and
pyrimidine bases. Intestinal secretion also provides nucleases and,
particularly, phosphatases, which split nucleotides (phosphoric esters of
nucleosides) into their components.
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| DIGESTION OF CARBOHYDRATES |
Dietary
carbohydrates may consist of monoglycerides such as glucose and fructose,
disaccharides such as lactose and sucrose, or polysaccharides. The processes
involved in the digestion of carbohydrates are therefore primarily
concerned with the enzymatic cleavage of polysaccharides
and oligosaccharides into monosaccharides. Polysaccharides include starch,
glycogen, and fibers such as cellulose, gums, and pectins. In human nutrition,
the most important carbohydrate is starch, which is a polysaccharide
occurring as an energy reservoir in plants, particularly cereals, grains,
roots, and tubers. The counterpart in animals is glycogen, another
polysaccharide ingested with meat and liver. In both starch and glycogen, a
large number of hexoses (monosaccharides) are linked
together, forming either a straight chain or a branched chain of molecules. The
linkage between these molecules varies, and to open them, the organism is
equipped with a variety of specifically active enzymes.
Starch-splitting
enzymes called amylases are secreted by the pancreas and, to a lesser extent,
by the salivary glands. The digestion of carbohydrates begins in the mouth with
the action of salivary amylase. Because salivary
amylase is inactivated by gastric acid in the stomach, the actions of the
enzyme mainly affect the outer portions of the food mass. Once it reaches the
stomach and the gastric acid has penetrated the food mass, digestion of
carbohydrates slows or stops until the food mass reaches the duodenum. In the
duodenum, carbohydrates are acted on by the more effective enzymes
α-amylase and β-amylase, which are synthesized in the
pancreas and then secreted in their active forms. The
action of the amylases yields the disaccharide maltose and a
polysaccharide fragment called dextrin, which cannot be further digested
by amylase. Therefore, except during the period of infancy, when the secretory
activity of the pancreas has not yet fully developed, the degradation of starch
into the disaccharide maltose and the monosaccharide glucose is
completed in the lower part of the duodenum and in the jejunum and ileum. The
splitting of maltose into two molecules of glucose is catalyzed by maltase,
an enzyme formed by the intestinal glands. Disaccharides are primarily digested
by intestinal brush-border enzymes such as sucrose-isomaltase, which
converts sucrose (common table sugar) into a molecule of glucose and a molecule
of fructose, and lactase-phlorizin hydrolase, which converts lactase
(milk sugar) into glucose and galactose. Other brush-border
disaccharidases include glucoamylase and trehalase. The end products, there-fore,
are simple monosaccharides, which the intestinal epithelial cell is prepared to
absorb.
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| DIGESTION OF FAT |
In
humans, cellulose is indigestible, because humans, in contrast to some animals,
lack enzymes capable of attacking the specific bonds of cellulose. The enzymes
derived from the bacterial flora of the human colonic microbiota can act on
cellulose and on the undigested starch reaching the distal gut. This action of
the microbiota produces increased osmotically active substances that attract
fluid into the lumen and produce gas through fermentation. Both result in
distention that increases colonic motility; when this distention is excessive,
it can lead to discomfort interpreted as “gas” and to increased flatulence and
bloating.
Lipids
include a variety of heterogeneous molecules often described as fats. The term
includes triglycerides, phospholipids, cholesterol, steroids, and fat-soluble
vitamins. From the dietary point of view, the triglycerides are of major
importance due to their high-energy value. Triglycerides, whether of plant
origin (unsaturated) or animal origin (mostly saturated), are esters of
glycerol and fatty acids. The esters are named triglycerides because the
three alcoholic hydroxyl groups of glycerol are bound
in an ester linkage to the carboxyl group (the group that determines the acid character)
of either saturated or unsaturated organic acids, such as palmitic, stearic, oleic,
or linoleic acid. The term neutral fat has also been used to describe these
important nutrients because no acidic group is free. In an aqueous milieu, fats
align with their hydrophobic groups adjacent to each other and their polar groups
facing the surrounding water. This arrangement
creates bilayers or micelles. Nonpolar lipids accumulate in the inner portions
of these micelles. Further digestion of fats requires access to these molecules
within the micelle. Bile salts and the coenzyme colipase are essential factors that
facilitate this access. Triglycerides are digested by hydrolyzation of
the ester linkage, yielding the components of the esters, namely, glycerol and
the various fatty the triglycerides lose
first one of their three acid molecules, leaving a diglyceride (i.e., a
glycerol ester containing only two acids), and this, in turn, is hydrolyzed to
a monoglyceride, which possesses only one acid molecule.
The
hydrolysis of triglycerides and phospholipids is accomplished by lipases and
phospholipases, respectively, that are secreted by the salivary glands,
stomach, pancreas, and intestinal glands. A limited amount of fat is digested
in the stomach by a lingual lipase originating in saliva and the gastric lipase
originating from the chief cells in the stomach. The gastric lipase can
function in an acidic environment, in contrast to other lipases, which act in a
nearly neutral environment. In most adults, this gastric lipase is of limited
significance, but it is important in patients with pancreatic insufficiency; it
is also important in infants, in whom it is capable of hydrolyzing the highly
emulsified fat of milk. The pancreas is the major source of bicarbonate, which
serves to neutralize gastric acidity, and of lipase activity. It also is the
source of colipase, which plays an important role as a cofactor at the
interface of water, bile salt, and lipid by enhancing lipolysis. The phospholipids
undergo hydrolysis into their component parts by secretions of a proenzyme from
the pancreas that is activated by trypsin to produce phospholipase A. This
hydrolysis produces glycerol, fatty acids, phosphate, and the special compound
characteristic of the particular phospholipid (choline, serine, inositol, or
ethanolamine). In contrast to the enzymes involved in protein and carbohydrate digestion, which act with a high degree of specificity on certain
compounds or chemically well- defined groups or bonds, the action of lipases of
animal or plant origin is far less specific.
In
the lower duodenum, fat is mixed with bile and dispersed into a fine emulsion.
The components of bile responsible for this action are the bile acids, mostly
glycocholic acid and taurocholic acid, which act as detergents. The result of
the emulsification of fat in the aqueous medium of the intestinal chyme is an
enormous increase of the surface of the fat particles, facilitating the
hydrolytic action of the pancreatic and intestinal lipases. The fatty acids,
whether ingested with food or arising as split products of fat hydrolysis,
combine in the intestine with bile salts and cations,
forming soluble soaps with sodium and potassium and insoluble soaps with
calcium and magnesium. Bile is important for the emulsification of ingested
water-insoluble or less-soluble fats in the digestion mixture.
Insoluble
soaps, the monoglycerides, are “ferried” through the lumen to the cellular
barrier with complexes of colipase and bile acids. The soluble alkali soaps aid
in the emulsification of fat and the stabilization of emulsified lipids by the
same principle that makes soap useful in the household for cleansing and
detergent effects.
Much
of ingested cholesterol is not esterified in the lumen, although some
hydrolysis occurs through the action of cholesterol esterase. Instead,
cholesterol can be taken up intact through
specific facilitated transport. Other lipids, such as vitamin A (and its
provitamin, carotene), vitamins E and K, and other steroids, including vitamin D,
are not broken down within the intestine.
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| DIGESTION OF FAT |
ABSORPTION
The
absorption of nearly all nutrients is achieved by the small intestinal cells of
the duodenal, jejunal, and ileal epithelia. The
small, but important, amount of nutrient absorption and the significant amount
of water and electrolyte absorption that take place in the colon are described
at the end of this section. Selective absorption also occurs across the oral
and gastric epithelia. The epithelial lining of the small intestine is
preeminently and specifically equipped for its function by its length and its
large surface area. The surface area of the intestinal tube is increased by the
presence of luminal folds, villi, and, most importantly, microvilli. Small
intestinal folds are arrayed in a special circular design perpendicular to the
axis of the lumen which enhances the turbulent flow of the luminal contents,
known as the plicae circulares. Villi further increase the surface area
15- to 30-fold, and microvilli increase the surface area an additional 20- to
40-fold.
Ions
are transported across the epithelium by ion channels and ion exchangers and by
cotransporters that facilitate diffusion, osmosis, and solvent drag. Other
complex molecular transport mechanisms involve specific receptor-mediated
transport proteins and other active transport mechanisms. The presence of
transport proteins on the apical surface and the tight junctions between cells
permit movement of fluid as the epithelium actively transports substances
against a concentration gradient. Ion-specific channel proteins permit the
movement of hydrophilic ions through the hydrophobic bilayer of the cell
membrane along concentration gradients (facilitated diffusion). These ion
channels are also “gated”, so that they permit transport only for a brief
period in which the channel is open; then the gate closes.
Water
crosses the intestinal wall in both directions, depending on hydraulic and
osmotic forces based on the osmolality of luminal contents and the location
within the small intestine. This occurs across the cell membrane and between
cells in the paracellular channels that are exquisitely regulated by tight
junctions and their regulatory and contractile proteins. Aquaporin water
channels are less common in the gut than in the renal tubules. If the aqueous
phase of the intestinal contents is hypotonic, water moves from the lumen
through the cells and between the cells through para-cellular spaces into the
blood. Alternatively, if the luminal content is hypertonic, water will be
transferred from the blood into the lumen. As solutes enter the wall, an
obligatory transport of water from the lumen occurs to keep the solution within
the tube isosmotic.
Most
minerals, such as the salts composed of sodium, potassium, and chloride ions,
move with the water across channels, but, in addition, specific ion pumps,
exchangers, and cotransport mechanisms exist to bring needed ions into the
epithelial cells and then into the circulation, often against a steep
concentration gradient. Active transport by ion pumps requires energy expenditure
through the hydrolysis of adenosine triphosphate. Carrier proteins can couple
electrolyte transport with specific nutrients, including glucose and amino
acids. For example, the cotransport of each molecule of glucose brings two
molecules of sodium into the epithelial cell. Chloride is transported into the
lumen by means of the chloride channel on the apical cell membrane, primarily
the cystic fibrosis transmembrane conductance regulator. It is absorbed across
tight junctions and via exchange proteins with bicarbonate.
Calcium
must be solubilized before it can be absorbed through acidification in the
stomach or at the brush-border surface by the action of the Na+-H+ exchanger. Absorption
through channels or by carriers is tightly regulated through vitamin D–mediated
processes. Once in the lumen, it is bound by a calcium-binding protein,
calbindin-D9k.
Like
calcium, magnesium is absorbed by both passive and active processes, primarily
in the duodenum and upper jejunum. Magnesium absorption is much less efficient
than is calcium absorption; this accounts for the efficacy of its salts to
function as osmotic laxatives.
A
man absorbs 1 mg of iron daily; 2 mg of iron daily is absorbed by menstruating
females, again primarily through the duodenum. Ferric iron must be solubilized
to ferrous iron to be absorbed. This occurs through the effect of gastric acid,
ascorbic acid, or brush-border reductases. The divalent brush-border
transporter transports this essential nutrient into the cell, where it is oxidized
by heme-oxidase before being transported out of the cell. Its absorption is
tightly regulated by the hepatic synthesis of the peptide hepcidin, based on
the needs of the body.
The
concentration of bile in the intestine diminishes as the chyme enters the
distal intestine. Effective active transport of bile acids by the distal ileum
is necessary to maintain healthy concentrations of these complex molecules.
Malabsorption will lead to bile salt diarrhea.
The
products of protein digestion formed by the combination of gastric, pancreatic,
and brush-border peptidases result in dipeptides or tripeptides and amino
acids that can diffuse to the cell membrane surface. There they are brought
into the cell by more than a dozen specific sodium-coupled transport mechanisms.
The rate of absorption for various amino acids is different, and quantitatively
most may be absorbed as dipeptides and tripeptides. Once in the enterocyte, all
are degraded further to isolated amino acids. Although some amino acids
entering the cells are synthesized within them, most are transported by the
basolateral membrane directly into the circulation. Under special
circumstances, intact protein molecules may be absorbed through specialized
channels and the process of pinocytosis associated with M cells as part of the
gut immune regulatory system.
Carbohydrates
are
absorbed almost exclusively in the form of monosaccharides, that is, as hexoses
(glucose, fructose, and galactose) or pentoses (ribose and deoxy- ribose).
Monosaccharides are absorbed via specific sodium-coupled cotransport proteins
that recognize only the D isomer of the molecule. Galactose is more rapidly
absorbed than is glucose. Fructose is absorbed via facilitated transport down a
concentration gradient via its own specific transport protein, GLUT5. Within
fairly wide limits, the rate of hexose transfer is independent of the
intraluminal concentration. The presence of enzymes (hexokinases) catalyzing
the conversion of hexoses to hexose phosphates in the intestinal mucosa and the
reduction of glucose and galactose absorption can occur when the hexokinases
are inhibited by phlorizin. The picture of the absorption of pentoses is still
less clear. The transfer of xylose, used now as an indicator of the efficiency
of intestinal absorption, may involve diffusion or phosphorylation, or both.
Lipolysis
hydrolyzes fats to diglycerides, then monoglycerides, and then completely
hydrolyzed fat components, glycerol, and fatty acids that enter the cell
through a specific transport mechanism, including fatty acid translocase CD36.
Once absorbed, the split products are transported in the cell by fatty acid–binding
proteins to the endoplasmic reticulum, where they are resynthesized back to
triglycerides. Other lipids are added, including apolipoproteins, in the Golgi
apparatus, and the product is packaged into secretory granules. These leave the
cell by exocytosis as chylomicrons, moving into the lymphatics to the rest of
the body. Some lipids exit the cell in very low density lipoproteins. Other
lipids and some phospholipids may be further
degraded, leave the cell, and enter the portal system. Similarly, cholesterol
is transported into the cell by specific transport proteins located on the
apical brush borders. It is processed within the cell and exits in chylomicrons
or very low density lipoproteins.
The
absorption of other lipids, cholesterol, phosphatides, and fat-soluble vitamins
is intimately related to the mechanisms of fat absorption. Although some cholesterol
may be esterified in the lumen, most is transported into the cell through
receptor-mediated transport. Free cholesterol and the cholesterol esters
leave the intestinal cells by way of the lymph stream. The absorption of the
hydrolytic products of phospholipid digestion (see above) follows the line
indicated for fat absorption.
Vitamin
A is a water-insoluble lipid derived from dietary carotenoid. The vitamin is
actually made up of a family of biologically active retinoids. These retinoids
are esterified to long-chain fatty acids that are hydrolyzed by pancreatic
enzymes. Absorption occurs via passive, noncarrier-mediated transport into the
cell, where the vitamin is further oxidized and eventually bound to
retinol-binding protein for distribution to the rest of the body. Active
vitamin D is the result of a complex series of steps, including actions in the
kidney, liver, and skin. Although the skin can synthesize vitamin D under
adequate exposure to sunlight, in more northern climates, absorption of the
inactive unesterified sterol precursors vitamin D3 (cholecalciferol) and D2 (ergocalciferol)
is important for their nutrient value. After absorption by the enterocyte, they
are exported in chylomicrons to the circulation, where they become bound to
transport proteins. In the liver, they are metabolized to 25-hydroxyvitamin D
and then to 1,25-dihdroxy vitamin D3 by the kidney.
The
mechanisms involved in the absorption of the water-soluble vitamins (thiamine,
riboflavin, nicotinic acid, pyridoxine, pantothenic acid, ascorbic acid, and
cyanocobalamin [vitamin B12]) involve vitamin-specific, complex, receptor-mediated
mechanisms after partial intraluminal metabolism. As discussed elsewhere,
vitamin B12 is absorbed by complex interactions of two binding proteins. The
salivary glands secrete a pH-dependent binding protein (R protein) known as
haptocorrin that protects the vitamin from intragastric digestion. Once the
complex reaches the duodenum, proteolysis releases haptocorrin, permitting the
intrinsic factor secreted by the gastric parietal cells to bind B12 and
facilitate its protection until absorbed in the distal ileum. The intrinsic
factor–vitamin B12 complex is bound to the cubam receptor on ileal epithelium.
There the complex is actively absorbed by endocytosis into the ileum.
Unlike
other important nutrients and vitamins, vitamin K is primarily derived from synthetic
actions of the microbiota and is absorbed by the colonic epithelium. Although
malabsorption of most fat-soluble vitamins is due to a deficiency of pancreatic
enzymes or bile salts, vitamin K deficiency more commonly results from
inadequate nutrition and the deleterious effects of antibiotics on the
microbiota.
As
mentioned, the role of the colon in absorbing nutrients to be used by the rest
of the body is negligible. Colonic epithelial cells, however, are able to
absorb short-chain fatty acids that are a major source of energy for the
epithelial cells. Effective absorption of fluid and electrolytes by the colon
is important and serves to limit the loss of fluid in the stool by nearly a
liter under normal circumstances and by more when small intestinal fluid
delivery to the colon increases during disease states. It also limits the
volume of fluid loss and the inconvenience
of frequent defecations.
