Chapter 25: Overview of Gastrointestinal Function & Regulation

After studying this chapter, you should be able to:

• Understand the functional significance of the gastrointestinal system, and in particular, its roles in nutrient assimilation, excretion, and immunity.

• Describe the structure of the gastrointestinal tract, the glands that drain into it, and its subdivision into functional segments.

• List the major gastrointestinal secretions, their components, and the stimuli that regulate their production.

• Describe water balance in the gastrointestinal tract and explain how the level of luminal fluidity is adjusted to allow for digestion and absorption.

• Identify the major hormones, other peptides, and key neurotransmitters of the gastrointestinal system.

• Describe the special features of the enteric nervous system and the splanchnic circulation.

The primary function of the gastrointestinal tract is to serve as a portal whereby nutrients and water can be absorbed into the body. In fulfilling this function, the meal is mixed with a variety of secretions that arise from both the gastrointestinal tract itself and organs that drain into it, such as the pancreas, gallbladder, and salivary glands. Likewise, the intestine displays a variety of motility patterns that serve to mix the meal with digestive secretions and move it along the length of the gastrointestinal tract. Ultimately, residues of the meal that cannot be absorbed, along with cellular debris, are expelled from the body. All of these functions are tightly regulated in concert with the ingestion of meals. Thus, the gastrointestinal system has evolved a large number of regulatory mechanisms that act both locally and over long distances to coordinate the function of the gut and the organs that drain into it.

The parts of the gastrointestinal tract that are encountered by the meal or its residues include, in order, the mouth, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, and anus. Throughout the length of the intestine, glandular structures deliver secretions into the lumen, particularly in the stomach and mouth. Also important in the process of digestion are secretions from the pancreas and the biliary system of the liver. The intestine itself also has a very substantial surface area, which is important for its absorptive function. The intestinal tract is functionally divided into segments by means of muscle rings known as sphincters, which restrict the flow of intestinal contents to optimize digestion and absorption. These sphincters include the upper and lower esophageal sphincters, the pylorus that retards emptying of the stomach, the ileocecal valve that retains colonic contents (including large numbers of bacteria) in the large intestine, and the inner and outer anal sphincters. After toilet training, the latter permits delaying the elimination of wastes until a time when it is socially convenient.

The intestine is composed of functional layers (Figure 25–1). Immediately adjacent to nutrients in the lumen is a single layer of columnar epithelial cells. This represents the barrier that nutrients must traverse to enter the body. Below the epithelium is a layer of loose connective tissue known as the lamina propria, which in turn is surrounded by concentric layers of smooth muscle, oriented circumferentially and then longitudinally to the axis of the gut (the circular and longitudinal muscle layers, respectively). The intestine is also amply supplied with blood vessels, nerve endings, and lymphatics, which are all important in its function.

The epithelium of the intestine is also further specialized in a way that maximizes the surface area available for nutrient absorption. Throughout the small intestine, it is folded up into fingerlike projections called villi (Figure 25–2). Between the villi are infoldings known as crypts. Stem cells that give rise to both crypt and villus epithelial cells reside toward the base of the crypts and are responsible for completely renewing the epithelium every few days or so. Indeed, the gastrointestinal epithelium is one of the most rapidly dividing tissues in the body. Daughter cells undergo several rounds of cell division in the crypts then migrate out onto the villi, where they are eventually shed and lost in the stool. The villus epithelial cells are also notable for the extensive microvilli that characterize their apical membranes. These microvilli are endowed with a dense glycocalyx (the brush border) that probably protects the cells to some extent from the effects of digestive enzymes. Some digestive enzymes are also actually part of the brush border, being membrane-bound proteins. These so-called “brush border hydrolases” perform the final steps of digestion for specific nutrients.

SALIVARY SECRETION

The first secretion encountered when food is ingested is saliva. Saliva is produced by three pairs of salivary glands (the parotid, submandibular, and sublingual glands) that drain into the oral cavity. It has a number of organic constituents that serve to initiate digestion (particularly of starch, mediated by amylase) and which also protect the oral cavity from bacteria (such as immunoglobulin A and lysozyme). Saliva also serves to lubricate the food bolus (aided by mucins). Secretions of the three glands differ in their relative proportion of proteinaceous and mucinous components, which results from the relative number of serous and mucous salivary acinar cells, respectively. Saliva is also hypotonic compared with plasma and alkaline; the latter feature is important to neutralize any gastric secretions that reflux into the esophagus.

The salivary glands consist of blind end pieces (acini) that produce the primary secretion containing the organic constituents dissolved in a fluid that is essentially identical in its composition to plasma. The salivary glands are actually extremely active when maximally stimulated, secreting their own weight in saliva every minute. To accomplish this, they are richly endowed with surrounding blood vessels that dilate when salivary secretion is initiated. The composition of the saliva is then modified as it flows from the acini out into ducts that eventually coalesce and deliver the saliva into the mouth. Na⁺ and Cl⁻ are extracted and K⁺ and bicarbonate are added. Because the ducts are relatively impermeable to water, the loss of NaCl renders the saliva hypotonic, particularly at low secretion rates. As the rate of secretion increases, there is less time for NaCl to be extracted and the tonicity of the saliva rises, but it always stays somewhat hypotonic with respect to plasma. Overall, the three pairs of salivary glands that drain into the mouth supply 1000–1500 mL of saliva per day.

Salivary secretion is almost entirely controlled by neural influences, with the parasympathetic branch of the autonomic nervous system playing the most prominent role (Figure 25–3). Sympathetic input slightly modifies the composition of saliva (particularly by increasing proteinaceous content), but has little influence on volume. Secretion is triggered by reflexes that are stimulated by the physical act of chewing, but is actually initiated even before the meal is taken into the mouth as a result of central triggers that are prompted by thinking about, seeing, or smelling food. Indeed, salivary secretion can readily be conditioned, as in the classic experiments of Pavlov where dogs were conditioned to salivate in response to a ringing bell by associating this stimulus with a meal. Salivary secretion is also prompted by nausea but inhibited by fear or during sleep.

Saliva performs a number of important functions: it facilitates swallowing, keeps the mouth moist, serves as a solvent for the molecules that stimulate the taste buds, aids speech by facilitating movements of the lips and tongue, and keeps the mouth and teeth clean. The saliva also has some antibacterial action, and patients with deficient salivation (xerostomia) have a higher than normal incidence of dental caries. The buffers in saliva help maintain the oral pH at about 7.0.

GASTRIC SECRETION

Food is stored in the stomach; mixed with acid, mucus, and pepsin; and released at a controlled, steady rate into the duodenum (Clinical Box 25–1).

ANATOMIC CONSIDERATIONS

The gross anatomy of the stomach is shown in Figure 25–4. The gastric mucosa contains many deep glands. In the cardia and the pyloric region, the glands secrete mucus. In the body of the stomach, including the fundus, the glands also contain parietal (oxyntic) cells, which secrete hydrochloric acid and intrinsic factor, and chief (zymogen, peptic) cells, which secrete pepsinogens (Figure 25–5). These secretions mix with mucus secreted by the cells in the necks of the glands. Several of the glands open onto a common chamber (gastric pit) that opens in turn onto the surface of the mucosa. Mucus is also secreted along with HCO₃⁻ by mucus cells on the surface of the epithelium between glands.

The stomach has a very rich blood and lymphatic supply. Its parasympathetic nerve supply comes from the vagi and its sympathetic supply from the celiac plexus.

ORIGIN & REGULATION OF GASTRIC SECRETION

The stomach also adds a significant volume of digestive juices to the meal. Like salivary secretion, the stomach readies itself to receive the meal before it is actually taken in, during the so-called cephalic phase that can be influenced by food preferences. Subsequently, there is a gastric phase of secretion that is quantitatively the most significant, and finally an intestinal phase once the meal has left the stomach. Each phase is closely regulated by both local and distant triggers.

The gastric secretions (Table 25–1) arise from glands in the wall of the stomach that drain into its lumen, and also from the surface cells that secrete primarily mucus and bicarbonate to protect the stomach from digesting itself, as well as substances known as trefoil peptides that stabilize the mucus-bicarbonate layer. The glandular secretions of the stomach differ in different regions of the organ. The most characteristic secretions derive from the glands in the fundus or body of the stomach. These contain the distinctive parietal cells, which secrete hydrochloric acid and intrinsic factor; and chief cells, which produce pepsinogens and gastric lipase (Figure 25–5). The acid secreted by parietal cells serves to sterilize the meal and also to begin the hydrolysis of dietary macromolecules. Intrinsic factor is important for the later absorption of vitamin B₁₂, or cobalamin. Pepsinogen is the precursor of pepsin, which initiates protein digestion. Lipase similarly begins the digestion of dietary fats.

There are three primary stimuli of gastric secretion, each with a specific role to play in matching the rate of secretion to functional requirements (Figure 25–6). Gastrin is a hormone that is released by G cells in the antrum of the stomach both in response to a specific neurotransmitter released from enteric nerve endings, known as gastrin-releasing peptide (GRP) or bombesin, and also in response to the presence of oligopeptides in the gastric lumen. Gastrin is then carried through the bloodstream to the fundic glands, where it binds to receptors not only on parietal (and likely, chief cells) to activate secretion, but also on so-called enterochromaffin-like cells (ECL cells) that are located in the gland, and release histamine. Histamine is also a trigger of parietal cell secretion, via binding to H₂-receptors. Finally, parietal and chief cells can also be stimulated by acetylcholine, released from enteric nerve endings in the fundus.

Gastric secretion that occurs during the cephalic phase is defined as being activated predominantly by vagal input that originates from the brain region known as the dorsal vagal complex, which coordinates input from higher centers. Vagal outflow to the stomach then releases GRP and acetylcholine, thereby initiating secretory function. However, before the meal enters the stomach, there are few additional triggers and thus the amount of secretion is limited. Once the meal is swallowed, on the other hand, meal constituents trigger substantial release of gastrin and the physical presence of the meal also distends the stomach and activates stretch receptors, which provoke a “vago-vagal” as well as local reflexes that further amplify secretion during the gastric phase. The presence of the meal also buffers gastric acidity that would otherwise serve as a feedback inhibitory signal to shut off secretion secondary to the release of somatostatin, which inhibits both G and ECL cells as well as secretion by parietal cells themselves (Figure 25–6). This probably represents a key mechanism whereby gastric secretion is terminated after the meal moves from the stomach into the small intestine.

Gastric parietal cells are highly specialized for their unusual task of secreting concentrated acid (Figure 25–7). The cells are packed with mitochondria that supply energy to drive the apical H⁺, K⁺-ATPase, or proton pump, that moves H⁺ ions out of the parietal cell against a concentration gradient of more than a million-fold. At rest, the proton pumps are sequestered within the parietal cell in a series of membrane compartments known as tubulovesicles. When the parietal cell begins to secrete, on the other hand, these vesicles fuse with invaginations of the apical membrane known as canaliculi, thereby substantially amplifying the apical membrane area and positioning the proton pumps to begin acid secretion (Figure 25–8). The apical membrane also contains potassium channels, which supply the K⁺ ions to be exchanged for H⁺, and Cl⁻ channels that supply the counterion for HCl secretion (Figure 25–9). The secretion of protons is also accompanied by the release of equivalent numbers of bicarbonate ions into the bloodstream, which are later used to neutralize gastric acidity once its function is complete (Figure 25–9).

The three agonists of the parietal cell—gastrin, histamine, and acetylcholine—each bind to distinct receptors on the basolateral membrane (Figure 25–8). Gastrin and acetylcholine promote secretion by elevating cytosolic free calcium concentrations, whereas histamine increases intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). The net effects of these second messengers are the transport and morphologic changes described above. However, it is important to be aware that the two distinct pathways for activation are synergistic, with a greater than additive effect on secretion rates when histamine plus gastrin or acetylcholine, or all three, are present simultaneously. The physiologic significance of this synergism is that high rates of secretion can be stimulated with relatively small changes in availability of each of the stimuli. Synergism is also therapeutically significant because secretion can be markedly inhibited by blocking the action of only one of the triggers (most commonly that of histamine, via H₂-antagonists that are widely used therapies for adverse effects of excessive gastric secretion, such as reflux).

Gastric secretion adds about 2.5 L/day to the intestinal contents. However, despite their substantial volume and fine control, gastric secretions are dispensable for the full digestion and absorption of a meal, with the exception of cobalamin absorption. This illustrates an important facet of gastrointestinal physiology, namely that digestive and absorptive capacities are markedly in excess of normal requirements. On the other hand, if gastric secretion is chronically reduced, individuals may display increased susceptibility to infections acquired via the oral route.

PANCREATIC SECRETION

The pancreatic juice contains enzymes that are of major importance in digestion (see Table 25–2). Its secretion is controlled in part by a reflex mechanism and in part by the gastrointestinal hormones secretin and cholecystokinin (CCK).

ANATOMIC CONSIDERATIONS

The portion of the pancreas that secretes pancreatic juice is a compound alveolar gland resembling the salivary glands. Granules containing the digestive enzymes (zymogen granules) are formed in the cell and discharged by exocytosis (see Chapter 2) from the apexes of the cells into the lumens of the pancreatic ducts (Figure 25–10). The small duct radicles coalesce into a single duct (pancreatic duct of Wirsung), which usually joins the bile duct to form the ampulla of the bile duct (also known as the ampulla of Vater) (Figure 25–11). The ampulla opens through the duodenal papilla, and its orifice is encircled by the sphincter of Oddi. Some individuals have an accessory pancreatic duct (duct of Santorini) that enters the duodenum more proximally.

COMPOSITION OF PANCREATIC JUICE

The pancreatic juice is alkaline (Table 25–3) and has a high HCO₃⁻ content (approximately 113 mEq/L vs 24 mEq/L in plasma). About 1500 mL of pancreatic juice is secreted per day. Bile and intestinal juices are also neutral or alkaline, and these three secretions neutralize the gastric acid, raising the pH of the duodenal contents to 6.0–7.0. By the time the chyme reaches the jejunum, its pH is nearly neutral, but the intestinal contents are rarely alkaline.

The pancreatic juice also contains a range of digestive enzymes, but most of these are released in inactive forms and only activated when they reach the intestinal lumen (see Chapter 26). The enzymes are activated following proteolytic cleavage by trypsin, itself a pancreatic protease that is released as an inactive precursor (trypsinogen). The potential danger of the release into the pancreas of a small amount of trypsin is apparent; the resulting chain reaction would produce active enzymes that could digest the pancreas. It is therefore not surprising that the pancreas also normally secretes a trypsin inhibitor.

Another enzyme activated by trypsin is phospholipase A₂. This enzyme splits a fatty acid off phosphatidylcholine (PC), forming lyso-PC. Lyso-PC damages cell membranes. It has been hypothesized that in acute pancreatitis, a severe and sometimes fatal disease, phospholipase A₂ is activated prematurely in the pancreatic ducts, with the formation of lyso-PC from the PC that is a normal constituent of bile. This causes disruption of pancreatic tissue and necrosis of surrounding fat.

Small amounts of pancreatic digestive enzymes normally leak into the circulation, but in acute pancreatitis, the circulating levels of the digestive enzymes rise markedly. Measurement of the plasma amylase or lipase concentration is therefore of value in diagnosing the disease.

REGULATION OF THE SECRETION OF PANCREATIC JUICE

Secretion of pancreatic juice is primarily under hormonal control. Secretin acts on the pancreatic ducts to cause copious secretion of a very alkaline pancreatic juice that is rich in HCO₃⁻ and poor in enzymes. The effect on duct cells is due to an increase in intracellular cAMP. Secretin also stimulates bile secretion. CCK acts on the acinar cells to cause the release of zymogen granules and production of pancreatic juice rich in enzymes but low in volume. Its effect is mediated by phospholipase C (see Chapter 2).

The response to intravenous secretin is shown in Figure 25–12. Note that as the volume of pancreatic secretion increases, its Cl⁻ concentration falls and its HCO₃⁻ concentration increases. Although HCO₃⁻ is secreted in the small ducts, it is reabsorbed in the large ducts in exchange for Cl⁻ (Figure 25–13). The magnitude of the exchange is inversely proportional to the rate of flow.

Like CCK, acetylcholine acts on acinar cells via phospholipase C to cause discharge of zymogen granules, and stimulation of the vagi causes secretion of a small amount of pancreatic juice rich in enzymes. There is evidence for vagally mediated, conditioned reflex secretion of pancreatic juice in response to the sight or smell of food.

BILIARY SECRETION

An additional secretion important for gastrointestinal function, bile, arises from the liver. The bile acids contained therein are important in the digestion and absorption of fats. In addition, bile serves as a critical excretory fluid by which the body disposes of lipid soluble end products of metabolism as well as lipid soluble xenobiotics. Bile is also the only route by which the body can dispose of cholesterol—either in its native form, or following conversion to bile acids. In this chapter and the next, the role of bile as a digestive fluid will be emphasized. In Chapter 28, a more general consideration of the transport and metabolic functions of the liver will be presented.

Bile

Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice. About 500 mL is secreted per day. Some of the components of the bile are reabsorbed in the intestine and then excreted again by the liver (enterohepatic circulation).

The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. The formation of these breakdown products of hemoglobin is discussed in detail in Chapter 28.

When considering bile as a digestive secretion, it is the bile acids that represent the most important components. They are synthesized from cholesterol and secreted into the bile conjugated to glycine or taurine, a derivative of cysteine. The four major bile acids found in humans are listed in Figure 25–14. In common with vitamin D, cholesterol, a variety of steroid hormones, and the digitalis glycosides, the bile acids contain the steroid nucleus (see Chapter 20). The two principal (primary) bile acids formed in the liver are cholic acid and chenodeoxycholic acid. In the colon, bacteria convert cholic acid to deoxycholic acid and chenodeoxycholic acid to lithocholic acid. In addition, small quantities of ursodeoxycholic acid are formed from chenodeoxycholic acid. Ursodeoxycholic acid is a tautomer of chenodeoxycholic acid at the 7-position. Because they are formed by bacterial action, deoxycholic, lithocholic, and ursodeoxycholic acids are called secondary bile acids.

The bile acids have a number of important actions: they reduce surface tension and, in conjunction with phospholipids and monoglycerides, are responsible for the emulsification of fat preparatory to its digestion and absorption in the small intestine (see Chapter 26). They are amphipathic, that is, they have both hydrophilic and hydrophobic domains; one surface of the molecule is hydrophilic because the polar peptide bond and the carboxyl and hydroxyl groups are on that surface, whereas the other surface is hydrophobic. Therefore, the bile acids tend to form cylindrical disks called micelles (Figure 25–15). Their hydrophilic portions face out and their hydrophobic portions face in. Above a certain concentration, called the critical micelle concentration, all bile salts added to a solution form micelles. Ninety to 95% of the bile acids are absorbed from the small intestine. Once they are deconjugated, they can be absorbed by nonionic diffusion, but most are absorbed in their conjugated forms from the terminal ileum (Figure 25–16) by an extremely efficient Na⁺–bile salt cotransport system (ABST) whose activity is secondarily driven by the low intracellular sodium concentration established by the basolateral Na⁺, K⁺ ATPase. The remaining 5–10% of the bile salts enter the colon and are converted to the salts of deoxycholic acid and lithocholic acid. Lithocholate is relatively insoluble and is mostly excreted in the stools; only 1% is absorbed. However, deoxycholate is absorbed.

The absorbed bile acids are transported back to the liver in the portal vein and reexcreted in the bile (enterohepatic circulation) (Figure 25–16). Those lost in the stool are replaced by synthesis in the liver; the normal rate of bile acid synthesis is 0.2–0.4 g/day. The total bile acid pool of approximately 3.5 g recycles repeatedly via the enterohepatic circulation; it has been calculated that the entire pool recycles twice per meal and 6–8 times per day.

INTESTINAL FLUID & ELECTROLYTE TRANSPORT

The intestine itself also supplies a fluid environment in which the processes of digestion and absorption can occur. Then, when the meal has been assimilated, fluid used during digestion and absorption is reclaimed by transport back across the epithelium to avoid dehydration. Water moves passively into and out of the gastrointestinal lumen, driven by electrochemical gradients established by the active transport of ions and other solutes. In the period after a meal, much of the fluid reuptake is driven by the coupled transport of nutrients, such as glucose, with sodium ions. In the period between meals, absorptive mechanisms center exclusively around electrolytes. In both cases, secretory fluxes of fluid are largely driven by the active transport of chloride ions into the lumen, although absorption still predominates overall.

Overall water balance in the gastrointestinal tract is summarized in Table 25–4. The intestines are presented each day with about 2000 mL of ingested fluid plus 7000 mL of secretions from the mucosa of the gastrointestinal tract and associated glands. Ninety-eight percent of this fluid is reabsorbed, with a daily fluid loss of only 200 mL in the stools.

In the small intestine, secondary active transport of Na⁺ is important in bringing about absorption of glucose, some amino acids, and other substances such as bile acids (see above). Conversely, the presence of glucose in the intestinal lumen facilitates the reabsorption of Na⁺. In the period between meals, when nutrients are not present, sodium and chloride are absorbed together from the lumen by the coupled activity of a sodium/hydrogen exchanger (NHE) and chloride/bicarbonate exchanger in the apical membrane, in a so-called electroneutral mechanism (Figure 25–17). Water then follows to maintain an osmotic balance. In the colon, moreover, an additional electrogenic mechanism for sodium absorption is expressed, particularly in the distal colon. In this mechanism, sodium enters across the apical membrane via an ENaC (epithelial sodium) channel that is identical to that expressed in the distal tubule of the kidney (Figure 25–18). This underpins the ability of the colon to desiccate the stool and ensure that only a small portion of the fluid load used daily in the digestion and absorption of meals is lost from the body. Following a low-salt diet, increased expression of ENaC in response to aldosterone increases the ability to reclaim sodium from the stool.

Despite the predominance of absorptive mechanisms, secretion also takes place continuously throughout the small intestine and colon to adjust the local fluidity of the intestinal contents as needed for mixing, diffusion, and movement of the meal and its residues along the length of the gastrointestinal tract. Cl⁻ normally enters enterocytes from the interstitial fluid via Na⁺–K⁺–2Cl⁻ cotransporters in their basolateral membranes (Figure 25–19), and the Cl⁻ is then secreted into the intestinal lumen via channels that are regulated by various protein kinases. The cystic fibrosis transmembrane conductance regulator (CFTR) channel that is defective in the disease of cystic fibrosis is quantitatively most important, and is activated by protein kinase A and hence by cAMP (Clinical Box 25–2).

Water moves into or out of the intestine until the osmotic pressure of the intestinal contents equals that of the plasma. The osmolality of the duodenal contents may be hypertonic or hypotonic, depending on the meal ingested, but by the time the meal enters the jejunum, its osmolality is close to that of plasma. This osmolality is maintained throughout the rest of the small intestine; the osmotically active particles produced by digestion are removed by absorption, and water moves passively out of the gut along the osmotic gradient thus generated. In the colon, Na⁺ is pumped out and water moves passively with it, again along the osmotic gradient. Saline cathartics such as magnesium sulfate are poorly absorbed salts that retain their osmotic equivalent of water in the intestine, thus increasing intestinal volume and consequently exerting a laxative effect.

Some K⁺ is secreted into the intestinal lumen, especially as a component of mucus. K⁺ channels are present in the luminal as well as the basolateral membrane of the enterocytes of the colon, so K⁺ is secreted into the colon. In addition, K⁺ moves passively down its electrochemical gradient. The accumulation of K⁺ in the colon is partially offset by H⁺–K⁺ ATPase in the luminal membrane of cells in the distal colon, with resulting active transport of K⁺ into the cells. Nevertheless, loss of ileal or colonic fluids in chronic diarrhea can lead to severe hypokalemia. When the dietary intake of K⁺ is high for a prolonged period, aldosterone secretion is increased and more K⁺ enters the colonic lumen. This is due in part to the appearance of more Na⁺, K⁺ ATPase pumps in the basolateral membranes of the cells, with a consequent increase in intracellular K⁺ and K⁺ diffusion across the luminal membranes of the cells.

The various functions of the gastrointestinal tract, including secretion, digestion, and absorption (Chapter 26), and motility (Chapter 27), must be regulated in an integrated way to ensure efficient assimilation of nutrients after a meal. There are three main modalities for gastrointestinal regulation that operate in a complementary fashion to ensure that function is appropriate. First, endocrine regulation is mediated by the release of hormones by triggers associated with the meal. These hormones travel through the bloodstream to change the activity of a distant segment of the gastrointestinal tract, an organ draining into it (eg, the pancreas), or both. Second, some similar mediators are not sufficiently stable to persist in the bloodstream, but instead alter the function of cells in the local area where they are released, in a paracrine fashion. Finally, the intestinal system is endowed with extensive neural connections. These include connections to the central nervous system (extrinsic innervation), but also the activity of a largely autonomous enteric nervous system that comprises both sensory and secretomotor neurons. The enteric nervous system integrates central input to the gut but can also regulate gut function independently in response to changes in the luminal environment. In some cases, the same substance can mediate regulation by endocrine, paracrine, and neurocrine pathways (eg, CCK, see below).

Biologically active polypeptides that are secreted by nerve cells and gland cells in the mucosa act in a paracrine fashion, but they also enter the circulation. Measurement of their concentrations in blood after a meal has shed light on the roles these gastrointestinal hormones play in the regulation of gastrointestinal secretion and motility.

When large doses of the hormones are given, their actions overlap. However, their physiologic effects appear to be relatively discrete. On the basis of structural similarity and, to a degree, similarity of function, the key hormones fall into one of two families: the gastrin family, the primary members of which are gastrin and CCK; and the secretin family, the primary members of which are secretin, glucagon, vasoactive intestinal peptide (VIP; actually a neurotransmitter, or neurocrine), and gastric inhibitory polypeptide (also known as glucose-dependent insulinotropic peptide, or GIP). There are also other hormones that do not fall readily into these families.

ENTEROENDOCRINE CELLS

More than 15 types of hormone-secreting enteroendocrine cells have been identified in the mucosa of the stomach, small intestine, and colon. Many of these secrete only one hormone and are identified by letters (G cells, S cells, etc). Others manufacture serotonin or histamine and are called enterochromaffin or ECL cells, respectively.

GASTRIN

Gastrin is produced by cells called G cells in the antral portion of the gastric mucosa (Figure 25–20). G cells are flask-shaped, with a broad base containing many gastrin granules and a narrow apex that reaches the mucosal surface. Microvilli project from the apical end into the lumen. Receptors mediating gastrin responses to changes in gastric contents are present on the microvilli. Other cells in the gastrointestinal tract that secrete hormones have a similar morphology.

The precursor for gastrin, preprogastrin, is processed into fragments of various sizes. Three main fragments contain 34, 17, and 14 amino acid residues. All have the same carboxyl terminal configuration (Table 25–5). These forms are also known as G 34, G 17, and G 14 gastrins, respectively. Another form is the carboxyl terminal tetrapeptide, and there is also a large form that is extended at the amino terminal and contains more than 45 amino acid residues. One form of derivatization is sulfation of the tyrosine that is the sixth amino acid residue from the carboxyl terminal. Approximately equal amounts of nonsulfated and sulfated forms are present in blood and tissues, and they are equally active. Another derivatization is amidation of the carboxyl terminal phenylalanine, which likely enhances the peptide’s stability in the plasma by rendering it resistant to carboxypeptidases.

Some differences in activity exist between the various gastrin peptides, and the proportions of the components also differ in the various tissues in which gastrin is found. This suggests that different forms are tailored for different actions. However, all that can be concluded at present is that G 17 is the principal form with respect to gastric acid secretion. The carboxyl terminal tetrapeptide has all the activities of gastrin but only 10% of the potency of G 17.

G 14 and G 17 have half-lives of 2–3 min in the circulation, whereas G 34 has a half-life of 15 min. Gastrins are inactivated primarily in the kidney and small intestine.

In large doses, gastrin has a variety of actions, but its principal physiologic actions are stimulation of gastric acid and pepsin secretion and stimulation of the growth of the mucosa of the stomach and small and large intestines (trophic action). Gastrin secretion is affected by the contents of the stomach, the rate of discharge of the vagus nerves, and bloodborne factors (Table 25–6). Atropine does not inhibit the gastrin response to a test meal in humans, because the transmitter secreted by the postganglionic vagal fibers that innervate the G cells is gastrin-releasing polypeptide (GRP; see below) rather than acetylcholine. Gastrin secretion is also increased by the presence of the products of protein digestion in the stomach, particularly amino acids, which act directly on the G cells. Phenylalanine and tryptophan are particularly effective. Gastrin acts via a receptor (CCK-B) that is related to the primary receptor (CCK-A) for cholecystokinin (see below). This likely reflects the structural similarity of the two hormones, and may result in some overlapping actions if excessive quantities of either hormone are present (eg, in the case of a gastrin-secreting tumor, or gastrinoma).

Acid in the antrum inhibits gastrin secretion, partly by a direct action on G cells and partly by release of somatostatin, a relatively potent inhibitor of gastrin secretion. The effect of acid is the basis of a negative feedback loop regulating gastrin secretion. Increased secretion of the hormone increases acid secretion, but the acid then feeds back to inhibit further gastrin secretion. In conditions such as pernicious anemia in which the acid-secreting cells of the stomach are damaged, gastrin secretion is chronically elevated.

CHOLECYSTOKININ

CCK is secreted by endocrine cells known as I cells in the mucosa of the upper small intestine. It has a plethora of actions in the gastrointestinal system, but the most important appear to be the stimulation of pancreatic enzyme secretion; the contraction of the gallbladder (the action for which it was named); and relaxation of the sphincter of Oddi, which allows both bile and pancreatic juice to flow into the intestinal lumen.

Like gastrin, CCK is produced from a larger precursor. Prepro-CCK is also processed into many fragments. A large CCK contains 58 amino acid residues (CCK 58). In addition, there are CCK peptides that contain 39 amino acid residues (CCK 39) and 33 amino acid residues (CCK 33), several forms that contain 12 (CCK 12) or slightly more amino acid residues, and a form that contains eight amino acid residues (CCK 8). All of these forms have the same five amino acids at the carboxyl terminal as gastrin (Table 25–5). The carboxyl terminal tetrapeptide (CCK 4) also exists in tissues. The carboxyl terminal is amidated, and the tyrosine that is the seventh amino acid residue from the carboxyl terminal is sulfated. Unlike gastrin, the nonsulfated form of CCK has not been found in tissues. The half-life of circulating CCK is about 5 min, but little is known about its metabolism.

In addition to its secretion by I cells, CCK is found in nerves in the distal ileum and colon. It is also found in neurons in the brain, especially the cerebral cortex, and in nerves in many parts of the body (see Chapter 7). In the brain, it may be involved in the regulation of food intake, and it appears to be related to the production of anxiety and analgesia.

In addition to its primary actions, CCK augments the action of secretin in producing secretion of an alkaline pancreatic juice. It also inhibits gastric emptying, exerts a trophic effect on the pancreas, increases the synthesis of enterokinase, and may enhance the motility of the small intestine and colon. There is some evidence that, along with secretin, it augments the contraction of the pyloric sphincter, thus preventing the reflux of duodenal contents into the stomach. Two CCK receptors have been identified. CCK-A receptors are primarily located in the periphery, whereas both CCK-A and CCK-B (gastrin) receptors are found in the brain. Both activate PLC, causing increased production of IP₃ and DAG (see Chapter 2).

The secretion of CCK is increased by contact of the intestinal mucosa with the products of digestion, particularly peptides and amino acids, and also by the presence in the duodenum of fatty acids containing more than 10 carbon atoms. There are also two protein releasing factors that activate CCK secretion, known as CCK-releasing peptide and monitor peptide, which derive from the intestinal mucosa and pancreas, respectively. Because the bile and pancreatic juice that enter the duodenum in response to CCK enhance the digestion of protein and fat, and the products of this digestion stimulate further CCK secretion, a sort of positive feedback operates in the control of CCK secretion. However, the positive feedback is terminated when the products of digestion move on to the lower portions of the gastrointestinal tract, and also because CCK-releasing peptide and monitor peptide are degraded by proteolytic enzymes once these are no longer occupied in digesting dietary proteins.

SECRETIN

Secretin occupies a unique position in the history of physiology. In 1902, Bayliss and Starling first demonstrated that the excitatory effect of duodenal stimulation on pancreatic secretion was due to a bloodborne factor. Their research led to the identification of the first hormone, secretin. They also suggested that many chemical agents might be secreted by cells in the body and pass in the circulation to affect organs some distance away. Starling introduced the term hormone to categorize such “chemical messengers.” Modern endocrinology is the proof of the correctness of this hypothesis.

Secretin is secreted by S cells that are located deep in the glands of the mucosa of the upper portion of the small intestine. The structure of secretin (Table 25–5) is different from that of CCK and gastrin, but very similar to that of GIP, glucagon, and VIP. Only one form of secretin has been isolated, and any fragments of the molecule that have been tested to date are inactive. Its half-life is about 5 min, but little is known about its metabolism.

Secretin increases the secretion of bicarbonate by the duct cells of the pancreas and biliary tract. It thus causes the secretion of a watery, alkaline pancreatic juice. Its action on pancreatic duct cells is mediated via cAMP. It also augments the action of CCK in producing pancreatic secretion of digestive enzymes. It decreases gastric acid secretion and may cause contraction of the pyloric sphincter.

The secretion of secretin is increased by the products of protein digestion and by acid bathing the mucosa of the upper small intestine. The release of secretin by acid is another example of feedback control: Secretin causes alkaline pancreatic juice to flood into the duodenum, neutralizing the acid from the stomach and thus inhibiting further secretion of the hormone.

GIP

GIP contains 42 amino acid residues and is produced by K cells in the mucosa of the duodenum and jejunum. Its secretion is stimulated by glucose and fat in the duodenum, and because in large doses it inhibits gastric secretion and motility, it was named gastric inhibitory peptide. However, it now appears that it does not have significant gastric inhibiting activity when administered in smaller amounts comparable to those seen after a meal. In the meantime, it was found that GIP stimulates insulin secretion. Gastrin, CCK, secretin, and glucagon also have this effect, but GIP is the only one of these that stimulates insulin secretion when administered at blood levels comparable to those produced by oral glucose. For this reason, it is often called glucose-dependent insulinotropic peptide. The glucagon derivative GLP-1 (7–36) (see Chapter 24) also stimulates insulin secretion and is said to be more potent in this regard than GIP. Therefore, it may also be a physiologic B cell–stimulating hormone of the gastrointestinal tract.

The integrated action of gastrin, CCK, secretin, and GIP in facilitating digestion and utilization of absorbed nutrients is summarized in Figure 25–21.

VIP

VIP contains 28 amino acid residues (Table 25–5). It is found in nerves in the gastrointestinal tract and thus is not itself a hormone, despite its similarities to secretin. VIP is, however, found in blood, in which it has a half-life of about 2 min. In the intestine, it markedly stimulates intestinal secretion of electrolytes and hence of water. Its other actions include relaxation of intestinal smooth muscle, including sphincters; dilation of peripheral blood vessels; and inhibition of gastric acid secretion. It is also found in the brain and many autonomic nerves (see Chapter 7), where it often occurs in the same neurons as acetylcholine. It potentiates the action of acetylcholine in salivary glands. However, VIP and acetylcholine do not coexist in neurons that innervate other parts of the gastrointestinal tract. VIP-secreting tumors (VIPomas) have been described in patients with severe diarrhea.

MOTILIN

Motilin is a polypeptide containing 22 amino acid residues that is secreted by enterochromaffin cells and Mo cells in the stomach, small intestine, and colon. It acts on G-protein–coupled receptors on enteric neurons in the duodenum and colon and produces contraction of smooth muscle in the stomach and intestines in the period between meals (see Chapter 27).

SOMATOSTATIN

Somatostatin, the growth hormone–inhibiting hormone originally isolated from the hypothalamus, is secreted as a paracrine by D cells in the pancreatic islets (see Chapter 24) and by similar D cells in the gastrointestinal mucosa. It exists in tissues in two forms, somatostatin 14 and somatostatin 28, and both are secreted. Somatostatin inhibits the secretion of gastrin, VIP, GIP, secretin, and motilin. Its secretion is stimulated by acid in the lumen, and it probably acts in a paracrine fashion to mediate the inhibition of gastrin secretion produced by acid. It also inhibits pancreatic exocrine secretion; gastric acid secretion and motility; gallbladder contraction; and the absorption of glucose, amino acids, and triglycerides.

OTHER GASTROINTESTINAL PEPTIDES

Peptide YY

The structure of peptide YY is discussed in Chapter 24. It also inhibits gastric acid secretion and motility and is a good candidate to be the gastric inhibitory peptide (Figure 25–21). Its release from the jejunum is stimulated by fat.

Others

Ghrelin is secreted primarily by the stomach and appears to play an important role in the central control of food intake (see Chapter 26). It also stimulates growth hormone secretion by acting directly on receptors in the pituitary (see Chapter 18).

Substance P (Table 25–5) is found in endocrine and nerve cells in the gastrointestinal tract and may enter the circulation. It increases the motility of the small intestine. The neurotransmitter GRP contains 27 amino acid residues, and the 10 amino acid residues at its carboxyl terminal are almost identical to those of amphibian bombesin. It is present in the vagal nerve endings that terminate on G cells and is the neurotransmitter producing vagally mediated increases in gastrin secretion. Glucagon from the gastrointestinal tract may be responsible (at least in part) for the hyperglycemia seen after pancreatectomy.

Guanylin is a gastrointestinal polypeptide that binds to guanylyl cyclase. It is made up of 15 amino acid residues (Table 25–5) and is secreted by cells of the intestinal mucosa. Stimulation of guanylyl cyclase increases the concentration of intracellular cyclic 3′,5′-guanosine monophosphate (cGMP), and this in turn causes increased secretion of Cl⁻ into the intestinal lumen. Guanylin appears to act predominantly in a paracrine fashion, and it is produced in cells from the pylorus to the rectum. In an interesting example of molecular mimicry, the heat-stable enterotoxin of certain diarrhea-producing strains of Escherichia coli has a structure very similar to guanylin and activates guanylin receptors in the intestine. Guanylin receptors are also found in the kidneys, the liver, and the female reproductive tract, and guanylin may act in an endocrine fashion to regulate fluid movement in these tissues as well, and particularly to integrate the actions of the intestine and kidneys.

Two major networks of nerve fibers are intrinsic to the gastrointestinal tract: the myenteric plexus (Auerbach plexus), between the outer longitudinal and middle circular muscle layers, and the submucous plexus (Meissner plexus), between the middle circular layer and the mucosa (Figure 25–1). Collectively, these neurons constitute the enteric nervous system. The system contains about 100 million sensory neurons, interneurons, and motor neurons in humans—as many as are found in the whole spinal cord—and the system is probably best viewed as a displaced part of the central nervous system (CNS) that is concerned with the regulation of gastrointestinal function. It is sometimes referred to as the “little brain” for this reason. It is connected to the CNS by parasympathetic and sympathetic fibers but can function autonomously without these connections (see below). The myenteric plexus innervates the longitudinal and circular smooth muscle layers and is concerned primarily with motor control, whereas the submucous plexus innervates the glandular epithelium, intestinal endocrine cells, and submucosal blood vessels and is primarily involved in the control of intestinal secretion. The neurotransmitters in the system include acetylcholine, the amines norepinephrine and serotonin, the amino acid γ-aminobutyrate (GABA), the purine adenosine triphosphate (ATP), the gases NO and CO, and many different peptides and polypeptides. Some of these peptides also act in a paracrine fashion, and some enter the bloodstream, becoming hormones. Not surprisingly, most of them are also found in the brain.

EXTRINSIC INNERVATION

The intestine receives a dual extrinsic innervation from the autonomic nervous system, with parasympathetic cholinergic activity generally increasing the activity of intestinal smooth muscle and sympathetic noradrenergic activity generally decreasing it while causing sphincters to contract. The preganglionic parasympathetic fibers consist of about 2000 vagal efferents and other efferents in the sacral nerves. They generally end on cholinergic nerve cells of the myenteric and submucous plexuses. The sympathetic fibers are postganglionic, but many of them end on postganglionic cholinergic neurons, where the norepinephrine they secrete inhibits acetylcholine secretion by activating α₂ presynaptic receptors. Other sympathetic fibers appear to end directly on intestinal smooth muscle cells. The electrical properties of intestinal smooth muscle are discussed in Chapter 5. Still other fibers innervate blood vessels, where they produce vasoconstriction. It appears that the intestinal blood vessels have a dual innervation: they have an extrinsic noradrenergic innervation and an intrinsic innervation by fibers of the enteric nervous system. VIP and NO are among the mediators in the intrinsic innervation, which seems, among other things, to be responsible for the increase in local blood flow (hyperemia) that accompanies digestion of food. It is unsettled whether the blood vessels have an additional cholinergic innervation.

The mucosal immune system was mentioned in Chapter 3, but it bears repeating here that the continuity of the intestinal lumen with the outside world also makes the gastrointestinal system an important portal for infection. Similarly, the intestine benefits from interactions with a complex community of commensal (ie, nonpathogenic) bacteria that provide beneficial metabolic functions as well as likely increasing resistance to pathogens. In the face of this constant microbial stimulation, it is not surprising that the intestine of mammals has developed a sophisticated set of both innate and adaptive immune mechanisms to distinguish friend from foe. Indeed, the intestinal mucosa contains more lymphocytes than are found in the circulation, as well as large numbers of inflammatory cells that are placed to rapidly defend the mucosa if epithelial defenses are breached. It is likely that immune cells, and their products, also impact the physiologic function of the epithelium, endocrine cells, nerves and smooth muscle, particularly at times of infection and if inappropriate immune responses are perpetuated, such as in inflammatory bowel diseases (see Chapter 3).

A final general point that should be made about the gastrointestinal tract relates to its unusual circulatory features. The blood flow to the stomach, intestines, pancreas, and liver is arranged in a series of parallel circuits, with all the blood from the intestines and pancreas draining via the portal vein to the liver (Figure 25–22). The blood from the intestines, pancreas, and spleen drains via the hepatic portal vein to the liver and from the liver via the hepatic veins to the inferior vena cava. The viscera and the liver receive about 30% of the cardiac output via the celiac, superior mesenteric, and inferior mesenteric arteries. The liver receives about 1300 mL/min from the portal vein and 500 mL/min from the hepatic artery during fasting, and the portal supply increases still further after meals.

• The gastrointestinal system evolved as a portal to permit controlled nutrient uptake in multicellular organisms. It is functionally continuous with the outside environment.

• Digestive secretions serve to chemically alter the components of meals (particularly macromolecules) such that their constituents can be absorbed across the epithelium. Meal components are acted on sequentially by saliva, gastric juice, pancreatic juice, and bile, which contain enzymes, ions, water, and other specialized components.

• The intestine and the organs that drain into it secrete about 8 L of fluid per day, which is added to water consumed in food and beverages. Most of this fluid is reabsorbed, leaving only approximately 200 mL to be lost to the stool. Fluid secretion and absorption are both dependent on the active epithelial transport of ions, nutrients, or both.

• Gastrointestinal functions are regulated in an integrated fashion by endocrine, paracrine, and neurocrine mechanisms. Hormones and paracrine factors are released from enteroendocrine cells in response to signals coincident with the intake of meals.

• The enteric nervous system conveys information from the central nervous system to the gastrointestinal tract, but also often can activate programmed responses of secretion and motility in an autonomous fashion.

• The intestine harbors an extensive mucosal immune system that regulates responses to the complex microbiota normally resident in the lumen, as well as defending the body against invasion by pathogens.

• The intestine has an unusual circulation, in that the majority of its venous outflow does not return directly to the heart, but rather is directed initially to the liver via the portal vein.