Physiology_Levy

Physiology_Levy. Gastroesophageal reflux disease (GERD) is commonly referred to as heartburn or indigestion. It occurs when the lower esophageal sphincter allows the acidic contents of the stomach to reflux back into the distal part of the esophagus. This region of the esophagus, unlike the stomach, does not have a robust system to protect the mucosal lining. Thus the acid will activate pain fibers and thereby result in discomfort and pain. This is not an uncommon phenomenon, even in healthy individuals. In the long term, continual reflux can result in damage to the esophageal mucosa. In this case, this condition is classed as GERD and can be treated by H2 receptor antagonists that reduce gastric acid secretion (e.g., ranitidine [Zantac]) or by proton pump inhibitors (e.g., omeprazole [Prilosec]). The esophagus, the UES, and the lower esophageal sphincter (LES) serve two main functions (


Physiology_Levy

Physiology_Levy. The esophagus, the UES, and the lower esophageal sphincter (LES) serve two main functions ( Fig. 28.6 ). First, they propel food from the mouth to the stomach. Second, the sphincters protect the airway during swallowing and protect the esophagus from acidic gastric secretions.


Physiology_Levy

Physiology_Levy. The stimuli that initiate the changes in smooth muscle activity that result in these propulsive and protective functions are mechanical and consist of pharyngeal stimulation during swallowing and distention of the esophageal wall itself. The pathways are exclusively neural and involve both extrinsic and intrinsic reflexes. Mechanosensitive afferents in both the extrinsic (vagus) nerves and intrinsic neural pathways respond to esophageal distention. These pathways include activated reflex pathways via the brain-stem (extrinsic, vagus) or solely intrinsic pathways. The striated muscle is regulated from the nucleus ambiguus in the brainstem, and the smooth muscle is regulated by parasympathetic outflow via the vagus nerve. The changes in function resulting from mechanosensitive stimuli and activation of reflex pathways are peristalsis of striated and smooth muscle, relaxation of the LES, and relaxation of the proximal portion of the stomach.


Physiology_Levy

Physiology_Levy. Functional Anatomy of the Esophagus and Associated Structures The esophagus, like the rest of the GI tract, has two muscle layers—circular and longitudinal—but the esophagus is one of two places in the gut where striated muscle occurs, the other being the external anal sphincter. The type of muscle (striated or smooth) in the esophagus varies along its length. The UES and LES are formed by thickening of striated or circular smooth muscle, respectively. Motor Activity During the Esophageal Phase The UES, esophagus, and LES act in a coordinated manner to propel material from the pharynx to the stomach. At the end of a swallow, a bolus passes through the UES, and the presence of the bolus, via stimulation of mechanoreceptors and reflex pathways, initiates a peristaltic wave (alternating contraction and relaxation of the muscle) along the esophagus that is called primary peristalsis (


Physiology_Levy

Physiology_Levy. Fig. 28.7 ). This wave moves down the esophagus slowly (3–5 cm/s). Distention of the esophagus by the moving bolus initiates another • Fig.28.6The esophagus and associated sphincters have multiple functions involved in movement of food from the mouth to the stomach and also in protection of the airway and esophagus. PropulsivefunctionsProtectiveeffectsFood transfer to esophagus Allows entry of food into esophagus Transports bolus from pharynx to stomach Allows entry of food into stomach Protects airway from swallowed material Protects airway from gastric reflux Clears material refluxed from stomach Protects esophagus from gastric reflux LES Esophagus UES Pharynx


Physiology_Levy

Physiology_Levy. CHAPTER 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal • Fig. 28.7 Changes in pressure in the different regions of the pharynx, esophagus, and associated sphincters initiated during a swallow. The pressure trace is a diagrammatic representation from that obtained during manometry in an awake human. Stimulation of the pharynx by the presence of a bolus initiates a decrease in pressure (= opening) of the UES and a peristaltic wave of contraction along the esophagus. Stimulation of the pharynx also relaxes the smooth muscle of the LES to prepare for entry of food. • Fig. 28.8 Swallowing in the form of pharyngeal stimulation induces neural reflex relaxation of the LES and the proximal part of the stomach to allow entry of food.


Physiology_Levy

Physiology_Levy. • Fig. 28.8 Swallowing in the form of pharyngeal stimulation induces neural reflex relaxation of the LES and the proximal part of the stomach to allow entry of food. wave called secondary peristalsis. Frequently, repetitive secondary peristalsis is required to clear the esophagus of the bolus. Stimulation of the pharynx by the swallowed bolus also produces reflex relaxation of the LES and the most proximal region of the stomach. Thus when the bolus reaches the LES, it is already relaxed to allow passage of the bolus into the stomach. Similarly the portion of the stomach that receives the bolus is relaxed. In addition, esophageal distention produces further receptive relaxation of the stomach. The proximal part of the stomach relaxes at the same time as the LES; this occurs with each swallow, and its function is to allow the stomach to accommodate large volumes with a minimal rise in intragastric pressure. This process is called receptive relaxation ( Fig. 28.8


Physiology_Levy

Physiology_Levy. Fig. 28.8 The LES also has important protective functions. It is involved in preventing acid reflux from the stomach back into the esophagus. An insufficient tonic contraction of the LES is associated with reflux disease, a gradual erosion of the esophageal mucosa, which is not as well protected as the gastric and duodenal mucosa. There is also some evidence that peristalsis in the absence of swallowing (secondary peristalsis) is important for clearing refluxed gastric contents. 1. The cephalic and oral phases of the meal share many characteristics and prepare the remainder of the GI tract for the meal; these responses are neurally mediated, predominantly by the efferent vagus nerve. 2. Salivary secretion has important functions and, together with chewing of the food, allows the formation of a bolus that can be swallowed and passed along the esophagus to the stomach. 3.


Physiology_Levy

Physiology_Levy. 2. Salivary secretion has important functions and, together with chewing of the food, allows the formation of a bolus that can be swallowed and passed along the esophagus to the stomach. 3. The ionic composition of salivary secretion varies with the flow rate, which is stimulated during a meal. The primary secretion comes from cells in the acini and is modified by epithelial cells as it passes through the ducts. 4. Regulation of salivary secretion is exclusively neural; parasympathetic innervation is most important in the response to food. Catalan MA, et al. Salivary gland secretion. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. 5. The swallowing reflex is a rigidly ordered sequence of events that propel food from the mouth to the pharynx and from there to the stomach. 6.


Physiology_Levy

Physiology_Levy. 5. The swallowing reflex is a rigidly ordered sequence of events that propel food from the mouth to the pharynx and from there to the stomach. 6. The major function of the esophagus is to propel food from the mouth to the stomach. The esophagus has sphincters at either end that are involved in protective functions important in swallowing and preserving the integrity of the esophageal mucosa. 7. Esophageal peristalsis (primary) is stimulated by mechanical stimulation of the pharynx, and secondary peristalsis is stimulated by distention of the esophageal wall. 8. Esophageal function and the associated sphincters are regulated by extrinsic and intrinsic neural pathways. Lee MG, et al. Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev. 2012;92:39-74. Mittal RK. Motor Function of the Pharynx, Esophagus, and its Sphincters. San Rafael, CA: Morgan & Claypool Life Sciences; 2011.


Physiology_Levy

Physiology_Levy. Mittal RK. Motor Function of the Pharynx, Esophagus, and its Sphincters. San Rafael, CA: Morgan & Claypool Life Sciences; 2011. Upon completion of this chapter the student should be able to answer the following questions: 1. What are the major functions of the monogastric stomach? 2. What are the gross functional regions of the stomach? 3. What is the role of the gastric epithelium in digestion and absorption? 4. What is the role of the proton pump in parietal cell function? 5. What are some examples of how gastric acid secretion is regulated during the postprandial period? 6. What are the differences between gastric mucosal protection and defense? 7. What are the components of the functional anatomy of GI smooth muscle? 8. What is the significance of gap junctions, interstitial cells of Cajal, and pacemaker cells in the functioning of GI smooth muscle? 9.


Physiology_Levy

Physiology_Levy. 8. What is the significance of gap junctions, interstitial cells of Cajal, and pacemaker cells in the functioning of GI smooth muscle? 9. How is the basic electrical rhythm (slow wave) generated, how is it regulated by chemical messengers (hormones, paracrine, neurotransmitters), and what causes contractions associated with the slow wave to occur? 10. What physiological events in gastric motility occur in the gastric phase? n this chapter, gastrointestinal (GI) tract physiology when food is in the stomach (i.e., the gastric phase of digestion) will be discussed. This includes gastric function and its regulation, in addition to changes in function that occur in more distal regions of the GI tract. The main functions of the stomach are to act as a temporary reservoir for the meal and to initiate protein digestion through secretion of acid and the enzyme precursor pepsinogen. Other functions are listed in Box 29.1


Physiology_Levy

Physiology_Levy. Box 29.1 Food entering the stomach from the esophagus causes mechanical stimulation of the gastric wall via distention and stretching of smooth muscle. Food—predominantly oligopeptides and amino acids—also provides chemical stimulation when present in the gastric lumen. Regulation of gastric function during the gastric phase is dependent on endocrine, paracrine, and neural pathways. These pathways are activated by mechanical and chemical stimuli, which result in intrinsic and extrinsic neural reflex pathways that are important for regulation of gastric function. Afferent neurons that pass from the GI tract to the central nervous system (and to a lesser extent to the spinal cord) via the vagus nerve respond to these mechanical and chemical stimuli and activate parasympathetic outflow.


Physiology_Levy

Physiology_Levy. The endocrine pathways include the release of gastrin, which stimulates gastric acid secretion, and the release of somatostatin, which inhibits gastric secretion. Important paracrine pathways include histamine release, which stimulates gastric acid secretion. The responses elicited by activation of these pathways include both secretory and motor responses; secretory responses include secretion of acid, pepsinogen, mucus, intrinsic factor, gastrin, lipase, and HCO3 − . Overall these secretions initiate protein digestion and protect the gastric mucosa. Motor responses (changes in activity of smooth muscle) include inhibition of motility of the proximal part of the stomach (receptive relaxation) and stimulation of motility of the distal part of the stomach, which causes antral peristalsis. These changes in motility play important roles in storage and mixing of the meal with secretions and are also involved in regulating the flow of contents out of the stomach.


Physiology_Levy

Physiology_Levy. Functional Anatomy of the Stomach The stomach is divided into three regions: the cardia, the corpus (also referred to as the fundus or body), and the antrum ( Fig. 29.1 ). However, when discussing the physiology of the stomach, it is helpful to think of it as subdivided into two functional regions: the proximal and distal parts of the stomach. The proximal portion of the stomach (called proximal because it is the most cranial) and the distal portion of the stomach (furthest away from the mouth) have quite different functions in the postprandial response to a meal, which will be discussed later. The lining of the stomach is covered with a columnar epithelium folded into gastric pits; each pit is the opening of a duct into which one or more gastric glands empty (Fig.


Physiology_Levy

Physiology_Levy. The lining of the stomach is covered with a columnar epithelium folded into gastric pits; each pit is the opening of a duct into which one or more gastric glands empty (Fig. 29.2 ). The gastric pits account for a significant fraction of the total surface area of the gastric mucosa. The gastric mucosa is divided into three distinct regions based on the structure of the glands. The small cardiac glandular region, located just below the lower esophageal sphincter (LES), primarily contains mucus-secreting gland cells. The remainder of the gastric mucosa is divided into the oxyntic or parietal (acid-secreting) gland region, located above the gastric notch (equivalent to the proximal part of the stomach), and the pyloric gland region, located below the notch (equivalent to the distal part of the stomach). The structure of a gastric gland from the oxyntic glandular region is illustrated in


Physiology_Levy

Physiology_Levy. The structure of a gastric gland from the oxyntic glandular region is illustrated in Fig. 29.2 . Surface epithelial cells extend slightly into the duct opening. The opening of the gland is called the isthmus and is lined with surface mucous cells and a few parietal cells. Mucous neck cells are located in the narrow neck of the gland. Parietal or oxyntic cells, which secrete HCl and intrinsic factor (involved in absorption of vitamin B12), and chief or peptic cells, which secrete pepsinogens, are located deeper in the gland. Oxyntic glands also contain enterochromaffin-like (ECL) cells that secrete histamine, and D cells that secrete somatostatin. Parietal cells are particularly numerous in glands in the fundus, whereas mucus-secreting cells are more numerous in glands •BOX 29.1FunctionsoftheStomach Storage—acts as temporary reservoir for the meal Secretion of H+ to kill microorganisms and convert pepsinogen to its active form


Physiology_Levy

Physiology_Levy. Storage—acts as temporary reservoir for the meal Secretion of H+ to kill microorganisms and convert pepsinogen to its active form Secretion of intrinsic factor to absorb vitamin B12 (cobalamin) Secretion of mucus and HCO3 − to protect the gastric mucosa Secretion of water for lubrication and to provide aqueous suspension of nutrients Motor activity for mixing secretions (H+ and pepsin) with ingested food Coordinated motor activity to regulate the emptying of contents into the duodenum of the pyloric (antral) glandular region. In addition the pyloric glands contain G cells that secrete the hormone gastrin. The parietal glands are also divided into regions: the neck (mucous neck cells and parietal cells) and the base (peptic/chief and parietal cells). Endocrine cells are scattered throughout the glands.


Physiology_Levy

Physiology_Levy. The fluid secreted into the stomach is called gastric juice. Gastric juice is a mixture of the secretions of the surface epithelial cells and the secretions of gastric glands. One of the most important components of gastric juice is H+, which is secreted against a very large concentration gradient. Thus H+ secretion by the parietal mucosa is an energy-intensive process. The cytoplasm of the parietal cell is densely packed with mitochondria, which have been estimated to fill 30% to 40% of the cell’s volume. One major function of H+ is conversion of inactive pepsinogen (the major enzyme product of the stomach) to pepsins, which initiate protein digestion in the stomach. Additionally, H+ ions are important for preventing invasion and colonization of the gut by bacteria and other pathogens that may be ingested with food. The stomach also secretes significant amounts of HCO3 − and mucus, which are important for protection of the gastric mucosa against the acidic and peptic luminal


Physiology_Levy

Physiology_Levy. that may be ingested with food. The stomach also secretes significant amounts of HCO3 − and mucus, which are important for protection of the gastric mucosa against the acidic and peptic luminal environment. The gastric epithelium also secretes intrinsic factor, which is necessary for absorption of vitamin B12 (cobalamin). The functions of other components of gastric juice are redundant with secretions provided more distally in the GI tract.


Physiology_Levy

Physiology_Levy. Composition of Gastric Secretions Like other GI secretions, gastric juice consists of inorganic and organic constituents together with water. Among the important components of gastric juice are HCl, salts, • Fig.29.1The three functional regions of the stomach. The regions have different luminal secretions and patterns of smooth muscle activity indicative of their unique functions in response to food. CHAPTER 29 The Gastric Phase of the Integrated Response to a Meal 531 Opening of gastric pit Opening of gastric pit • Fig. 29.2 Representation of the structure of the gastric mucosa showing a section through the wall of the stomach (A) and detail of the structure of gastric glands and cell types in the mucosa (B). pepsins, intrinsic factor, mucus, and HCO3 − . Secretion of all these components increases after a meal. Inorganic Constituents of Gastric Juice


Physiology_Levy

Physiology_Levy. pepsins, intrinsic factor, mucus, and HCO3 − . Secretion of all these components increases after a meal. Inorganic Constituents of Gastric Juice The ionic composition of gastric juice depends on the rate of secretion. The higher the secretory rate, the higher the concentration of H+ ions. At lower secretory rates, [H+] decreases and [Na+] increases. [K+] is always higher in gastric juice than in plasma. Consequently, prolonged vomiting may lead to hypokalemia. At all rates of secretion, Cl− is the major anion of gastric juice. Gastric HCl converts pepsinogens to active pepsins and provides the acid pH at which pepsins are active.


Physiology_Levy

Physiology_Levy. The rate of gastric H+ secretion varies considerably among individuals. In humans, basal (unstimulated) rates of gastric H+ production typically range from about 1 to 5 mEq/hr. During maximal stimulation, HCl production rises to 6 to 40 mEq/hr. The basal rate is greater at night and lowest in the early morning. The total number of parietal cells in the stomach of normal individuals varies greatly, and this variation is partly responsible for the wide range in basal and stimulated rates of HCl secretion. Organic Constituents of Gastric Juice The predominant organic constituent of gastric juice is pepsinogen, the inactive proenzyme of pepsin. Pepsins, often collectively called “pepsin,” are a group of proteases secreted by the chief cells of the gastric glands. Pepsinogens are contained in membrane-bound zymogen granules in the chief cells. Zymogen granules release their contents by exocytosis when chief cells are stimulated to secrete 29.1 Response to a Meal


Physiology_Levy

Physiology_Levy. Table 29.1 ). Pepsinogens are converted to active pepsins by the cleavage of acid-labile linkages. The lower the pH, the more rapid the conversion. Pepsins also act proteolytically on pepsinogens to form more pepsin. Pepsins are most proteolytically active at pH 3 and below. Pepsins may digest as much as 20% of the protein in a typical meal but are not required for digestion, because their function can be replaced by that of pancreatic proteases. When the pH of the duodenal lumen is neutralized, pepsins are inactivated by the neutral pH. Intrinsic factor, a glycoprotein secreted by parietal cells of the stomach, is required for normal absorption of vitamin B12. Intrinsic factor is released in response to the same stimuli that elicit secretion of HCl by parietal cells. Cellular Mechanisms of Gastric Acid Secretion Fig. 29.3 ). Branching secretory canaliculi course through the cytoplasm • Fig. 29.3


Physiology_Levy

Physiology_Levy. Cellular Mechanisms of Gastric Acid Secretion Fig. 29.3 ). Branching secretory canaliculi course through the cytoplasm • Fig. 29.3 Parietal cell ultrastructure. A, A resting parietal cell showing the tubulovesicular apparatus in the cytoplasm and the intracellular canaliculus. B, An activated parietal cell that is secreting acid. The tubulovesicles have fused with the membranes of the intracellular canaliculus, which is now open to the lumen of the gland and lined with abundant long microvilli. • Fig. 29.4 Mechanism of H+ and Cl− secretion by an activated parietal cell in the gastric mucosa. ATP, adenosine triphosphate.


Physiology_Levy

Physiology_Levy. • Fig. 29.4 Mechanism of H+ and Cl− secretion by an activated parietal cell in the gastric mucosa. ATP, adenosine triphosphate. and are connected by a common outlet to the cell’s luminal surface. Microvilli line the surfaces of the secretory canaliculi. The cytoplasm of unstimulated parietal cells contains numerous tubules and vesicles called the tubulovesicular system. The membranes of tubulovesicles contain the transport proteins responsible for secretion of H+ and Cl− into the lumen of the gland. When parietal cells are stimulated to secrete HCl (see


Physiology_Levy

Physiology_Levy. Fig. 29.3 ), tubulovesicular membranes fuse with the plasma membrane of the secretory canaliculi. This extensive membrane fusion greatly increases the number of H+/K+ antiporters in the plasma membrane of the secretory canaliculi. When parietal cells secrete gastric acid at the maximal rate, H+ is pumped against a concentration gradient that is about 1 million–fold. Thus the pH is 7 in the parietal cell cytosol and 1 in the lumen of the gastric gland. The cellular mechanism of H+ secretion by the parietal cell is depicted in


Physiology_Levy

Physiology_Levy. The cellular mechanism of H+ secretion by the parietal cell is depicted in Fig. 29.4 . Cl− enters the cell across the basolateral membrane in exchange for HCO3 − generated in the cell by the action of carbonic anhydrase, which produces HCO3 − and H+ . H+ is secreted across the luminal membrane by H+,K+-ATPase in exchange for K+ . K+ recycles across the luminal membrane via a K+ channel. Cl− enters the lumen via an ion channel (a CLC family Cl− channel) located in the luminal membrane. Increased intracellular Ca++ and cyclic adenosine monophosphate (cAMP) stimulate luminal membrane conduction of Cl− and K+ . Increased K+ conductance hyperpolarizes the luminal membrane


Physiology_Levy

Physiology_Levy. CHAPTER 29 The Gastric Phase of the Integrated Response to a Meal 533 potential, which increases the driving force for efflux of Cl− across the luminal membrane. The K+ channel in the basolateral membrane also mediates the efflux of K+ that accumulates in the parietal cell via the activity of H+,K+-ATPase. In addition, cAMP and Ca++ promote trafficking of Cl− channels into the luminal membrane, as well as fusion of cytosolic tubulovesicles containing H+,K+-ATPase with the membrane of the secretory canaliculi (see Figs. 29.3 29.4 ). Parietal cell secretion of H+ is also accompanied by transport of HCO3 − into the bloodstream to maintain intracellular pH. Secretion of HCO3 −


Physiology_Levy

Physiology_Levy. Figs. 29.3 29.4 ). Parietal cell secretion of H+ is also accompanied by transport of HCO3 − into the bloodstream to maintain intracellular pH. Secretion of HCO3 − The surface epithelial cells also secrete a watery fluid that contains Na+ and Cl− in concentrations similar to those in plasma but with higher K+ and HCO3 − concentrations. HCO3 − is entrapped by the viscous mucus that coats the surface of the stomach; thus the mucus secreted by the resting mucosa lines the stomach with a sticky alkaline coat. When food is eaten, rates of secretion of both mucus and HCO3 − increase. Secretion of Mucus Secretions that contain mucins are viscous and sticky and are collectively termed mucus. Mucins are secreted by mucous neck cells located in the necks of gastric glands and by the surface epithelial cells of the stomach. Mucus is stored in large granules in the apical cytoplasm of mucous neck cells and surface epithelial cells and is released by exocytosis.


Physiology_Levy

Physiology_Levy. Gastric mucins are about 80% carbohydrate by weight and consist of four similar monomers of about 500,000 Da each that are linked together by disulfide bonds (Fig. 29.5 These tetrameric mucins form a sticky gel that adheres to the surface of the stomach. This gel is subject to proteolysis by pepsins that cleave disulfide bonds near the center of the tetramers. Proteolysis releases fragments that do not form gels and thus dissolves the protective mucous layer. Maintenance of the protective mucous layer requires continuous synthesis of new tetrameric mucins to replace the mucins cleaved by pepsins. Mucus is secreted at a significant rate in the resting stomach. Secretion of mucus is stimulated by some of the same stimuli that enhance acid and pepsinogen secretion, especially acetylcholine released from parasympathetic nerve endings near the gastric glands. If the gastric mucosa is mechanically deformed, neural reflexes are evoked to enhance mucus secretion.


Physiology_Levy

Physiology_Levy. Regulation of Gastric Secretion Parasympathetic innervation via the vagus nerve is the strongest stimulant of gastric H+ secretion. Extrinsic efferent fibers terminate on intrinsic neurons that innervate parietal cells, ECL cells that secrete the paracrine mediator histamine, and endocrine cells that secrete the hormone gastrin. In addition, vagal stimulation results in secretion of pepsinogen, mucus, HCO3 − , and intrinsic factor. Stimulation of the parasympathetic nervous system also occurs during the cephalic and oral phase of the meal. However, the gastric phase produces the largest stimulation of gastric secretion of the postprandial period ( Fig. 29.6 Stimulation of gastric acid secretion is an excellent example of a “feed-forward” (or cascade) response that uses endocrine, paracrine, and neural pathways. Activation of intrinsic neurons by vagal efferent activity results in release


Physiology_Levy

Physiology_Levy. Protein core: protected from further proteolysisGlycosylated part of by carbohydrate chains peptide cores (resistant to Sheath of branched proteolysis) carbohydrate chains with average of 15 Nonglycosylated part of sugars per chain peptide cores with disulfide bridges joining subunits (site of proteolysis) • Fig.29.5Schematic representation of the structure of gastric mucins before and after hydrolysis by pepsin. Intact mucins are tetramers of four similar monomers of about 500,000 Da. Each monomer is largely covered by carbohydrate side chains that protect it from proteolytic degradation. The central portion of the mucin tetramer, near the disulfide cross-links, is more susceptible to proteolytic digestion. Pepsins cleave bonds near the center of the tetramers to release fragments about the size of monomers.


Physiology_Levy

Physiology_Levy. • Fig.29.6Neural regulation of gastric acid secretion in the gastric phase of the meal is mediated by the vagus nerve. The stimulation that occurs in the cephalic and oral phases (before food reaches the stomach) results in stimulation of parietal cells to secrete acid and chief cells to secrete pepsinogen. Thus when food reaches the stomach, protein digestion is initiated by generating protein hydrolysate, which further stimulates secretion of gastrin from the mucosa of the gastric antrum. In addition, gastric distention activates a vagovagal reflex that further stimulates gastric acid and pepsinogen secretion. ˜ H+ ˜ Pepsinogen Endocrine (gastrin) Oligopeptides Protein Pepsin Pepsin pH 2.0 Pepsinogen ˜ H+ ˜ Pepsinogen ˜ Gastrin • Intrinsic neural pathways are also activated by distention Distention Dorsal vagal complex Neural (vagovagal) of acetylcholine from nerve terminals, which activates cells in the gastric epithelium. Parietal cells express muscarinic receptors and are


Physiology_Levy

Physiology_Levy. Distention Dorsal vagal complex Neural (vagovagal) of acetylcholine from nerve terminals, which activates cells in the gastric epithelium. Parietal cells express muscarinic receptors and are activated to secrete H+ in response to vagal efferent nerve activity. In addition, parasympathetic activation, via gastrin-releasing peptide from intrinsic neurons, releases gastrin from G cells located in the gastric glands in the gastric antrum (see


Physiology_Levy

Physiology_Levy. Fig. 29.6 ). Gastrin enters the bloodstream and, via an endocrine mechanism, further stimulates the parietal cell to secrete H+ . Parietal cells express cholecystokinin type 2 (CCK2) receptors for gastrin. Histamine is also secreted in response to vagal nerve stimulation, and ECL cells express muscarinic and gastrin receptors. Thus gastrin and vagal efferent activity induce release of histamine, which potentiates the effects of both gastrin and acetylcholine on the parietal cell. Hence activation of parasympathetic (vagal) outflow to the stomach is very efficient at stimulating the parietal cell to secrete acid ( Fig. 29.7


Physiology_Levy

Physiology_Levy. Fig. 29.7 In the gastric phase the presence of food in the stomach is detected and activates vagovagal reflexes to stimulate secretion. Food in the stomach results in distention and stretch, which are detected by afferent (or sensory) nerve endings in the gastric wall. These are the peripheral terminals of vagal afferent nerves that transmit information to the brainstem and thereby drive activity in vagal efferent fibers, a vagovagal reflex (see Fig. 29.6 ). In addition, digestion of proteins increases the concentration of oligopeptides and free amino acids in the lumen, which are detected by chemosensors in the gastric mucosa. Oligopeptides and amino acids also stimulate vagal afferent activity. The exact nature of the


Physiology_Levy

Physiology_Levy. ACETYLCHOLINE, GASTRIN, AND HISTAMINE STIMULATE THE PARIETAL CELL • Fig.29.7The parietal cell is regulated by neural, hormonal, and paracrine pathways. Activation of vagal parasympathetic preganglionic outflow to the stomach acts in three ways to stimulate gastric acid secretion. There is direct neural innervation and activation of the parietal cell via release of acetylcholine (A) from enteric neurons, which acts on the parietal cell via muscarinic receptors. In addition, neural activation of the ECL cell stimulates release of histamine (H), which acts via a paracrine pathway to stimulate the parietal cell. Finally, G cells located in gastric glands in the gastric antrum are activated by release of gastrin-releasing peptide (GRP) from enteric neurons, which acts on the G cell to stimulate release of gastrin (G). Gastrin thereafter acts via a humoral pathway to stimulate the parietal cell.


Physiology_Levy

Physiology_Levy. chemosensors is not clear but may involve endocrine cells that release their contents to activate nerve endings. This topic will be discussed in more detail in Chapter 30. There is also an important negative feedback mechanism whereby the presence of acid in the distal part of the stomach (antrum) induces a feedback loop to inhibit the parietal cell such that meal-stimulated H+ secretion does not go unchecked. When the concentration of H+ in the lumen reaches a certain threshold (<pH 3), somatostatin is released from endocrine cells in the antral mucosa. Somatostatin has a paracrine action on neighboring G cells to decrease the release of gastrin and thereby decrease gastric acid secretion (Fig. 29.8 The receptors on the parietal cell membrane for acetylcholine, gastrin, and histamine, as well as the intracellular second messengers by which these secretagogues act, are shown in


Physiology_Levy

Physiology_Levy. Fig. 29.9 . Histamine is the strongest agonist of H+ secretion, whereas gastrin and acetylcholine are much • Fig.29.8Feedback regulation of gastric acid secretion by release of somatostatin and its action on G cells in the gastric antrum. Endocrine cells in the mucosa of the gastric antrum sense the presence of H+and secrete somatostatin. This in turn acts on specific receptors on G cells to inhibit release of gastrin and thus bring about inhibition of gastric acid secretion. Circulation G cell – + D cell Antral lumen GastrinSomatostatin weaker agonists. However, histamine, acetylcholine, and gastrin potentiate one another’s actions on the parietal cell. Antagonists of H2 histamine receptors (e.g., cimetidine [Tagamet]) block secretagogue-stimulated acid secretion. Thus much of the response to gastrin results from gastrinstimulated release of histamine. Gastrin also has important trophic effects; elevation of gastrin levels causes ECL cells to increase in size and number. Binding of


Physiology_Levy

Physiology_Levy. to gastrin results from gastrinstimulated release of histamine. Gastrin also has important trophic effects; elevation of gastrin levels causes ECL cells to increase in size and number. Binding of histamine to H2 receptors on parietal cell plasma membranes activates adenylyl cyclase and elevates the cytosolic concentration of cAMP. These events stimulate H+ secretion by activating basolateral K+ channels and apical Cl− channels and by causing more H+,K+-ATPase molecules and Cl− channels to be inserted into the apical plasma membrane (see


Physiology_Levy

Physiology_Levy. Fig. 29.4 ). Acetylcholine binds to M3 muscarinic receptors and opens Ca++ channels in the apical plasma membrane. Acetylcholine also elevates intracellular [Ca++] by promoting release of Ca++ from intracellular stores, which enhances H+ secretion by activating basolateral K+ channels and causing more H+,K+-ATPase molecules and Cl− channels to be inserted into the apical plasma membrane. Gastrin enhances acid secretion by binding to CCK2 receptors (Fig. 29.10 Digestion in the Stomach Some digestion of nutrients occurs in the stomach. However, this is not required for full digestion of a meal; intestinal digestion is sufficient. Some amylase-mediated digestion of carbohydrates occurs in the stomach. Amylase is sensitive to pH and inactivated at low pH; however, some amylase is active even in the acidic gastric environment of the stomach because of substrate protection. Thus when carbohydrate occupies the active site of amylase, it protects the enzyme from degradation.


Physiology_Levy

Physiology_Levy. • Fig.29.9Vagal parasympathetic stimulation of gastric secretions via enteric neurons. Vagal preganglionic neurons innervate the myenteric and submucosal plexus. The terminals of the vagal preganglionic neurons innervate many enteric neurons and thus bring about changes in function as described in Fig. 29.7 . ACh, acetylcholine; GRP, gastrin-releasing peptide.


Physiology_Levy

Physiology_Levy. Fig. 29.7 . ACh, acetylcholine; GRP, gastrin-releasing peptide. • Fig.29.10Signal transduction mechanisms showing the mechanism of action of agonists (secretagogues) and antagonists that regulate secretion in parietal cells. Acetylcholine (ACh) binds to muscarinic M3 receptors. Histamine acts via the H2 receptor. Gastrin binds to the cholecystokinin type 2 (CCK2) receptor. Activation of M3 and CCK2 receptors results in opening of Ca++ channels and release of Ca++ from intracellular stores and thus an increase in cytosolic [Ca++]. Activation of H2 receptors activates adenylyl cyclase to increase intracellular levels of cAMP. Ac, adenylyl cyclase; ACh, acetylcholine; CCK, cholecystokinin; DAG, diacylglycerol; EGF, epidermal growth factor; IP3, inositol triphosphate; PGE2, prostaglandin E2; PIP2, phosphatidylinositol 4,5-diphosphate; PKC, protein kinase C; PLC, protein lipase C; TGF-α, transforming growth factor α.


Physiology_Levy

Physiology_Levy. Digestion of lipids also starts in the stomach. The mixing patterns of gastric motility result in formation of an emulsion of lipids and gastric lipase, which attaches to the surface of lipid droplets in the emulsion and generates free fatty acids and monoglyceride from dietary triglyceride. However, the extent of hydrolysis of triglyceride is approximately 10%, and hydrolysis is not essential for normal digestion and absorption of dietary lipids. Moreover, as discussed in the next chapter, the products of lipolysis are not available for absorption in the stomach because of its low luminal pH. Mucus and HCO3 − protect the surface of the stomach from the effects of H+ and pepsins. The protective mucus gel that forms on the luminal surface of the stomach, as well as alkaline secretions entrapped within it, constitute a gastric mucosal barrier that prevents damage to the mucosa by gastric contents (


Physiology_Levy

Physiology_Levy. Fig. 29.11 ). The mucus gel layer, which is about 0.2 mm thick, effectively separates the HCO3 −-rich secretions of the surface epithelial cells from the acidic contents of the gastric lumen. The mucus allows the pH of epithelial cells to be maintained at nearly neutral despite a luminal pH of about 2. Mucus also slows the diffusion of acid and pepsins to the epithelial cell surface. Protection of the gastric epithelium depends on both mucus and HCO3 − secretion. To understand GI motility it is necessary to review some properties of smooth muscle function. The motion of the gut wall governs the flow of the luminal contents along its length; the main patterns of motility are mixing (segmentation) and propulsion (peristalsis). In addition, smooth muscle activity in the stomach and colon subserves a storage function.


Physiology_Levy

Physiology_Levy. • Fig.29.11The surface of the stomach is protected by the gastric mucosal barrier. Buffering by the HCO3 −-rich secretions and the high viscosity of the layer of mucus allow the pH at the cell surface to remain near 7, whereas the pH in the gastric juice in the lumen is 2. Functional Anatomy of Gastrointestinal Smooth Muscle The smooth muscle in the GI tract is similar in structure to other smooth muscle found in the body. Fusiform cells are packed together in bundles surrounded by a connective tissue sheath. Gap junctions functionally couple the smooth muscle cells so that contraction of bundles occurs synchronously. The interstitial cells of Cajal (ICCs) are a specialized group of cells in the intestinal wall that are involved in transmission of information from enteric neurons to smooth muscle cells (


Physiology_Levy

Physiology_Levy. Fig. 29.12 ). It is also thought that ICCs are “pacemaker” cells that have the capacity to generate the basic electrical rhythm, or slow-wave activity, that is a consistent feature of GI smooth muscle ( Fig. 29.13). Electrophysiology of Gastrointestinal Smooth Muscle The cyclic variation in resting membrane potential of GI smooth muscle is called the basic electrical rhythm or slow wave. The frequency of slow waves is 3 to 5 per minute in the stomach and about 12 to 20 per minute in the small intestine; it decreases to 6 to 8 per minute in the colon. The frequency of the slow wave is set by a pacemaker region in the different regions of the GI tract (see Fig. 29.13 ). Slow waves are thought to be generated by ICCs. These cells are located in a thin layer between the longitudinal and Slow waves are generated in interstitial cells of Cajal


Physiology_Levy

Physiology_Levy. Fig. 29.13 ). Slow waves are thought to be generated by ICCs. These cells are located in a thin layer between the longitudinal and Slow waves are generated in interstitial cells of Cajal Slow wave conducted to smooth muscle cells • Fig.29.12Diagrammatic representation of the interstitial cells of Cajal network in the smooth muscle wall of the GI tract. circular layers of the muscularis externa and in other places in the wall of the GI tract. Interstitial cells have properties of both fibroblasts and smooth muscle cells. Their long processes form gap junctions with the longitudinal and circular smooth muscle cells; the gap junctions enable the slow waves to be conducted rapidly to both muscle layers. Because gap junctions electrically and chemically couple the smooth muscle cells of both longitudinal and circular layers, the slow wave spreads throughout the smooth muscle of each segment of the GI tract.


Physiology_Levy

Physiology_Levy. 538 SECTION6Berne & Levy Physiology • Fig.29.13Amplitude of slow wave determines the strength of muscle contraction. The slow wave will initiate a contraction in smooth muscle when it reaches a threshold amplitude. The amplitude of the slow wave is altered by release of neurotransmitters from enteric neurons. At rest Stimulated Inhibited Membrane potential Muscle tone Membrane potential Muscle tone Membrane potential Muscle tone


Physiology_Levy

Physiology_Levy. There are times when the gastric mucosal barrier fails. Superficial breakdowns of the GI lining not involving the submucosa are called erosions. They generally heal without intervention. In contrast, breakdowns of the GI lining involving the muscularis and deeper layers are called ulcers. Gastric and duodenal erosions and ulcers occur as a result of an imbalance between the mechanisms that protect the mucosa and aggressive factors that can break it down. A healthy stomach/duodenum has ample natural protection against the destructive effects of H+ . Factors that magnify the harmful effect of H+ on the stomach/duodenum or act separately from H+ include pepsin, bile, the bacterium Helicobacter pylori, and the class of drugs known as nonsteroidal antiinflammatory drugs (NSAIDs). Indeed, ulcer disease is becoming more common as the population ages and has more need of NSAIDs for non-GI complaints such as arthritis. Alcohol, tobacco, and caffeine are also risk factors for ulcers. Infectious


Physiology_Levy

Physiology_Levy. disease is becoming more common as the population ages and has more need of NSAIDs for non-GI complaints such as arthritis. Alcohol, tobacco, and caffeine are also risk factors for ulcers. Infectious agents can also cause gastritis (inflammation of the gastric epithelium). H. pylori is a spiral bacterium that has now become widely recognized as one factor that can lead to gastritis, ulcer formation, and in humans, gastric carcinoma. H. pylori exists in the stomach because it secretes an enzyme, urease, that converts urea to NH3, which is used to buffer H+ by forming NH4 + . An aggressive regimen of antibiotic treatment, sometimes in combination with an H+,K+-ATPase inhibitor, can often eliminate the infection, after which the gastritis and ulcer symptoms improve.


Physiology_Levy

Physiology_Levy. The amplitude and, to a lesser extent, the frequency of the slow wave can be modulated by the activity of intrinsic and extrinsic nerves and by hormones and paracrine substances. If the depolarization of the slow wave exceeds the threshold, a train of action potentials may be triggered during the peak of the slow wave.


Physiology_Levy

Physiology_Levy. Action potentials in GI smooth muscle are more prolonged (10–20 msec) than those in skeletal muscle and have little or no overshoot. The rising phase of the action potential is caused by flow of ions through channels that conduct both Ca++ and Na+ and are relatively slow to open. The Ca++ that enters the cell during the action potential helps initiate contraction. The extent of depolarization of the cells and the frequency of action potentials are enhanced by some hormones and paracrine agonists and by neurotransmitters from excitatory enteric nerve endings (e.g., acetylcholine and substance P). Inhibitory hormones and neuroeffector substances (e.g., vasoactive intestinal polypeptide and nitric oxide) hyperpolarize the smooth muscle cells and may diminish or abolish action potential spikes.


Physiology_Levy

Physiology_Levy. Slow waves that are not accompanied by action potentials elicit little or no contraction of the smooth muscle cells. Much stronger contractions are evoked by the presence of action potentials. The greater the number of action potentials that occur at the peak of a slow wave, the more intense the contraction of the smooth muscle. Because smooth muscle cells contract rather slowly (about a 10th as fast as skeletal muscle cells), the individual contractions caused by each action potential in a train do not cause distinct twitches; rather they sum temporally to produce a smoothly increasing level of tension.


Physiology_Levy

Physiology_Levy. Between the trains of action potentials, the tension developed by GI smooth muscle falls, but not to zero. This nonzero resting, or baseline, tension of smooth muscle is called tone. The tone of GI smooth muscle is altered by neuroeffectors, hormones, paracrine substances, and drugs and is important in the sphincters and also in regions where storage of contents is important, such as the stomach and colon. Specialized Patterns of Motility Peristalsis is a moving ring of contraction that propels material along the GI tract. It involves neurally mediated contraction and relaxation of both muscle layers. Peristalsis occurs in the pharynx, esophagus, gastric antrum, and the small and large intestine.


Physiology_Levy

Physiology_Levy. Segmental contractions produce narrow areas of contracted segments between relaxed segments. These movements allow mixing of the luminal contents with GI tract secretions and increase exposure to the mucosal surfaces where absorption occurs. Segmentation occurs predominantly in the small and large intestine. There are also characteristic pathological patterns of motility. During spasm, maximal contractile activity occurs continuously in a dysregulated manner. In ileus, contractile activity is markedly decreased or absent; it often results from irritation of the peritoneum, such as occurs in surgery, peritonitis, and pancreatitis. Functional Anatomy of the Stomach


Physiology_Levy

Physiology_Levy. Functional Anatomy of the Stomach As discussed, the stomach is divided into two functional regions—proximal and distal, with sphincters at either end. The LES and cardia (defined as the region of the stomach immediately surrounding the LES) have important functions. Relaxation of the LES and cardia allows entry of food from the esophagus into the stomach and the release of gas, called belching. By maintaining tone, reflux of contents from the stomach back into the esophagus is prevented. The proximal part of the stomach (the fundus together with the corpus or body) produces slow changes in tone compatible with its reservoir function. It is important for receiving and storing food and for mixing the contents with gastric juice (


Physiology_Levy

Physiology_Levy. Table 29.2 ). Generation of tone in the proximal portion of the stomach is also an important driving force in the regulation of gastric emptying. Low tone and consequently low intragastric pressure are associated with delayed or slow gastric emptying, and an increase in tone in this region is required for gastric emptying to occur.


Physiology_Levy

Physiology_Levy. The distal part of the stomach is important in the mixing of gastric contents and for propulsion through the pylorus and into the duodenum. The muscle layers in the region of the gastric antrum are much thicker than in the more proximal regions of the stomach, and thus the antrum is capable of producing strong phasic contractions. Contractions initiated by the slow wave begin in the midportion of the stomach and move toward the pylorus. The strength of these contractions varies during the postprandial period. In the gastric phase of the meal the pylorus is usually closed, and these antral contractions serve to mix the gastric contents and reduce the size of solid particles (grinding). However, eventually these antral contractions are also important in emptying the stomach of its contents.


Physiology_Levy

Physiology_Levy. The pyloric sphincter is the gastroduodenal junction and is defined as an area of thickened circular muscle. This is a region of high pressure generated by tonic smooth muscle contraction. It is important in regulating gastric emptying. Control of Gastric Motility in the Gastric Phase Gastric motility is highly regulated and coordinated to perform the functions of storage and mixing. Regulation of emptying of contents into the small intestine, an important part of gastric motor function, will be considered in detail in the discussion of the duodenal phase of the meal, because the controls are generated in the duodenum.


Physiology_Levy

Physiology_Levy. The stimuli regulating gastric motor function that result from the presence of the meal in the stomach are both mechanical and chemical and include distention and the presence of products of protein digestion (amino acids and small peptides). The pathways regulating these processes are predominantly neural and consist of vagovagal reflexes initiated by extrinsic vagal afferent fibers that terminate in the muscle and mucosa. Mucosal afferents respond to chemical stimuli, and mechanosensitive afferents respond to distention and contraction of smooth muscle. This afferent stimulation results in reflex activation of vagal efferent (parasympathetic) outflow and activation of enteric neurons that innervate the smooth muscle. Activation of enteric neurons produces both inhibitory and excitatory effects on gastric smooth muscle; these effects vary depending on the region of the stomach. Thus distention of the gastric wall results in inhibition of smooth muscle in the proximal portion of the


Physiology_Levy

Physiology_Levy. effects on gastric smooth muscle; these effects vary depending on the region of the stomach. Thus distention of the gastric wall results in inhibition of smooth muscle in the proximal portion of the stomach and subsequent reflex accommodation, which allows entry and storage of the meal to occur with minimal increase in intragastric pressure.


Physiology_Levy

Physiology_Levy. In contrast, the predominant motor pattern of the distal part of the stomach in the gastric phase of the meal is activation of smooth muscle to produce and strengthen the antral contractions. The rate of antral contractions is set by the gastric pacemaker; however, the magnitude of the contractions is regulated by release of neurotransmitters from enteric neurons, including substance P and acetylcholine, which increase the level of depolarization of the smooth muscle and therefore produce stronger contractions. In this phase of the meal the pylorus is mostly closed. Thus antral contractions will tend to move the contents toward the pylorus; however, because the pylorus is closed, the contents will be returned to the more proximal part of the stomach. In this way the gastric contents will be mixed. In addition, antral contractions can occlude the lumen, and thus larger particles will be dispersed, a process referred to as grinding ( Fig. 29.14


Physiology_Levy

Physiology_Levy. Fig. 29.14 Onset of terminal Complete terminal antral contraction antral contraction • Force for retropulsion is increased pressure in terminal antrum as the antral contraction approaches the closed pylorus. •Fig.29.14Coordinated activity in the smooth muscle of the proximal and distal portions of the stomach and the pyloric sphincter results in mixing and grinding in the gastric antrum. The peristaltic wave moves down the gastric body and antrum toward the pylorus. If the pylorus is closed, the contents of the gastric antrum are retropulsed back into the more proximal part of the stomach. This pattern of motility results in grinding and mixing of the food with secretions from the gastric wall and eventually leads to a reduction in particle size and the presence of digestive products that will empty into the duodenum. 1. The main functions of the stomach are storage and initiation of protein digestion. 2.


Physiology_Levy

Physiology_Levy. 1. The main functions of the stomach are storage and initiation of protein digestion. 2. Regulation of gastric function is driven by extrinsic and intrinsic neural pathways together with key humoral (gastrin) and paracrine (histamine) mediators. 3. The key secretions from the stomach are acid and pepsinogen, which together begin protein digestion. 4. H+ is secreted across the apical plasma membrane of parietal cells via H+,K+-ATPase. 5. The stomach also secretes intrinsic factor, which is involved in absorption of vitamin B12. Huizinga JD, Chen JH. Interstitial cells of Cajal: update on basic and clinical science. Curr Gastroenterol Rep. 2014;16:363. Hunt RH, et al. The stomach in health and disease. Gut. 2015;64:1650-1668. Said H, et al. Gastroduodenal mucosal defense mechanisms. Curr Opin Gastroenterol. 2015;31:486-491. 6.


Physiology_Levy

Physiology_Levy. Hunt RH, et al. The stomach in health and disease. Gut. 2015;64:1650-1668. Said H, et al. Gastroduodenal mucosal defense mechanisms. Curr Opin Gastroenterol. 2015;31:486-491. 6. The gastric epithelium secretes HCO3 − and mucus to form a gel-like mucosal barrier that protects it against the acidic and peptic luminal contents. 7. The smooth muscle of the gut wall undergoes cyclic changes in membrane potential, termed the basic electrical rhythm or the slow wave. 8. The interstitial cells of Cajal are pacemakers in the gut wall, and they set the frequency of the slow wave. 9. The proximal part of the stomach undergoes a slow change in tone compatible with its storage function. 10. The distal part of the stomach undergoes phasic contractions that can vary considerably in strength. 11. Gastric emptying is regulated by vagovagal reflexes. Sanders KM, et al. Regulation of gastrointestinal smooth muscle function by interstitial cells. Physiology (Bethesda). 2016;31:316-326.


Physiology_Levy

Physiology_Levy. 11. Gastric emptying is regulated by vagovagal reflexes. Sanders KM, et al. Regulation of gastrointestinal smooth muscle function by interstitial cells. Physiology (Bethesda). 2016;31:316-326. Schubert ML. Functional anatomy and physiology of gastric secretion. Curr Opin Gastroenterol. 2015;31:479-485. Schubert ML. Regulation of gastric acid secretion. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Upon completion of this chapter the student should be able to answer the following questions: 1. How are the various components of a mixed meal digested and absorbed in the small intestine? 2. What are the constituents and functions of pancreatic juice, and how is their secretion controlled? 3. How do bile acids assist with digestion and assimilation of lipids? 4. What are the mechanisms that provide for appropriate levels of fluidity of the intestinal contents? 5.


Physiology_Levy

Physiology_Levy. 3. How do bile acids assist with digestion and assimilation of lipids? 4. What are the mechanisms that provide for appropriate levels of fluidity of the intestinal contents? 5. What are the motor patterns of the small intestine in the postprandial period as well as during fasting, and what functions do these patterns subserve?


Physiology_Levy

Physiology_Levy. he small intestine is the critical portion of the intestinal tract for assimilation of nutrients. In this site the meal is mixed with a variety of secretions that permit its digestion and absorption, and motility functions ensure adequate mixing and exposure of the intestinal contents (chyme) to the absorptive surface. The small intestine has many specializations that enable it to perform its functions efficiently. One of the most obvious specializations is the substantial surface area of the mucosa; this is achieved in a number of different ways. The small intestine is essentially a long tube that is coiled inside the abdominal cavity, there are folds of the full thickness of the mucosa and submucosa, the mucosa has finger-like projections called villi, and finally, each epithelial cell has microvilli on its apical surface. Thus a large surface area exists over which digestion and absorption occur.


Physiology_Levy

Physiology_Levy. The main characteristic of the small intestinal phase of the response to a meal is controlled delivery of chyme from the stomach to match the digestive and absorptive capacity of the intestine. In addition there is further stimulation of pancreatic and biliary secretion and emptying of these secretions into the small intestine. Therefore the function of this region is highly regulated by feedback mechanisms that involve hormonal, paracrine, and neural pathways.


Physiology_Levy

Physiology_Levy. The stimuli that regulate these processes are both mechanical and chemical and include distention of the intestinal wall and the presence of increased [H+], high osmolarity, and nutrients in the intestinal lumen. These stimuli result in a set of changes that represent the intestinal phase of the response to the meal: (1) increased pancreatic secretion, (2) increased gallbladder contraction, (3) relaxation of the sphincter of Oddi, (4) regulation of gastric emptying, (5) inhibition of gastric acid secretion, and (6) interruption of the migrating motor complex (MMC). The goal of this chapter is to discuss how such changes are brought about and how they result ultimately in assimilation of nutrients. Changes in small intestinal function that occur after the meal has passed through will also be addressed. Gastric Emptying in the Small Intestinal Phase


Physiology_Levy

Physiology_Levy. Gastric Emptying in the Small Intestinal Phase Immediately after a meal the stomach may contain up to a liter of material that will empty slowly into the small intestine. The rate of gastric emptying is dependent on the macronutrient content of the meal and the amount of solids it contains. Thus solids and liquids of similar nutritional composition will empty at different rates. Liquids empty rapidly, but solids do so only after a lag phase, which means that after a solid meal, there is a period of time during which little or no emptying occurs (Fig. 30.1


Physiology_Levy

Physiology_Levy. Regulation of gastric emptying is achieved by alterations in motility of the proximal part of the stomach (fundus and corpus) and distal part of the stomach (antrum and pylorus) as well as in the duodenum. Motor function in these regions is highly coordinated. Recall that during the esophageal and gastric phase of the meal, the predominant reflex response is receptive relaxation. At the same time, peristaltic movements in the more distal part of the stomach (antrum) mix the gastric contents with gastric secretions. The pyloric sphincter is largely closed. Even if it opens periodically, little emptying will occur, because the proximal portion of the stomach is relaxed and the antral pump (antral contractions) is not very strong. Subsequently, gastric emptying is brought about by an increase in tone (intraluminal pressure) in the proximal portion of the stomach, increased strength of antral contractions (increased strength of the •Fig. 30.1


Physiology_Levy

Physiology_Levy. emptying is brought about by an increase in tone (intraluminal pressure) in the proximal portion of the stomach, increased strength of antral contractions (increased strength of the •Fig. 30.1 Ratesofemptyingofdifferentmealsfromadog’sstomach.Asolution(1%glucose)isemptiedfasterthanadigestiblesolid(cubedliver).Notethelagphaseforemptyingofthesolids,whichisrelatedtothetimeneededtoreduceparticlesbelow2mminsize.(AdaptedfromHinderRA,KellyKA.Am J Physiol 1977;233:E335.)100 80 60 40 20 21 3 4 % emptied Hours400 mL 1% glucose 50 g cubed liver Protein Glucose


Physiology_Levy


Physiology_Levy

Physiology_Levy. antral pump), opening of the pylorus to allow the contents to pass, and simultaneous inhibition of duodenal segmental contractions. Liquids and the semiliquid chyme flow down the pressure gradient from the stomach to the duodenum.


Physiology_Levy

Physiology_Levy. As the meal enters the small intestine, it feeds back via both neural and hormonal pathways to regulate the rate of gastric emptying based on the chemical and physical composition of the chyme. Afferent neurons, predominantly of vagal origin, respond to nutrients, [H+], and the hyperosmotic content of chyme as it enters the duodenum. Reflex activation of vagal efferent outflow decreases the strength of antral contractions, contracts the pylorus, and decreases proximal gastric motility (with a decrease in intragastric pressure), thereby resulting in inhibition (slowing) of gastric emptying. This same pathway is responsible for the inhibition of gastric acid secretion that occurs when nutrients are in the duodenal lumen. Cholecystokinin (CCK) is released from endocrine cells in the duodenal mucosa in response to such nutrients. This hormone is physiologically important, in addition to its role in neural pathways, in the regulation of gastric emptying, gallbladder contraction, relaxation


Physiology_Levy

Physiology_Levy. mucosa in response to such nutrients. This hormone is physiologically important, in addition to its role in neural pathways, in the regulation of gastric emptying, gallbladder contraction, relaxation of the sphincter of Oddi, and pancreatic secretion. Recent evidence suggests that CCK acts both directly (inhibits gastric emptying) and indirectly (stimulates vagal afferent fiber discharge to produce an indirect vagovagal reflex–mediated decrease in gastric emptying).


Physiology_Levy

Physiology_Levy. How then can gastric emptying proceed in the face of these inhibitory pathways? The amount of chyme in the duodenum decreases as it passes further down the small intestine into the jejunum; thus the strength of intestinal feedback inhibition fades as there is less activation of duodenal sensory mechanisms by nutrients. At this time, intragastric pressure in the proximal portion of the stomach increases, thereby moving material into the antrum and toward the antral pump. Antral peristaltic contractions again deepen and culminate in opening of the pylorus and release of gastric contents into the duodenum.


Physiology_Levy

Physiology_Levy. Most of the nutrients ingested by humans are in the chemical form of macromolecules. However, such molecules are too large to be assimilated across the epithelial cells that line the intestinal tract and must therefore be broken down into their smaller constituents by processes of chemical and enzymatic digestion. Secretions arising from the pancreas are quantitatively the largest contributors to enzymatic digestion of the meal. The pancreas also provides additional important secretory products that are vital for normal digestive function. Such products include substances that regulate the function or secretion (or both) of other pancreatic products, as well as water and bicarbonate ions. The latter are involved in neutralizing gastric acid so that the small intestinal lumen has a pH approaching 7.0. This is important because pancreatic enzymes are inactivated by high levels of acidity and also because neutralization of gastric acid reduces the likelihood that the small intestinal


Physiology_Levy

Physiology_Levy. 7.0. This is important because pancreatic enzymes are inactivated by high levels of acidity and also because neutralization of gastric acid reduces the likelihood that the small intestinal mucosa will be injured by such acid acting in combination with pepsin. Quantitatively the pancreas is the largest contributor to the supply of bicarbonate ions needed to neutralize the gastric acid load, although the biliary ductules and duodenal epithelial cells also contribute.


Physiology_Levy

Physiology_Levy. As in the salivary glands, the pancreas has a structure that consists of ducts and acini. The pancreatic acinar cells line the blind ends of a branching ductular system that eventually empties into the main pancreatic duct and from there into the small intestine under control of the sphincter of Oddi. Also in common with salivary glands, a primary secretion arises in the acini, which is subsequently modified as it passes through the pancreatic ducts. In general the acinar cells supply the organic constituents of the pancreatic juice in a primary secretion whose ionic composition is comparable to that of plasma, whereas the ducts dilute and alkalinize the pancreatic juice while reabsorbing chloride ions (Fig. 30.2 ). The major constituents of pancreatic juice, which amounts to approximately 1.5 L/day in adult humans, are listed in


Physiology_Levy

Physiology_Levy. Box 30.1 . This list also outlines the functions of pancreatic secretory products. Many of the digestive enzymes produced by the pancreas, particularly the proteolytic enzymes, are produced as inactive precursor forms. Storage in these inactive forms is critically important in preventing the pancreas from digesting itself.


Physiology_Levy

Physiology_Levy. Characteristics and Control of Ductular Secretion In this section we consider how the pancreatic ductular cells contribute to the flow and composition of pancreatic juice in the postprandial period. The ducts of the pancreas can be considered the effector arm of a pH regulatory Lobules of acinar and ductal parenchyma Secretion of H2O and – Extralobular HCO3 in response to ductal system absorption of Cl˜ Cl˜


Physiology_Levy

Physiology_Levy. Lobules of acinar and ductal parenchyma Secretion of H2O and – Extralobular HCO3 in response to ductal system absorption of Cl˜ Cl˜ Direction of fluid movement •Fig. 30.2 Locationsofimportanttransportprocessesinvolvedintheelaborationofpancreaticjuice.AcinarfluidisisotonicandresemblesplasmainitsconcentrationsofNa+ ,K+ ,Cl− ,andHCO3− .SecretionofacinarfluidandtheproteinsitcontainsisstimulatedprimarilybyCCK.Thehormonesecretinstimulatessecretionofwaterandelectrolytesfromthecellsthatlinetheextralobularducts.Thesecretin-stimulatedsecretionisricherinHCO3− thantheacinarsecretionbecauseofCl−/HCO3− exchange.(AdaptedfromSwansonCH,SolomonAK.J Gen Physiol 1973;62:407.) system designed to respond to luminal acid in the small intestine and secrete just enough bicarbonate to restore pH to neutrality (


Physiology_Levy

Physiology_Levy. Fig. 30.3 ). This regulatory function also requires mechanisms to sense luminal pH and convey this information to the pancreas as well as other epithelia (e.g., biliary ductules and the duodenal epithelium itself) capable of secreting bicarbonate. The pH-sensing mechanism is embodied in specialized endocrine cells known as S cells, localized within the small intestinal epithelium. When luminal pH falls below approximately 4.5, S cells are triggered to release secretin in response to the increase in [H+]. The components of this regulatory loop constitute a self-limited system. Thus as secretin evokes secretion of bicarbonate, pH in the small intestinal lumen will rise and the signal for release of secretin from S cells will be terminated.


Physiology_Levy

Physiology_Levy. At the cellular level, secretin stimulates epithelial cells to secrete bicarbonate into the ductular lumen, with water following via the paracellular route to maintain osmotic equilibrium. Secretin increases cyclic adenosine monophosphate (cAMP) in the ductular cells and thereby opens cystic fibrosis transmembrane conductance regulator (CFTR) • BOX 30.1 Products of Pancreatic Acinar Cells


Physiology_Levy

Physiology_Levy. Precursors of Proteases channels (Fig. 30.4 ) and causes an outflow of Cl− into the duct lumen. This secondarily drives the activity of an adjacent antiporter that exchanges the chloride ions for bicarbonate. CFTR is also permeable to bicarbonate. Thus the bicarbonate secretory process is dependent on CFTR, which provides an explanation for the defects in pancreatic function seen in the disease cystic fibrosis, in which CFTR is mutated. The bicarbonate needed for this secretory process is derived from two sources. Some is taken up across the basolateral membrane of the ductular epithelial cells via the sodium-bicarbonate cotransporter type 1 (NBC-1) symporter. Recall that the process of gastric acid secretion results in an increase in circulating bicarbonate ions, which can serve as a source of bicarbonate to be secreted by the pancreas. However, bicarbonate can also be generated intracellularly via the activity of the enzyme carbonic anhydrase. The net effect is to move HCO3 − into


Physiology_Levy

Physiology_Levy. of bicarbonate to be secreted by the pancreas. However, bicarbonate can also be generated intracellularly via the activity of the enzyme carbonic anhydrase. The net effect is to move HCO3 − into the lumen and thereby increase the pH and volume of pancreatic juice.


Physiology_Levy

Physiology_Levy. •Fig. 30.3 ParticipationofsecretinandHCO3−secretioninaclassicnegative-feedbackloopthatrespondstoafallinluminalpHintheduodenum.˜ pH in duodenum S cells Ductular bicarbonate secretion Secretin release ˜°°° •Fig. 30.4 Iontransportpathwaysinpancreaticductcells.CA,carbonicanhydrase;CFTR,cysticfibrosistransmembraneconductanceregulator;NBC-1,sodium/bicarbonatecotransporter(symporter)type1;NHE-1,sodium-hydrogenexchanger(antiporter)type1.NBC-1 NHE-1 Duct cell 2K˜Cl °HCO3 Duct lumen CFTR Na˜Na˜3Na˜2HCO3 H2CO3 CO2 ˜ H2O H2O ˜CO2 ˜H˜H2CO3 CA Cl °Na˜K˜H2O °2HCO3 °H˜˜ HCO3 °°HCO3° Characteristics and Control of Acinar Secretion In contrast to the pancreatic ductules, where secretin is the most important physiological agonist, CCK plays the predominant role at the level of the acinar cells. Thus it is important to understand how release of CCK is controlled during the small intestinal phase of the response to a meal.


Physiology_Levy

Physiology_Levy. CCK is the product of I cells, which are also localized in the small intestinal epithelium. These classic enteroendocrine cells release CCK into the interstitial space when specific food components are present in the lumen, particularly free fatty acids and certain amino acids. Release of CCK may occur following direct interaction of fatty acids or amino acids, or both, with the I cells. Release of CCK is also regulated by two luminally acting releasing factors that can stimulate the I cell. The first of these, CCK-releasing peptide, is secreted by paracrine cells within the epithelium into the small intestinal lumen in response to products of fat •Fig. 30.5 MechanismsresponsibleforcontrollingreleaseofCCKfromduodenalIcells.ACh,acetylcholine;CCK-RP,CCK-releasingpeptide;GRP,gastrin-releasingpeptide.Solidarrowsrepresentstimulatoryeffects,whereasdashedarrowsindicateinhibition.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.) and protein digestion. The second


Physiology_Levy

Physiology_Levy. Physiology. NewYork:McGraw-Hill;2006.) and protein digestion. The second releasing factor, monitor peptide, is released by pancreatic acinar cells into pancreatic juice. Both CCK-releasing peptide and monitor peptide can also be released in response to neural input, which is particularly important in initiating pancreatic secretion during the cephalic and gastric phases, thereby preparing the system to digest the meal as soon as it enters the small intestine.


Physiology_Levy

Physiology_Levy. What is the significance of these CCK-releasing factors? Their primary role is to match CCK release, as well as the resulting availability of pancreatic enzymes, to the need for these enzymes to digest the meal in the small intestinal lumen ( Fig. 30.5 ). Because the releasing factors are peptides, they will be subject to proteolytic degradation by enzymes such as pancreatic trypsin in exactly the same way as dietary protein. However, when dietary protein is ingested, it is present in much greater amounts in the lumen than the releasing factors and thus “competes” with the releasing factors for proteolytic degradation. The net effect is that the releasing factors will be protected from breakdown while the meal is in the small intestine and are therefore available to continue stimulation of CCK release from I cells. However, once the meal has been digested and absorbed, the releasing factors are degraded and the signal for release of CCK is shut off.


Physiology_Levy

Physiology_Levy. CCK evokes secretion by pancreatic acinar cells in two ways. First, it is a classic hormone that travels through the bloodstream to encounter acinar cell CCK1 receptors. However, CCK also stimulates neural reflex pathways that impinge on the pancreas. Vagal afferent nerve endings in •Fig. 30.6 Receptorsofthepancreaticacinarcellandregulationofsecretion.ThethickblackarrowindicatesthatCa++-dependentsignalingpathwaysplaythemostprominentrole.ACh,acetylcholine;CCK,cholecystokinin;GRP,gastrin-releasingpeptide;VIP,vasoactiveintestinalpolypeptide;M3,M3muscarinicreceptor;CCK-1;CCKreceptortype1.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.) the wall of the small intestine are responsive to CCK by virtue of their expression of CCK1 receptors. As described earlier for the effect of CCK on gastric emptying, binding of CCK activates a vagovagal reflex that can further enhance acinar cell secretion via activation of pancreatic enteric neurons and release of a series of


Physiology_Levy

Physiology_Levy. effect of CCK on gastric emptying, binding of CCK activates a vagovagal reflex that can further enhance acinar cell secretion via activation of pancreatic enteric neurons and release of a series of neurotransmitters such as acetylcholine, gastrin-releasing peptide, and vasoactive intestinal polypeptide (VIP).


Physiology_Levy

Physiology_Levy. The secretory products of pancreatic acinar cells are largely presynthesized and stored in granules that cluster toward the apical pole of acinar cells (


Physiology_Levy

Physiology_Levy. Fig. 30.6 ). The most potent stimuli of acinar cell secretion, including CCK, acetylcholine, and gastrin-releasing peptide (GRP), act by mobilizing intracellular Ca++ . Stimulation of acinar cells results in phosphorylation of a series of regulatory and structural proteins within the cell cytosol that move the granules closer to the apical membrane, where the granules fuse with the plasma membrane. The contents of the granule are then discharged into the acinar lumen and washed out by an exudate of plasma crossing the tight junctions, linking the acinar cells together, and subsequently by ductular secretions. In the period between meals the granule constituents are resynthesized by the acinar cells and then stored until needed to digest the next meal. Resynthesis may be stimulated by the same agonists that evoke the initial secretory response.


Physiology_Levy

Physiology_Levy. Another important digestive juice that is mixed with the meal in the small intestinal lumen is bile. Bile is produced by the liver, and the mechanisms that are involved, as well as the specific constituents, will be discussed in greater detail in when we address the transport and metabolic functions of the liver. However, for purposes of the current discussion, bile is a secretion that serves to aid in digestion and absorption of lipids. Bile flowing out of the liver is stored and concentrated in the gallbladder until it is released in response to ingestion of a meal. Contraction of the gallbladder, as well as relaxation of the sphincter of Oddi, are evoked predominantly by CCK.


Physiology_Levy

Physiology_Levy. When considering the small intestinal phase of meal assimilation, the bile constituents we are most concerned with are the bile acids. These form structures known as micelles that serve to shield the hydrophobic products of lipid digestion from the aqueous environment of the lumen. Bile acids are in essence biological detergents, and large quantities are needed on a daily basis for optimal lipid absorption—as much as 1 to 2 g/day. The majority of the bile acid pool is recycled from the intestine back to the liver after each meal via the enterohepatic circulation (Fig. 30.7 ). Thus bile acids are synthesized in a conjugated form that limits their ability to passively cross the epithelium •Fig. 30.7 Enterohepaticcirculationofbileacids.Activeuptakeofconjugatedbileacidsoccursviatheapicalsodium-dependentbileacidtransporter(asbt).


Physiology_Levy

Physiology_Levy. lining the intestine so that they are retained in the lumen to participate in lipid assimilation (discussed in detail under that heading). However, when the meal contents reach the terminal ileum, after lipid absorption has been completed, the conjugated bile acids are reabsorbed by a symporter, the apical Na+-dependent bile acid transporter (asbt), that specifically takes up conjugated bile acids in association with sodium ions. Only a minor portion of the bile acid pool is left to spill over into the colon in health, and here bile acids become deconjugated and subject to passive reabsorption (see Fig. 30.7).


Physiology_Levy

Physiology_Levy. Fig. 30.7). The net effect is to cycle the majority of the bile acid pool between the liver and intestine on a daily basis, coincident with signals arising in the postprandial period. Bile acids also exert biological actions beyond their role as detergents by binding to both cell surface and nuclear receptors in a variety of cell types throughout the body. In this way they regulate their own synthesis as well as other metabolic processes. The most important physiological function of the small intestine is to take up the products of digestion of ingested nutrients. Quantitatively the most significant nutrients (macronutrients) fall into three classes: carbohydrates, proteins, and lipids. The small intestine is critical not only


Physiology_Levy

Physiology_Levy. The Small Intestinal Phase of the Integrated Response to a Meal for absorption of nutrients into the body but also for the final stages of their digestion into molecules that are simple enough to be transported across the intestinal epithelium. We will consider the processes involved in assimilation of each of these nutrients in turn, beginning with carbohydrates. Carbohydrate digestion occurs in two phases: in the lumen of the intestine and then on the surface of enterocytes in a process known as brush border digestion. The latter is important in generating simple absorbable sugars only at the point where they can be absorbed. This may therefore limit their exposure to the small number of bacteria present in the small intestinal lumen that might otherwise use these sugars as nutrients. Digestion of Carbohydrates


Physiology_Levy

Physiology_Levy. Digestion of Carbohydrates Dietary carbohydrates are composed of several different molecular classes. Starch, the first of these, is a mixture of both straightand branched-chain polymers of glucose. The straight-chain polymers are called amylose and the branched-chain molecules are called amylopectin (Fig.


Physiology_Levy

Physiology_Levy. 30.8 ). Starch is a particularly important source of calories, especially in developing countries, and is found predominantly in cereal products. Disaccharides are a second class of carbohydrate nutrients that includes sucrose (consisting of glucose and fructose) and lactose (consisting of glucose and galactose), the latter being an important caloric source in infants. It is, however, a key principle that the intestine can absorb only monosaccharides and not larger carbohydrates. Finally, many food items of vegetable origin contain dietary fiber, which consists of carbohydrate polymers that cannot be digested by human enzymes. These polymers are instead digested by bacteria present largely in the colonic lumen (see ), thereby allowing salvage of their caloric value.


Physiology_Levy

Physiology_Levy. Dietary disaccharides are hydrolyzed to their component monomers directly on the surface of small intestinal epithelial cells by brush border digestion, mediated by a family of membrane-bound, heavily glycosylated hydrolytic enzymes synthesized by small intestinal epithelial cells. Brush border hydrolases critical to the digestion of dietary carbohydrates include sucrase, isomaltase, glucoamylase, and lactase ( Table 30.1). Glycosylation of these hydrolases is believed to protect them to some extent from degradation by luminal pancreatic proteases. However, between meals the hydrolases are degraded and must therefore be resynthesized by the enterocyte to participate in digesting the next carbohydrate meal. Sucrase/isomaltase and glucoamylase are synthesized in quantities that are in excess of requirements, and assimilation of their products into the body is limited by the availability of specific membrane transporters for these monosaccharides (see


Physiology_Levy

Physiology_Levy. Uptake of Carbohydrates). Lactase, in contrast, shows a developmental decline in expression after weaning. The relative paucity of lactase means that digestion of lactose, rather than uptake of the resulting products, is rate limiting for assimilation. If lactase levels fall below a certain threshold, the disease of lactose intolerance results. •Fig. 30.8 Structureofamylopectinandtheactionofamylase.Thebluecirclesrepresentglucosemonomerslinkedbyα-1,4bonds.Theblackcirclesrepresentglucoseunitslinkedbyα-1,6bondsatthebranchpoints.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Digestion of starch occurs in two phases. The first takes place in the lumen and is actually initiated in the oral cavity via the activity of salivary amylase, as discussed in . Salivary amylase, however, is not essential for starch digestion, although it may assume greater importance in neonates or patients in whom the output of pancreatic enzymes is impaired by disease. Quantitatively the most significant contributor to the luminal digestion of starch is pancreatic amylase. Both enzymes hydrolyze internal α-1,4 bonds in both amylose and amylopectin, but not external bonds nor the α-1,6 bonds that form the branch points in the amylopectin molecule (see


Physiology_Levy

Physiology_Levy. Fig. 30.8 ). Thus digestion of starch by amylase is of necessity incomplete and results in short oligomers of glucose, including dimers (maltose) and trimers (maltotriose), as well as the simplest branching structures, which are called α-limit dextrins. Thus to allow absorption of its constituent monosaccharides, starch must also undergo brush border digestion. At the brush border, straight-chain glucose oligomers can be digested by the hydrolases glucoamylase, sucrase, or isomaltase (see Table 30.1 ). All yield free glucose monomers, which can then be absorbed by the mechanisms discussed later. For α-limit dextrins, on the other hand, isomaltase activity is critical because it is the only enzyme that can cleave α-1,6 bonds that make up the branch points as well as α-1,4 bonds. Uptake of Carbohydrates


Physiology_Levy

Physiology_Levy. Uptake of Carbohydrates Water-soluble monosaccharides resulting from digestion must next be transported across the hydrophobic plasma membrane of the enterocyte. The sodium/glucose transporter 1 (SGLT1) is a symporter that takes up glucose (and galactose) against its concentration gradient by coupling its transport to that of Na+ (


Physiology_Levy

Physiology_Levy. Fig. 30.9 ). Once inside the cytosol, glucose and galactose can be retained for the epithelium’s metabolic needs or can exit the cell across its basolateral pole via a transporter known as GLUT2. Fructose, in contrast, is taken up across the apical membrane by GLUT5. However, •Fig. 30.9 Absorptionofglucose,galactose,andfructoseinthesmallintestine.GLUT,glucosetransporter;SGLT1,sodium/glucosetransporter1.GlucoseGalactoseFructoseFructoseGLUT2GLUT5 GLTI?K+ATP because fructose transport is not coupled to that of Na+, its uptake is relatively inefficient and can easily be overwhelmed if large quantities of food containing this sugar are ingested. The symptoms that occur from this malabsorption are similar to those experienced by a lactose-intolerant patient who consumes lactose.


Physiology_Levy

Physiology_Levy. Proteins are also water-soluble polymers that must be digested into their smaller constituents before absorption is possible. Their absorption is more complicated than that of carbohydrates because they contain 20 different amino acids and short oligomers of these amino acids (dipeptides, tripeptides, and perhaps even tetrapeptides) can also be transported by enterocytes. The body, particularly the liver (see ), has substantial ability to interconvert various amino acids subject to the body’s needs. However, some amino acids, termed the essential amino acids, cannot be synthesized by the body either de novo or from other amino acids and thus must be obtained from the diet. The amino acids that must be obtained in this way in humans are shown in Fig. 30.10


Physiology_Levy

Physiology_Levy. Fig. 30.10 Araregeneticdisorderresultsinaninabilityoftheintestinetoabsorbglucoseorgalactose.ThisdiseasehasbeenmappedtoavarietyofmutationsintheSGLT1 genethatresultinafaultyorunexpressedproteinor,morecommonly,failureoftheproteintotrafficappropriatelytotheapicalmembraneofenterocytes.Inpatientscarryingsuchmutations,malabsorbedglucosecontributestodiarrhealandothersymptoms,asdiscussedearlierforlactoseintolerance.Despitetherarityofthedisease,itisimportantintermsoftheinsightitprovidedintoacriticalprocessofintestinalepithelialtransport. •Fig. 30.10 Naturallyoccurringdietaryaminoacids.Thoseinboxesareessentialaminoacidsthatcannotbesynthesizedbyhumansandthusmustbeobtainedfromthediet.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.)Amino acids NeutralBasicArg HisLys AcidicGlu, Gln Asp, Asn AllphaticGly, Ala AromaticTyr Phe Try HydroxylSer Thr SulfurCys Met IminoPro HydroxyproLeu lleVal , , , , Digestion of Proteins


Physiology_Levy

Physiology_Levy. Digestion of Proteins Proteins can be hydrolyzed to long peptides simply by virtue of the acidic pH that exists in the gastric lumen. However, for assimilation of proteins into the body, three phases of enzymatically mediated digestion are required (


Physiology_Levy

Physiology_Levy. Fig. 30.11 ). Like acid hydrolysis, the first of these phases takes place in the gastric lumen and is mediated by pepsin, the product of chief cells localized to the gastric glands. When gastric secretion is activated by signals coincident with ingestion of a meal, pepsin is released from the chief cells as the inactive precursor pepsinogen. At acidic pH, this precursor is autocatalytically cleaved to yield the active enzyme. Pepsin is highly specialized to act in the stomach, since it is activated by low pH. The enzyme cleaves proteins at sites of neutral amino acids, with a preference for aromatic or large aliphatic side chains. Because such amino acids occur only relatively infrequently in a given protein, pepsin is not capable of digesting protein fully into a form that can be absorbed by the intestine. Instead it yields a mixture of intact protein, large peptides (the majority), and a limited number of free amino acids.


Physiology_Levy

Physiology_Levy. On moving into the small intestine, the partially digested protein encounters the proteases provided in pancreatic juice. Recall that these enzymes are secreted in inactive forms. How then are they activated to begin the process of protein digestion? In fact, activation of proteases is delayed until these enzymes are in the lumen by virtue of the localized presence of an activating enzyme, enterokinase, only on the brush border of small intestinal epithelial cells (


Physiology_Levy

Physiology_Levy. Fig. 30.12 ). Enterokinase cleaves trypsinogen to yield active trypsin. Trypsin in turn cleaves all the other protease precursors secreted by the pancreas, thereby resulting in a mixture of enzymes that can almost completely digest the vast majority of dietary proteins. Trypsin is an endopeptidase that cleaves proteins only at internal bonds within the peptide chain rather than releasing individual amino acids from the end of the chain. Trypsin is specific for cleavage at basic amino acids, and such cleavage results in a set of shorter peptides with a basic amino acid at their C-terminus. The two other pancreatic endopeptidases, chymotrypsin and elastase, have a similar mechanism of action but cleave at sites of neutral •Fig. 30.11 Hierarchyofproteasesandpeptidasesthatfunctioninthestomachandsmallintestinetodigestdietaryprotein.Proteinsareabsorbedaseithersingleaminoacids(70%)orshortpeptides(30%).(AdaptedfromVanDykeRW.In:SleisengerMH,FordtranJS[eds].Gastrointestinal Disease. 4thed.


Physiology_Levy

Physiology_Levy. Philadelphia:Saunders;1989.) •Fig. 30.12 Conversionoftheinactiveproenzymesofpancreaticjuicetoactiveenzymesbytheactionoftrypsin.Trypsinogeninpancre-aticjuiceisproteolyticallyconvertedtoactivetrypsinbyenterokinaseexpressedonthesurfaceofepithelialcellsoftheduodenumandjejunum.Trypsinthenactivatestheotherproenzymesasshown. amino acids. The peptides that result from endopeptidase activity are then acted on by pancreatic ectopeptidases. These enzymes cleave single amino acids from the end of a peptide chain, and those present in pancreatic juice are specific for either neutral (carboxypeptidase A) or basic (carboxypeptidase B) amino acids situated at the C-terminus. Thus the products that result after digestion of a protein meal by gastric and pancreatic secretions include neutral and basic amino acids, as well as short peptides that have acidic amino acids at their C-termini and thus are resistant to carboxypeptidase A or B (Fig. 30.13


Physiology_Levy

Physiology_Levy. B (Fig. 30.13 The final phase of protein digestion takes place at the brush border. Mature enterocytes express a variety of peptidases on their brush borders, including both amino-peptidases and carboxypeptidases that generate products suitable for uptake across the apical membrane (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 30.11 ). However, it should be noted that even with the substantial complement of active proteolytic enzymes, some dietary peptides are either relatively or totally resistant to hydrolysis. In particular, peptides containing either proline or glycine are digested very slowly. Fortunately the intestine can take up short peptides in addition to single amino acids. The majority of peptides taken up into the enterocyte in their intact form are then subjected to a final stage of digestion in the cytosol of the enterocyte to liberate their constituent amino acids for use in the cell or elsewhere in the body (Fig. 30.14 ). However, some di-and tripeptides may also be transported into the blood in their intact form.


Physiology_Levy

Physiology_Levy. •Fig. 30.13 Luminaldigestionofpeptidesresultingfrompartialproteolysisinthestomach.AA,aminoacid.(RedrawnfromBarrettKE.Gastrointestinal Physiology. NewYork:McGraw-Hill;2006.)Peptide with C-terminal neutral AA Carboxypeptidase AChymotrypsin Elastase Large peptides Trypsin Peptide with C-terminal basic AA Short peptides free neutral and basic AAs SerArg Carboxypeptidase B Ser Arg •Fig. 30.14 Awidevarietyofdipeptidesandtripeptidesaretakenupacrossthebrushbordermembranebytheproton-coupledsymporterknownaspeptide transporter 1 (PepT1).Theprotongradientiscreatedbytheactionofsodium/hydrogenexchangers(NHEs)intheapicalmembrane.Peptidesarelargelydigestedinthecytosoltotheirconstituentaminoacidsforexporttothebody,butasmallproportionmaybeexportedintact. Uptake of Peptides and Amino Acids


Physiology_Levy

Physiology_Levy. Uptake of Peptides and Amino Acids The body is also endowed with a series of plasma membrane transporters capable of promoting uptake of the water-soluble products of protein digestion. Given the large number of amino acids, there is a relatively large number of specific transporters (see Figs. 30.11 30.14 ). Amino acid transporters are of clinical interest because their absence in a variety of genetic disorders results in diminished ability to transport the relevant amino acid or acids. However, such mutations are often clinically silent, at least from a nutritional standpoint, because the amino acid in question can be assimilated by other transporters with overlapping specificity or in the form of peptides. This does not rule out the possibility of pathology in other organ systems in


Physiology_Levy

Physiology_Levy. The Small Intestinal Phase of the Integrated Response to a Meal which the transporter of interest may normally be expressed (e.g., cystinuria). In general, amino acid transporters have reasonably broad specificity and usually transport a subset of amino acids (e.g., neutral, anionic, or cationic) but with some overlap in their affinity for particular amino acids. Furthermore, some (but not all) of the amino acid transporters are symporters that carry their substrate amino acids in conjunction with obligatory uptake of Na+ . The small intestine is also notable for its ability to take up short peptides (see


Physiology_Levy

Physiology_Levy. The small intestine is also notable for its ability to take up short peptides (see Fig. 30.14 ). The primary transporter responsible for such uptake is called peptide transporter 1 (PepT1) and is a symporter that transports peptides in conjunction with protons. Amino acids liberated from these peptides that are not required by the enterocyte are in turn exported across the basolateral membrane and enter blood capillaries to be transported to the liver via the portal vein. PepT1 is also of clinical interest because it can mediate the uptake of so-called peptidomimetic drugs, which include a variety of antibiotics as well as cancer chemotherapeutic agents. The mechanisms by which amino acids and peptidomimetic drugs exit the enterocyte are not fully understood but are presumed to involve additional transport proteins.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Lipids, defined as substances that are more soluble in organic solvents than in water, are the third major class of macronutrients making up the human diet. Lipids supply more significant calories on a per-gram basis than proteins or carbohydrates do and are thus of major nutritional significance; they also have a propensity to contribute to obesity if consumed in excessive amounts. Lipids also dissolve volatile compounds that contribute to food’s taste and aroma.


Physiology_Levy

Physiology_Levy. The predominant form of lipid in the human diet is triglyceride, found in oils and other fats. The majority of these triglycerides have long-chain fatty acids (carbon chains > 12 carbons) esterified to the glycerol backbone. Additional lipid is supplied in the form of phospholipids and cholesterol, mostly arising from cell membranes. It is also important to consider that the intestine is presented daily not only with dietary lipid but also with lipid originating from the liver in biliary secretions, as described in more detail in . Indeed, the cholesterol supplied in bile exceeds that provided in the diet on a daily basis in all but the most egg-loving individuals. Finally, though present in only trace amounts, the fat-soluble vitamins (A, D, E, K) are essential nutrients that should be supplied in the diet to avoid disease. These substances are almost entirely insoluble in water and thus require special handling to promote their uptake into the body.


Physiology_Levy

Physiology_Levy. Emulsification and Solubilization of Lipids When a fatty meal is ingested, the lipid becomes liquefied at body temperature and floats on the surface of the gastric contents. This would limit the area of the interface between the aqueous and lipid phases of the gastric contents and thus restrict access of enzymes capable of breaking down the lipid to forms that can be absorbed. This is because the lipolytic enzymes, as proteins, reside in the aqueous phase. Therefore an early stage in the assimilation of lipid is its emulsification. The mixing action of the stomach churns the dietary lipid into a suspension of fine droplets, which vastly increases the surface area of the lipid phase. Lipid absorption is also facilitated by formation of a micellar solution with the aid of bile acids supplied in biliary secretions. Details of this process will be discussed subsequently. Digestion of Lipids


Physiology_Levy

Physiology_Levy. Digestion of Lipids Lipid digestion begins in the stomach. Gastric lipase is released in large quantities from gastric chief cells; it adsorbs to the surface of fat droplets dispersed in the gastric contents and hydrolyzes component triglycerides to diglycerides and free fatty acids. However, little lipid assimilation can take place in the stomach because of the acidic pH of the lumen, which results in protonation of the free fatty acids released by gastric lipase. Lipolysis is also incomplete in the stomach because gastric lipase, despite its optimum catalytic activity at acidic pH, is not capable of hydrolyzing the second position of the triglyceride ester, which means that the molecule cannot be fully broken down into components that can be absorbed into the body. There is also little if any breakdown of cholesterol esters or the esters of fat-soluble vitamins. Indeed, gastric lipolysis is dispensable in healthy individuals because of the marked excess of pancreatic enzymes.


Physiology_Levy

Physiology_Levy. The majority of lipolysis takes place in the small intestine in health. Pancreatic juice contains three important lipolytic enzymes that are optimized for activity at neutral pH. The first of these is pancreatic lipase. This enzyme differs from the stomach enzyme in that it is capable of hydrolyzing both the 1 and 2 positions of triglyceride to yield a large quantity of free fatty acids and monoglycerides. At neutral pH, the head groups of the free fatty acids are charged, and thus these molecules migrate to the surface of the oil droplets. Lipase also displays an apparent paradox in that it is inhibited by bile acids, which also form part of the small intestinal contents. Bile acids adsorb to the surface of the oil droplets and cause lipase to dissociate. However, lipase activity is sustained by an important cofactor, colipase, which is also supplied in pancreatic juice. Colipase is a bridging molecule that binds to bile acids and to lipase; it anchors lipase to the oil droplet even


Physiology_Levy

Physiology_Levy. by an important cofactor, colipase, which is also supplied in pancreatic juice. Colipase is a bridging molecule that binds to bile acids and to lipase; it anchors lipase to the oil droplet even in the presence of bile acids.