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The Small Intestinal Phase of the Integrated Response to a Meal
Learning Objectives
Upon completion of this chapter, you should be able to answer the following questions:
- 1
What are the mechanisms that regulate gastric emptying to match nutrient delivery to the digestive and absorptive capacity of the small intestine?
- 2
What are the characteristic secretory products of the exocrine pancreas, from which cell types do they arise, and how is secretion regulated?
- 3
What is the physiological role of bile?
- 4
How are the three macronutrients—carbohydrates, proteins, and lipids—assimilated into the body via the small intestine?
- 5
What mechanisms control the quantities of fluid and electrolytes entering and leaving the gut lumen?
- 6
What patterns of motility characterize the gut in its fed and fasted state, and how are they produced?
The 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.
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.
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 the 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
Immediately after a meal, the stomach contains up to a liter of material, which empties 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. 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 ).
IN THE CLINIC
The gastrointestinal (GI) tract plays a major role in the sensing and signaling of ingested nutrients by activating neural and endocrine pathways connecting with other signals, such as fat energy storage and utilization, that together regulate energy homeostasis. Satiety signals from the GI tract are involved in the short-term regulation of food intake, such as meal size and duration. For example, the luminal contents activate vagal afferent pathways leading to suppression of meal size. In addition, several GI hormones released by nutrients also influence food intake. Cholecystokinin (CCK) is a well-described satiety hormone; it is released by nutrients and decreases food intake after exogenous administration. Other GI hormones in this class include glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). In both lean and obese humans, injection of exogenous PYY inhibits food intake. An analog of GLP-1, liraglutide, is approved as an agent for weight control in humans.
Regulation of gastric emptying is achieved by alterations in motility of the proximal (fundus and corpus) and distal (antrum and pylorus) parts of the stomach as well as 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 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.
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 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. In addition to its role in neural pathways, this hormone is physiologically important in the regulation of gastric emptying, gallbladder contraction, relaxation of the sphincter of Oddi, and pancreatic secretion. Recent evidence suggests that CCK both acts directly to inhibit gastric emptying and also stimulates vagal afferent fiber discharge to produce an indirect vagovagal reflex–mediated decrease in gastric emptying.
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 the sensory mechanisms in the duodenum 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.
IN THE CLINIC
Surgical treatment of obesity, so-called bariatric surgery, can achieve substantial and lasting weight loss and also help associated health problems such as insulin resistance, hyperlipidemia, and elevated blood pressure. Initially, surgery involved jejunoileal bypass, the removal of a substantial part of the absorptive small intestine, but this procedure is associated with malabsorption and subsequent undesirable sequelae such as diarrhea. A variety of revised surgical approaches to obesity have been devised, including Roux-en-Y gastric bypass and vertical sleeve gastrectomy, many of which can be performed laparoscopically. The mechanism by which these procedures are thought to be successful lie in the small size of the residual gastric pouch, whereby meal size is decreased because of early satiety, and a beneficial effect of the bypass on the profiles of gastrointestinal hormones. Recent data imply that effects of surgery on bile acids and the microbiome may contribute to both weight loss and the metabolic benefits.
Pancreatic Secretion
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 products 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 mucosa will be injured by such acid acting in combination with pepsin. 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.
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 Table 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.
AT THE CELLULAR LEVEL
Pancreatitis can result when enzymes secreted by pancreatic acinar cells become proteolytically activated before they have reached their appropriate site of action in the small intestinal lumen. Indeed, pancreatic juice contains a variety of trypsin inhibitors to reduce the risk of premature activation because trypsin is the activator of other pro-forms of enzymes secreted in pancreatic juice. A second level of protection lies in the fact that trypsin can be degraded by other trypsin molecules. Despite these defenses, some individuals are susceptible to hereditary pancreatitis that occurs spontaneously in the absence of known risk factors. In some of these patients, there is a mutation in trypsin that renders it resistant to degradation by other trypsin molecules. Others harbor mutations in trypsin inhibitors, rendering the inhibitors inactive. In any event, if other defenses have been breached and trypsin becomes active prematurely, a vicious cycle of enzyme activation ensues and bouts of pancreatitis follow.
TABLE 30.1
Products of Pancreatic Acinar Cells
| Precursors of Proteases |
| Trypsinogen |
| Chymotrypsinogen |
| Proelastase |
| Procarboxypeptidase A |
| Procarboxypeptidase B |
| Starch-Digesting Enzymes |
| Amylase |
| Lipid-Digesting Enzymes or Precursors |
| Lipase |
| Nonspecific esterase |
| Prophospholipase A 2 |
| Nucleases |
| Deoxyribonuclease |
| Ribonuclease |
| Regulatory Factors |
| Procolipase |
| Trypsin inhibitors |
| Monitor peptide |
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 system designed to respond to luminal acid in the small intestine and secrete just enough bicarbonate to restore pH to neutrality ( 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 localized within the small intestinal epithelium, known as S cells. 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.
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 cAMP in the ductular cells and thereby opens cystic fibrosis transmembrane conductance regulator (CFTR) Cl − 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 that are 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 NBC-1 symporter (for sodium-bicarbonate cotransporter type 1). 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 HCO 3 − into the lumen and thereby increase the pH and volume of pancreatic juice.
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.
IN THE CLINIC
Cystic fibrosis (CF) is a genetic disease that affects the function of a variety of epithelial organs, including the lung, intestine, biliary system, and pancreas. Previously, the disease was almost uniformly fatal during adolescence as a result of severe respiratory infections, but improved antibiotics, drugs that improve the clearance of mucus from the lungs, and correction of pancreatic insufficiency and undernutrition, as well as the recent FDA approval of drugs including Kalydeco and Orkambi that address mutant CFTR, now extend life even into the fifth decade or later. CF is caused by a mutation in CFTR, which impairs the ability to hydrate and alkalinize the luminal contents. In the gastrointestinal system, specifically, this can result in intestinal obstruction, duodenal mucosal injury, and damage to the liver and biliary system, as well as the pancreas. In many CF patients the exocrine pancreas is dysfunctional, and these patients must be given digestive enzyme supplements to maintain adequate nutrient digestion. In other patients with milder mutations, pancreatitis may develop later in life in the absence of other classic CF symptoms, presumably because of retention of digestive enzymes in the pancreas. In either case, improved recognition and treatment of the pulmonary complications of CF mean that gastrointestinal symptoms, such as liver failure, reduced bile flow, pancreatitis, obstruction, and maldigestion/malabsorption of nutrients, are acquiring increased importance as facets of the disease that must be managed in adults, often by multidisciplinary teams of physicians and other health care professionals.
CCK is the product of I cells, which are localized in the small intestinal epithelium. These classic enteroendocrine cells release CCK into the interstitial space when specific food components, particularly free fatty acids and certain amino acids, are present in the lumen. 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 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 and protein digestion. The second releasing factor, monitor peptide, is released by pancreatic acinar cells into pancreatic juice ( Fig. 30.5 ). 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.
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. 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.
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 CCKA receptors. However, CCK also stimulates neural reflex pathways that impinge on the pancreas. Vagal afferent nerve endings in the wall of the small intestine express CCKA 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 neurotransmitters such as acetylcholine, gastrin-releasing peptide, and vasoactive intestinal polypeptide (VIP).
The secretory products of pancreatic acinar cells are largely synthesized and stored in granules that cluster toward the apical pole of acinar cells ( 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, with which they subsequently fuse. 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.
Biliary Secretion
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 Chapter 32 . However, for purposes of the current discussion, bile serves to aid in the 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.
When considering the small intestinal phase of meal assimilation, the bile constituents that 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 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 intestinal epithelium so that they are retained in the lumen to participate in lipid assimilation (see later). 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 ). 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.
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