NROSCI 1070-2070November 18, 2015

Gastrointestinal1

Function of the GI System• The digestive system has two primary roles:

—Digestion, or the chemical and mechanical breakdown of foods into small molecules that can absorbed, or moved across the intestinal mucosa into the bloodstream. In order to accomplish these functions, the

secretion of enzymes, hormones, mucus, and paracrines by the gastrointestinal organs is needed.

—Motility, or controlled movement of materials through the digestive tract is also required.

Challenges of the GI System

• Almost 7 liters of fluid must be released into the lumen of the digestive tract per day to allow for digestion and absorption to occur. Clearly, most of this fluid must be reabsorbed or dehydration will occur.

• Furthermore, the inner surface of the digestive tract is technically in contact with the external environment; for this reason, protective mechanisms are needed. In part, these mechanisms must protect against the secretions of the GI tract, including acid and enzymes.

Anatomy of the GI System

Anatomy of the GI System• The organs involved in digestion and absorption

include:

1. Salivary glands 5. Liver2. Esophagus 6. Pancreas3. Stomach 7. Large intestine4. Small intestine

• In addition, 7 sphincters control the movement of material and secretions between the organs.

• The total length of the GI tract is about 15 feet, of which 13 feet are comprised of intestine.

• The processed material within the GI tract is referred to as chyme.

Wall of GI Tract • The wall of both the intestines and stomach is similar, in that it contains four (or five) layers: 1.Mucosa2.Submucosa 3.Muscle layer

(sometimes divided into 2 layers)

4.Serosa

Wall of GI Tract

•The mucosa is composed of epithelial cells, the lamina propria (connective tissue), and muscularis mucosa (specialized smooth muscle). •The mucosa has a number of specializations to increase surface area. –Within the stomach, these occur as folds

called rugae. –Within the small intestine, a number of

fingerlike projections, or villi, are present. The individual cells on the villi have further specializations that increase surface area; these specializations are called microvilli.

• In addition, invaginations (called gastric glands in the stomach and crypts in the intestine) exist in the GI tract. These invaginations are lined with secretory cells.

Multiple Secretory Cells are Present• As an example, the stomach contains the

following secretory cells:1. Mucus-secreting cells2. Parietal cells (secrete hydrochloric acid)3. Chief cells (secrete pepsin)4. G cells (secrete the hormone gastrin)5. Enterochromaffin cells (secrete histamine)6. D Cells (secrete somatostatin)• A multiplicity of secretory cell types are also

present in the small intestine

Wall of GI Tract

•The submucosal layer contains large blood vessels and lymph vessels, and the submucosal plexus, a major component of the enteric nervous system. •The muscle layer of the gut is composed of two layers of smooth muscle: an inner circular layer and an outer longitudinal layer. Contraction of the circular layer decreases the

diameter of the lumenContraction of the longitudinal layer shortens the

tube Between the two layers of muscle is the

myenteric plexus, another component of the enteric nervous system

• The outer serosa forms the wall of the GI tract. It is an extension of the peritoneal membrane that lines the abdominal cavity. Sheets of mesentery connect with the serosa to hold the intestines in place.

GI Smooth Muscle• The cells in each bundle of smooth muscle are linked by gap junctions;

therefore, electrical signals travel easily from cell to cell. Thus, a layer of GI smooth muscle forms a syncytium, in that an action potential elicited anywhere in a bundle will evoke a contraction of all surrounding muscle cells.

• Three types of electrical activity are important in control of contraction of gastrointestinal smooth muscle:

1. Slow waves2. Spikes3. Resting membrane potential

• Most gastrointestinal contractions occur rhythmically, and the slow waves play a key role in controlling these contractions.

GI Smooth Muscle

• Slow waves are slow oscillations that occur at different frequencies at different points in the gut (3/minute in the body of the stomach to 12/minute in the duodenum). These slow waves are presumably due to cycling changes in activity in the Na+-K+ pump. The slow waves mainly reflect the entry of sodium into the smooth muscle cell, and do not cause muscle contraction (calcium triggers smooth muscle contraction).

GI Smooth Muscle• Spike potentials occur when voltage-gated channels that pass calcium

and sodium open. • The opening of these channels allows calcium to enter the smooth muscle

cell, which induces contraction. • These channels have slow kinetics, which results in very long-lasting

spikes. • Thus, if the resting membrane potential is sufficiently depolarized, the

spike potentials will occur at the crest of the slow waves.

• In other words, control of resting membrane potential is all important in determining whether gastrointestinal smooth muscle cells will contract.

GI Smooth Muscle•Depolarization of GI smooth muscle cells can be induced by:

1. Muscle stretch2. Acetylcholine (released

by cells of enteric nervous system)

3. Some specific gastrointestinal hormones

• Hyperpolarization of GI smooth muscle cells can be induced by:

1. Norepinephrine and epinephrine (e.g., the effects of the sympathetic nervous system)

The Enteric Nervous System

• Two “plexuses” of nerve cells comprise the enteric nervous system of the gut. The first plexus is in the submucosal layer The second plexus is between the longitudinal and

circular smooth muscle (myenteric plexus) • These nerve cells receive innervation by the

sympathetic and parasympathetic nervous system, but can function without this input.• The enteric nervous system plays the

fundamental role in neural control of GI function.

Evidence that the Enteric Nervous System is a “Little Brain”

• The neurons of the enteric nervous system release more than 20 neurotransmitters and neuromodulators, many of which are identical to molecules found in the brain. These neuro-transmitters are sometimes called “non-adrenergic, non-cholinergic” to distinguish them from the “traditional” autonomic neurotransmitters: norepinephrine and acetylcholine.

• The support cells of neurons in the enteric nervous system are more similar to the astroglia of the brain than to the Schwann cells of the peripheral nervous system

• The capillaries that surround ganglia within the enteric nervous system are not very permeable and create a diffusion barrier that is similar to the blood-brain barrier of cerebral blood vessels

• Reflexes resulting from stimulation of sensory receptors in GI tract can be integrated and elicited entirely within the enteric nervous system. Thus, the enteric nervous system must have the “sophistication” of coordinating these responses.

Organization of the Enteric Nervous System• In general, the enteric nervous system is organized into two

sheets: the submucosal plexus and the myenteric plexus.

• The submucosal plexus mainly regulates secretory functions and vasomotor control, whereas the myenteric plexus mainly regulates motility.

• In reality, the cell bodies in the submucosal and myenteric plexus are concentrated into ganglia, with interganglionic fiber tracts interconnecting them.

Organization of the Enteric Nervous System• The submucosal and myenteric layers appear to largely subserve different

functions: the submucosal layer participates in regulating secretion and blood flow whereas the myenteric layer is involved in motility.

• However, there also seems to be coordination between these functions. There is good electrophysiological evidence that submucus neurons receive cholinergic and non-cholinergic excitatory input and non-cholinergic inhibitory inputs from myenteric neurons.

• Similarly, a population of submucus neurons project to the myenteric plexus. • The precise role of these interconnections in influencing GI function is

currently unknown.

Function of the Enteric Nervous System• In large part, the enteric nervous system serves as a “pattern generator” for the carefully coordinated sequence of contractions that results in motility. By relinquishing this control to the periphery, the central autonomic systems do not have to worry about coordinating this activity. In large part, the pacemaker system in the heart or the brainstem respiratory pattern generator serve a similar role. •One clear response that the enteric nervous system produces is the “migrating action potential complex” (or “migrating motor complex”) which propagates through both normal gut and that removed from the body and placed in a tissue bath. Many hours after eating a meal, when the digestive system is not influenced by chemical inputs from the lumen, this special pattern of activity propagates through the stomach and small intestine about once every 90 min. Because this response involves a contraction that sweeps through most of the digestive tract, it must be precisely coordinated. The occurrence of this response, which apparently takes place to sweep debris out of the gut, shows the extent of influences of the enteric nervous system. •Propulsive and mixing contractions can also take place in the isolated gut, suggesting that the enteric nervous system also controls these responses.

Influences on the Enteric Nervous System•The enteric nervous system and its target tissues receive inputs from the sympathetic and parasympathetic nervous systems, which influence motility, secretion and blood flow. Perhaps these influences are analogous to the sympathetic and parasympathetic influences on the pacemaker system of the heart (which serve to regulate rate, but not pattern of activity).•The parasympathetic influences to the upper GI tract are mediated by the vagus nerve. In contrast, the distal half of the colon is innervated by the sacral division of the parasympathetic nervous system. The postganglionic parasympathetic neurons are components of the enteric nervous system. •The sympathetic nervous system mainly influences motility through inputs to the enteric nervous system, but to some extent through direct influences on smooth muscle cells.

Influences on the Enteric Nervous System•Many afferents originating in the gastrointestinal tract influence central nervous system activity. These afferents can be activated by irritation of the gut mucosa, distension of the gut, or the presence of specific chemical substances in the gut.

–Some of these afferents are “local,” in that their cell bodies and terminations are in the enteric nervous system.

–Some of these afferents also make connections in prevertebral sympathetic ganglia.

– In other cases, the cell bodies are in the dorsal root ganglia; the axons of these afferents course in sympathetic nerves.

–Other gastrointestinal afferents course in the vagus nerve to the brainstem; their cell bodies are in the nodose ganglion.

Influences on the Enteric Nervous System•A number of hormones affect gastrointestinal motility; some of these agents also affect secretion.

–Cholecystokinin is secreted by “I” cells in the mucosa of the small intestine, mainly in response to breakdown products of fat. This hormone causes the expulsion of bile from the gall bladder into the stomach. In addition, it inhibits stomach motility, so that food is emptied from the stomach into the intestine more slowly.

–Secretin is secreted by “S” cells in the mucosa of the duodenum, in response to gastric acid released by the stomach. It acts to inhibit motility throughout the GI tract.

–Gastric inhibitory peptide, secreted by the mucosa of the upper small intestine, is similar to cholecystokinin in that it slows emptying of materials from the stomach.

– The hormone gastrin, which is released by cells in the antrum of the stomach in response to the presence of certain foods and stomach distension, has a mild stimulatory effect on stomach motility.

Motility and Secretion in

the GI System

Motility: Types of Contractions in the GI System

• There are three major types of contractions of gastrointestinal smooth muscle:1) Tonic, sustained contractions (mainly in sphincters).2) Peristaltic contractions (move food forward in GI tract)3) Segmental contractions (responsible for mixing food with GI secretions and pushing it against the wall of the mucosal layer)

Motility: Peristaltic and Segmental

Contractions

Motility: Mastication & Deglutition

• Mechanical digestion of food begins in the oral cavity with chewing. The lips, tongue and teeth contribute to mastication of food, creating a softened mass that can be easily swallowed. Mastication is an important process, as it increases the surface area of food that will be exposed to digestive enzymes.

• Swallowing (deglutition) occurs in three stages:

• A voluntary stage, which initiates the swallowing process

• An involuntary pharyngeal stage.• An esophageal stage.

Motility: Mastication & Deglutition

• The voluntary stage of swallowing involves the moving of food into the pharynx by the actions of the tongue.

Motility: Mastication & Deglutition

• The involuntary pharyngeal stage of swallowing is triggered by the stimulation of receptors near the opening of the pharynx, whose axons terminate in nucleus tractus solitarius.

• Stimulation of these receptors evokes a coordinated response that involves outflow along cranial nerves 5, 9, 10 and 12.

• Contraction of pharyngeal muscles causes closing of the glottis, the opening between the pharynx and larynx, so that no materials move into the airway. At the same time, respiration is inhibited and the upper esophageal sphincter relaxes.

Motility: Mastication & Deglutition•The esophageal stage of swallowing has two

components: primary peristalsis and secondary peristalsis. •Primary peristalsis is a continuation of the swallowing reflex that began in the pharynx. •Secondary peristalsis is initiated by distention of the esophagus by a large bolus of food, which triggers reflex contractions. •The afferents that evoke secondary peristalsis send their axons through the vagus nerve, which also carries the efferent outflow from the brainstem to the esophagus.

• The musculature of the upper third if the esophagus, like that of the pharynx, is striated muscle, which is controlled by the vagus nerve.

• The lower two-thirds of the esophagus contains smooth muscle, whose activity is mainly controlled by the enteric nervous system.

• Thus, even if the vagus nerve is sectioned, swallowing can occur if food reaches the lower part of the esophagus.

Motility in the Stomach• The activity of the enteric nervous system also causes the relaxation of the

lower esophageal sphincter when a bolus of food approaches. The tight closing of this sphincter is needed to prevent reflux of acid from the stomach into the esophagus.

• When food enters the stomach, it stimulates receptors, and through a “vasovagal reflex” induces relaxation of the stomach wall so the stomach can be distended with food. The contractions of the stomach are mainly weak, and for the purpose of mixing food with stomach secretions. At the antrum of the stomach, contractions are more intense, and aid in stomach emptying.

• With each slow wave some materials are pushed through the pyloric sphincter into the duodenum. Typically, the pyloric sphincter is only partially contracted, which allows liquid materials to pass along. The degree of constriction of the pylorus can be increased or decreased by nervous and hormonal signals.

• Motility in the stomach is influenced most prominently by hormonal factors: gastrin release from the stomach has a stimulatory effect, whereas cholecystokinin, secretin and gastric inhibitory peptide release from the duodenum inhibit stomach motility.

Motility in the Small Intestine• Both mixing and propulsive contractions occur in the small

intestine. These contractions occur no more rapidly than a rate of 12/minute, the frequency of occurrence of slow waves in the small bowel.

• The rate of motility is influenced by distension of the intestine, which effects the excitability of cells of the enteric nervous system.

• A number of hormones released from the small intestine also modestly enhance motility in the small intestine.

• Irritation of the bowel wall or central nervous system influences can induce the enteric nervous system to rapidly empty the digestive system. This “peristaltic rush” helps to remove toxins when they are present.

• The ileocecal valve permits one way movement of materials from the small intestine into the colon. Its physical structure of overlapping “lips” assists with this process.

Motility in the Large Intestine• The regulation of motility in the colon is similar to that in

the small intestine. • The main functions of the colon are to absorb water from

residual products of digestion and to store the material until elimination. • Mixing contractions, which are called haustrations in the

colon, can be very intense, but are needed to expose the fecal material to the intestine wall to permit reabsorption of water. • Strong propulsive movements occur in the distal part of

the colon to force feces into the rectum.

Defecation• Elimination of wastes is usually triggered by the entry of

material into the rectum. • Afferent signals affect the enteric nervous system of the

distal colon, causing propulsive movements of further materials towards the anus. • The enteric nervous system also causes the relaxation of

the internal anal sphincter. • At the same time, afferents whose cell bodies are in the

sacral dorsal root ganglia evoke a conscious sensation of a filled rectum. These inputs can induce a voluntary relaxation of the external anal sphincter, which is composed of striated muscle. • Thus, both conscious and autonomic activity is required

for defecation to take place.

Secretion in the GI Tract•As noted previously, about 7 liters of secretions enter the GI system per day, as summarized in the following table:

• Most of this fluid most be reabsorbed or dehydration will occur. Most of the absorption occurs in the small intestine, although some occurs in the colon. •Only about 0.15 L of water per day are lost in the feces.

Salivary Glands 1.5 LLiver (Bile) 0.5 LStomach Secretions

2.0 L

Pancreas Secretions

1.5 L

Intestine Secretions

1.5 L

TOTAL 7.0 L

Secretion: Digestive Enzymes

•Digestive enzymes are secreted by exocrine glands (salivary glands and the pancreas) or by epithelial cells in the stomach and small intestine. •These enzymes are proteins, and are packaged by the Golgi apparatus into secretory vesicles and stored within the cell until needed. •On demand, they are released into the extracellular space by exocytosis. •Some of these enzymes become mixed with chyme, and others are attached to the brush border (microvilli) on the epithelial cells.

Secretion: Digestive Enzymes•Some digestive enzymes are secreted in an

inactive proenzyme form, and must be activated by other agents. – Amongst these enzymes are pepsinogen in the

stomach and the pancreatic enzymes chymotrypsinogen, procarboxypeptidase, procolipase, and prophospholipase. – These pancreatic enzymes are converted to their active

form by trypsin, a conversion product of the pancreatic enzyme trypsinogen. – Trypsinogen is converted to trypsin through the actions

of the brush border enzyme enteropeptidase (also known as enterokinase).

Question for Discussion

Why are some GI enzymes released in an inactive

form?

Table of GI Enzymes

Clinical Note

• Inhibition of GI enzymes can be used therapeutically• An example is Xenical (orlistat), which

reversibly inhibits lipases and prevents lipids from being absorbed.• Xenical is used to treat obesity.•What major side effect would you expect

to be associated with this drug?

Other GI Secretions• In addition to digestive enzymes, mucus is secreted by

specialized cells in the stomach, small intestine, and colon. –This viscous secretion is composed primarily of glycoproteins

that are collectively called mucins. –Mucus functions to form a protective lining over the GI

mucosa and to lubricate the contents of the gut. –Mucus is secreted by globlet cells in the stomach and

intestine. –The release signals for mucus include parasympathetic

innervation, a variety of neuropeptides found in the enteric nervous system, and cytokines from immune cells.

– Infections of the gut enhance mucus secretion as the digestive system attempts to protect itself.

Other GI Secretions• Another secretion that aids in digestion is bile, a non-enzyme

solution secreted by liver cells. • The key components of bile are: salts for fat digestion, bile

pigments (e.g., bilirubin, a breakdown product of hemoglobin), and cholesterol. –The bile salts are formed by the combination of bile acids

(steroid detergents with polar side chains) with amino acids. • Bile is secreted into the hepatic ducts that lead to the gall

bladder. During a meal, contraction of the gall bladder sends bile into the duodenum through the common bile duct.

• Bile acts as a surfactant, that allows fats to form small droplets that have a large surface area for digestion.

• Bile salts are not altered during fat digestion, and are reabsorbed and taken through the hepatic portal system back to the liver.

Other GI Secretions• Hydrochloric acid is released by

parietal cells in the stomach. H+, which is derived from CO2 and water (this reaction is catalyzed by carbonic anhydrase), is actively pumped into the stomach in exchange for K+.

• Bicarbonate ion, another product of the reaction, then diffuses into the extracellular fluid and blood in exchange for Cl-.

• Acid secretion by the stomach is needed to denature proteins so they can be digested. Stomach enzymes work best at low pH.

Other GI Secretions• Bicarbonate ions are formed in the

pancreas from CO2, which combines with water under the influence of carbonic anhydrase to form carbonic acid. In turn, the carbonic acid dissociates to form HCO3

- and H+. • The bicarbonate is pumped from the

pancreas into the lumen by secondary active transport in exchange for Cl- ions.

• H+ is pumped into the blood, also by secondary active transport in exchange for Na+. • The secretion of HCO3

- into the lumen of the small intestine neutralizes stomach acid and assures that the environment remains alkaline.

Control of GI Secretions• Hormones play the predominant role in the control of GI

secretions.• In fact, the first hormone every discovered was a GI

hormone (secretin).• Many gastrointestinal hormones are generally

recognized, or have been proposed. Those that we will focus on in this course include:

Gastrin Cholecystokinin (CCK) Secretin

Vasoactive Intestinal Peptide (VIP)

Enteroglucagon Somatostatin

Gastric Inhibitory Protein (also called Glucose-Dependent Inslinotropic Hormone or GIP)

Control of Gastrin Secretion• Gastrin is synthesized by G cells in the stomach antrum, and its

secretion is triggered by peptides and amino acids in the lumen of the stomach and by parasympathetic influences on the enteric nervous system.

• Its targets are Enterochromaffin cells in the stomach (which release histamine) and parietal cells in the stomach (which release HCl).

• Acid secretion in the stomach is thus triggered both directly and indirectly by gastrin release, as the secretion of histamine from Enterochromaffin cells also enhances gastric acid secretion.

• Histamine in itself does not generally induce HCl secretion, but it greatly potentiates the effects of Gastrin on the parietal cells.

• Activity of the parasympathetic nervous system can also induce acid secretion by Parietal cells.

• Gastrin release is inhibited by somatostatin release from D cells in the stomach. As will be discussed below, this release is induced by the presence of large amounts of stomach acid. CCK & secretin release from the intestine have a similar effect.

Summary of Stomach Secretions

Summary of Stomach Secretions

Clinical Note

• A massive drug market exists to limit gastric acid secretion• One strategy is to block the histamine receptor

on parietal cells (e.g., cimetadine [Tagament], ranitidine [Zantac-75], famotidine [Pepcid]) • Another treatment has been inhibitors of the

ATP-ase (H+/K+ ATPase) that pumps H+ out of the parietal cells (e.g., omeprazole [Prilosec] and lansoprazole [Prevacid]).

Clinical Note

• The original use of anti-acid therapies was to treat peptic ulcers, damage to the stomach lining

• However, in the 1980s it was discovered that most peptic ulcer patients all had a chronic infection of their stomach wall by the bacterium Helicobactor pylori.

• Apparently, enzymes secreted by this bacterium break down the mucus layer.

• The “latest and greatest” drugs for treatment of peptic ulcer are aimed at destroying this bacterium.

Intrinsic Factor & Pernicious Anemia

• In addition to acid, parietal cells release intrinsic factor• Intrinsic factor is essential for the

absorption of Vitamin B12

• Lack of intrinsic factor results in pernicious anemia, as this vitamin is required to produce red blood cells

Control of CCK Secretion• CCK is a hormone released by endocrine cells in the small intestine.

Interestingly, it also appears to be a neurotransmitter in both the enteric nervous system and the brain.

• CCK release is stimulated by the presence of fatty acids and some amino acids in the duodenum.

• CCK acts on the gall bladder to induce contraction, and the release of bile into the small intestine (makes sense, as bile acts to emulsify fats).

• CCK also acts in the stomach (presumably on parietal cells) to reduce acid secretion; another effect is to reduce gastric motility. These effects also make sense, because the small intestine can only digest small amounts of fat at a time (and this response acts to slow stomach emptying).

• CCK also acts to stimulate bicarbonate secretion from the intestine and to enhance peristalsis in the small intestine.

• Finally, the hormone is a primary stimulant for pancreatic enzyme secretion.

Control of Secretin Secretion• The hormone secretin has some of the same effects as

CCK. • Like CCK, it is secreted by endocrine cells in the small

intestine. • Secretin release is stimulated by acid in the small

intestine. • The effects of this hormone include: a stimulation of

bicarbonate secretion from the pancreas, bile secretion from the liver, a stimulation of pepsinogen release in the stomach, and an inhibition of gastric acid secretion. • Gastric emptying is also inhibited by this hormone.

Control of VIP Secretion• Vasoactive Intestinal Peptide (VIP) is both a

hormone and a neurotransmitter. • In the gut, it is produced by cells in the enteric

nervous system. • The factors leading to VIP release are unknown,

but obviously the release is the result of activity in the enteric nervous system. • VIP acts to stimulate somatostatin release from D

cells in the stomach, stimulate bicarbonate release from the pancreas, and to decrease motility.

Control of GIP Secretion• GIP is released from endocrine cells in the small

intestine. • Although this hormone was once thought to inhibit gastric

acid secretion (hence its original name, gastric inhibitory peptide), the main role attributed to it today is the stimulation of insulin release from beta cells of the pancreas (hence its new name of glucose-dependent insulinotropic peptide). • The main trigger for the release of GIP is glucose and

amino acids in the small intestine. • The role of GIP in controlling acid secretion is now

debated, as the concentration needed to produce this effect is extremely high.

Control of Enteroglucagon Secretion• Another hormone released from endocrine cells

in the small intestine is Enteroglucagon. • This hormone may act together with GIP, as it

stimulates insulin secretion from the beta cells of the pancreas. • It is released when glucose is present in the

small intestine.

Control of Somatostatin Secretion• A final GI hormone is somatostatin, which is

released from D-cells of the stomach. • This hormone is not well understood, but seems

to inhibit gastric acid, pepsin, pancreatic enzyme, and bicarbonate secretion. • Its release appears to be triggered by acid in the

stomach and perhaps by the hormone VIP.

What Happens During a Meal?• Digestion has traditionally been divided into three phases: a

cephalic phase, a gastric phase, and an intestinal phase. – The cephalic phase is due to the effects of the brain on the enteric

nervous system, and begins when a person anticipates eating. During the cephalic phase, the parasympathetic nervous system induces the G cells to produce gastrin, the Enterochromaffin cells to release histamine, and the parietal cells (directly) to release HCl. In addition, Pepsinogen is induced to be released from chief cells.

– The gastric phase begins when food enters the stomach. The stimulants for initiation of the gastric phase include distension of the stomach and the presence of proteins and amino acids in the lumen. Initially, the distention induces vago-vagal reflexes that result in stomach relaxation to allow a large meal to enter. Then, the nervous system induces motility to begin. Acid and pepsinogen release are also reinforced during the gastric phase.

– The intestinal phase of digestion occurs when chyme begins to enter the small intestine. Feed-back then occurs to the stomach to restrict gastric motility and to slow the release of materials into the intestine.

The Intestinal Phase of Digestion

Summary: Control of Secretion

Blood Supply to the GI Tract •Virtually all of the blood leaving the GI

tract travels through the hepatic portal vein and through the liver. •Within the liver, reticuloendothelial cells that line the liver sinusoids remove bacterial and other large material that may enter the general blood stream from the GI tract. •Most of the non-fat, water soluble nutrients absorbed from the gut are also transported to the liver sinusoids. Here, liver cells absorb and store many of the nutrients. •Much intermediate processing of these nutrients also occurs in the liver. •Non—water-soluble, fat-based nutrients are almost all absorbed by the liver lymphatics and then conducted to the blood via the lymphatic system.

Control of GI Blood Flow• Under normal conditions, the blood flow in each area of the

gastrointestinal tract as well as in each layer of the gut wall is directly related to the level of local activity. –For example, blood flow to the intestinal villi increases during

absorption, and blood flow to the muscle layers increases during motility.

• The “local factors” affecting this blood flow are still unclear, but almost certainly include the gut peptide hormones (cholecystokinin, vasoactive intestinal peptide, gastrin, and secretin). These hormones typically induce vasodilation.

• The gut receives a huge blood supply during resting conditions. This blood supply can be markedly reduced by actions of the sympathetic nervous system in cases where the blood needs to be diverted elsewhere (e.g., exercising muscles).

Absorption by the GI System

Absorption by GI Tract• In general, almost all nutrient absorption occurs

in the small intestine; the only substances absorbed more proximally in the GI tract are lipid-soluble substances, including alcohol and aspirin. • The colon also is involved in absorbing water and

ions, as well as vitamins produced by the “intestinal flora”. • Both active transport and diffusion (both simple

and facilitated) are used to absorb materials in the gastrointestinal tract.

Na+ Absorption by GI Tract•One very important ion to be absorbed is sodium, as large amounts are lost into the lumen of the gastrointestinal tract in secretions. •Sodium is actively transported from intestinal epithelial cells into the bloodstream. •Because the epithelial cells are constantly pumping sodium into the blood, there is a concentration gradient for this ion that causes it to diffuse from the gut lumen into the epithelial cells. •The gastrointestinal tract makes use of this concentration gradient to move other substances. •The transport protein on the lumen side of the epithelial cells will only pass sodium if it combines with another appropriate substance, which is usually glucose. •Through this mechanism, glucose is moved into the epithelial cell. In other words, the initial active transport of sodium through the basolateral membrane provides the “force” that drags glucose into the epithelial cell. •A facilitated carrier for glucose exists on the basolateral membrane to move this sugar into the blood. •Similarly, co-transport mechanisms that use the Na+ gradient are mainly responsible for amino acid absorption.

H2O Absorption by GI Tract• In all parts of the body,

water is transported through simple diffusion. However, the concentration gradient that is set-up in the epithelial cells by the active transport of sodium at the basolateral membrane tends to “pull” water in from the lumen, and move it to the blood.

Fat Absorption by GI Tract• Fats are digested to small

droplets composed of monoglycerides and free fatty acids, which are called micelles.• Bile plays a critical role in this

process. Fats are not soluble in water, the major constituent of chyme. However, the bile salts surround the micelle and make the fats soluble.

• However, when a micelle becomes adjacent to the villi, it experiences a local acidic environment because of transport occurring at the membrane. The acidity causes the micelle to disintegrate, releasing the free fatty acids and monoglycerides that diffuse into the epithelial cell (as they are lipophilic).

• Cholesterol is transported on a specific, energy-dependent membrane transporter.

• Thus, micelles formed by bile are critical in transporting fats and cholesterol to the intestinal brush border for absorption; without bile the fats were pass through the colon undigested.

Clinical Note

• A new drug, Zetia (Ezetimibe), blocks the absorption of Cholesterol from the GI tract• Zetia is effective in cases where blocking

cholesterol synthesis is not adequate

Clinical Note• Lactase levels decease in most individuals as

they age, resulting in inability to digest milk sugar (lactose intolerance)• Between 30 and 50 million Americans are

lactose intolerant. Certain ethnic and racial populations are more widely affected than others. As many as 75 percent of all African Americans and American Indians and 90 percent of Asian Americans are lactose intolerant. The condition is least common among persons of northern European descent.

Fat Absorption by GI Tract• Once in the cytoplasm of the endothelial cell,

monoglycerides and free fatty acids move to the smooth endoplasmic reticulum, where they are re-synthesized into triglycerides.

• They then combine with cholesterol and proteins into large droplets called chylomicrons. Formation of chylomicrons is necessary to solubilize the fats.

• Because of their size, chylomicrons must be packaged into secretory vesicles in order to leave the epithelial cells by exocytosis.

• These particles are too large to cross the basement membrane of capillaries, and are instead absorbed into lymph vessels of the intestine.

• However, a few shorter fatty acids are able to diffuse across the capillary wall and into the blood.

Absorption of Materials by the Colon• As discussed previously, considerable water and ion absorption

occurs in the colon. • Furthermore, many bacteria typically live in the colon. These

bacteria normally derive their energy supply by digesting cellulose, which is not broken down in the colon and stomach. An end result of this digestion are vitamin K and B12. In particular, the vitamin K production can be important, as we typically consume too little of this important substance.

• These bacteria also generate gases, including carbon dioxide, hydrogen gas, and methane. Fermentation of some particular undigested foods can lead to a production of large amounts of these gases, and other foul-smelling products, which can have undesirable social consequences.

• In general, movement of materials across epithelial cells in the gastrointestinal system is achieved through very similar mechanisms as used in the kidney.

What Isn’t Absorbed?• Large molecules that can’t be digested (e.g.,

indigestible plant material such as cellulose) are eliminated as feces.

• Typical, feces are composed of about 25% water and 75% solids.

• The solid matter is composed, in addition to undigested foods, of dead bacteria, sloughed epithelial cells, and dried constituents of digestive juices.

• The color of feces comes from derivatives of bilirubin, a breakdown product of hemoglobin that is a constituent of bile.