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Gastrointestinal Physiology

Joseph P. Zbilut, PhD, DNSc Lab - 1229 Jelke - Tel: 942-6008 - Email: Joseph_P_Zbilut@rush.edu

Lectures: Tues. Jan. 18, 11-12 am; Wed., Jan. 19, 3-4; Mon., Jan. 24, 9-11 am; Tues., Jan 25, 10-11 am. Lecture Topic Readings (Sherwood, 3rd/4th) 1 Overview 546-555/559-568 2 Mouth, esophagus, stomach 555-565/568-575 3 Stomach, small intestine 565-584/575-592 4 Small and large intestines 584-591/592-605 5 Large intestine, review 591-599/605-611 Lectures are based on logical organization of material-they may or may not coincide with lecture hours. GI Workshop: Tues., Jan 25, 2-4 pm; or Wed., Jan 26, 1-3 pm. Supplemental Source: Johnson LR, (ed). Gastrointestinal Physiology. 5th Ed. Mosby, 1997. Figures are from Sherwood, L. Human Physiology, 3rd and 4th Eds., (West Publishing, Minneapolis/St. Paul, 1997 and 2001); and Johnson, LR. Essential Medical Physiology, (Raven Press, New York, 1992); outline based on Johnson (above) and Bullock J, et al. Physiology, 4th Ed., (Williams and Wilkins, Philadelphia, 2001). Please note—the question often is asked: “How should I study for the exam?” The following priorities may be useful: 1) lectures (often covers newest findings and an attempt to provide clinical context); 2) lecture notes; 3) text. Important terms are in bold letters--important (or tricky, or clinically interesting) concepts are in square boxes:

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I. DIGESTIVE SYSTEM: OVERVIEW

Objectives: • 1. Define motility, secretion, digestion and absorption • 2. Know the parts and functions of the gi tract • 3. Define peristalsis • 4. Describe neural control of the gi tract • 5. Describe hormonal control of the gi tract

A. Structure-composed of a long muscular tube-the gastrointestinal (GI) tract,

or alimentary canal plus a set of accessory organs (Figs 1-3) Fig. 1 - it's a tube!-essentially simple-with modifications to accomplish motility, secretion, digestion and absorption. GI related problems remain as one of the greatest

causes of global morbidity and mortality—and a chiefreason for people to see their physician.

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Fig 2

Fig 3

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B. Function. (Figs 4-6)--1) Motility, 2) Secretion, 3) Digestion, 4) Absorption Fig 4. Overview of digestive system

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Fig 5--basic chemical processes are simple: breakdown of large molecules to monomers

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Fig 6--all processes exquisitely controlled

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II. THE ORAL CAVITY, PHARYNX AND ESOPHAGUS Objectives:

• 1. Describe the composition of saliva • 2. Describe neural control of salvation • 3. List steps in swallowing • 4. Explain esophageal sphincter function A. Mastication-breaks down food to increase surface areas and allows

it to be exposed to salivary lipase and amylase.

B. Salivary glands. Saliva is secreted by parotif, sunlingual and submaxillary glands (Figs 7-9)

1. Composition of saliva. The salivary glands secrete a relatively

high volume of fluid (0.5-1 L/day containing electrolytes and proteins.)

Fig 7 Fig 8

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Fig 9

i. Electrolytes. Electrolyte concentration and osmolality both vary with secretory flow rates, but generally, in comparison to plasma, saliva is hypotonic and contains higher concentrations of potassium (K+) and bicarbonate (HCO3) and lower concentrations of sodium (Na+) and chloride (Cl).

ii. Proteins. Three types of proteins are found in saliva (not particularly important).

a. The enzymes, amylase (ptyalin) and lingual

lipase, begin the process of starch and fat digestion.

b. Mucin is a glycoprotein that lubricates the food.

c. Lysozyme destroys certain bacteria 2. Control of salivary secretion (Fig. 10)

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Fig 10

i. Salivary secretion is controlled entirely autonomic nervous system reflexes. a. Parasympathetic

Salivary secretion and composition are controlledsolely by the autonomic nervous system, incontrast, other parts of the gi tract include localreflexes and hormonal mechanisms as well.Nerve stimulation

Causes the salivary gland cells to secrete a large volume of watery fluid that is high in electrolytes but low in proteins.

b. Sympathetic nerve stimulation causes the salivary glands to secrete a small volume of fluid containing a high concentration of mucous.

ii. Salivary reflexes are elicited by the thought, aroma, or taste of food or by the presence of food with the alimentary canal.

iii. Salivary gland metabolism and growth are both stimulated by increased autonomic nervous system activity.

C. Peristalsis 1. Definition. Peristalsis is a coordinated pattern of smooth muscle

contraction and relaxation (we will talk about this more later). 2. Function. Peristalsis helps move food through the pharynx and

esophagus and within the stomach. Peristalsis plays a minor role in propelling food through the intestine (again, we'll speak about this more later).

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3. Mechanics. During peristalsis, contraction of a small section of proximal muscle is followed immediately by relaxation of the muscle just distal to it. The resulting wavelike motion moves food along the GI tract in a proximal (orad) to distal (caudad) direction.

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Deglutition (swallowing) (Fig. 11)

1. Phases of swallowing (Figs 11-14) Swallowing, coordinated by the brain stem, initiates primary peristalsis.

i. Oral ( voluntary) ii. Pharyngeal (coordinated

by medulla and pons) iii. Esophageal

GI 11 Fig 12 Modulation of Enteric Nervous System by Sympathetic Nerves Fig 13

Enteric Nervous System

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Fig 14

2. Sphincters involved in swallowing

i. The upper esophageal sphincter is composed of striated muscle and is completely under the control of the vagal fibers innervating the esophagus.

ii. The lower esophageal sphincter is composed of smooth muscle (not a "true sphincter"). Its tone is maintained by amyogenic process. Intrinsic nervous system neurons (with vagal input) cause the lower esophageal sphincter to relax during peristalsis. The synaptic transmitter released by these neurons is neither ACh nor norepinephrine and is thus called a nonadrenergic noncholinergic neural transmitter. Its identity is not known but may be either adenosine triphosphate (ATP) or vasoactive intestinal peptide (VIP).

3. Types of esophageal peristalsis. There are two types of

esophageal peristalsis primary (swallowing) and secondary (presence of food in esophageal peristalsis, primary (swallowing) and secondary (presence of food in esophagus not forced down by primary peristalsis--i.e., if the food gets "stuck" in the esophagus, the secondary peristalsis will attempt to move food down--a locally mediated reflex. (Not always successful).

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III. THE STOMACH

Objectives: • 1. Describe 3 major exocrine secretions of stomach • 2. Describe the mechanism of HCl secretion and its control • 3. Explain role of pepsinogen secretion • 4. Define and explain the mechanism for the basic electrical rhythm • 5. Describe factors regulating gastric motility • 6. Describe regulatory components of vomiting A. Anatomy (Fig. 14) Fig. 14

1. Functional components 2. Musculature 3. Innervation

B. Motility (Figs 15-17) 1. Function (Mixing with secretions and Propulsion of food boluses) 2. Receptive relaxation. When food is passed from the esophagus

to the stomach, the contractile activity of the fundus is inhibited, enabling it to easily accommodate 1-2 L of food (by stretching).

3. Peristalsis. Peristaltic contractions are initiated near the fundal-corpus border and proceed caudally, producing a peristaltic wave that propels the food towards the pylorus. Peristaltic contractions

GI 14 are produced by periodic changes in membrane potential, called slow waves, or the basic electrical rhythm (BER) produced by the interstitial cells of Cajal (located at boundaries of muscle layers--are not action potentials, but cyclically bring membrane closer or farther from threshold. The force of peristaltic contractions is controlled by gastrin and Ach.

Increasingly, it has become obvious that many “motility”problems/pathologies are related to neurotransmitters.

Fig. 15 Relationship of electrical signals to mechanical effects in stomach

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Fig 16 Gastric emptying and mixing as a result of antral peristaltic contractions: a) Gastric emptying. A peristaltic contraction originates in the upper fundus and sweeps down toward the pyloric sphincter, becoming more vigorous as it reaches the thick-muscled antrum. As the strong antral peristaltic contraction propels the chime forward, a small portion of chime is pushed through the partially open sphincter into the duodenum. The stronger the antral contraction, the more chime is empties. b) Gastric mixing. When the peristaltic contraction reaches the pyloric sphincter, the sphincter is tightly closed and no further emptying takes place. When chime that was being propelled forward hits the closed sphincter, it is tossed back into the antrum. Mixing of chime is accomplished as chime is propelled forward and tossed back into the antrum with each contraction.

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Fig 17

4. Control of gastric emptying i. Local reflexes

a. Excitatory effects. Gastrin, released into the circulation in response to antral distension or food breakdown products, enhances gastric contractions.

b. Inhibitory effects. A variety of intestinal hormones, collectively called enterogastrones, inhibit gastric contractions. Cholecystokinin (CCK), GIP (gastric inhibitory peptide), and secretin are known enterogastrones.

ii. Hormones a. Gastrin is released into the circulation in response to

antral distension or food breakdown products--it also enhances gastric contractions

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b. CCK is released from the duodenum in response to fat or protein digestion products. CCK probably acts by blocking the excitatory effects of gastrin on gastric smooth muscle.

c. Secretin is released from the duodenum in response to the presence of acid. Secretin most likely has a direct inhibitory effect on smooth muscle. (Note, there are several other hormones which are not completely understood, including motilin, which increases motility, and vasoactive intestinal peptid (VIP),

which increases pancreatic barcarbonate secretion, and acts as a neurotransmitter similar to Ach).

iii. Migrating motor complex (MMC). During the interdigestive period, any food left in the stomach is removed by the MMC. d. The MMC is a peristaltic wave that begins within the

stomach (similar to BER) and travels through the entire GI tract.

e. The peristaltic wave occurs every 60-90 minutes during the interdigestive period.

f. The hormone motilin, which is released from endocrine cells within the epithelium of the small intestine, increases the strength of the MMC.

5. Vomiting (or emesis) is the forceful expulsion of the food from the stomach and intestine. i. Initiation. Vomiting may be initiated by direct activation of

the vomiting center in the medulla or by activation of the chemoreceptor trigger zone within the area postrema of the brain stem. (Intestinal pressure wave (abdominal contractions) + reverse peristalsis>stomach>esophagus).

C. Gastric secretion 1. General considerations

i. Function. Gastric secretions aid in the breakdown of food into small particles and continue the process of digestion begun by salivary enzymes. About 2 L/day of gastric secretions are produced.

ii. Phases of gastric secretion a. The cephalic phase of gastric secretion is initiated by

the thought, sight, taste, or smell of food. It is dependent on the integrity of the vagal fibers innervating the stomach.

b. The gastric phase of secretion is initiated by the entry of food into the stomach.

c. The intestinal phase of secretion begins as the chyme begins to empty from the stomach into the duodenum.

iii. Types of cells a. Oxyntic glands are located in the fundus and corpus

of the stomach. They contain three types of secretory cells.

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1. The parietal (oxyntic) cells secrete HCl. These cells are also responsible for the secretion of intrinsic factor, which is necessary for the absorption of vitamin B12 by the ileum of the small intestine.

2. Peptic (chief) cells secrete pepsinogen, the precursor for the proteolytic enzyme pepsin.

3. Mucous cells secrete mucus. b. Pyloric glands are located in the antrum and pyloric

regions of the stomach. They contain G cells and

some mucous cells. G cells are responsible for the release of the hormone gastrin.

2. HCl secretion (Figs 18-19) Fig 18

The stomach mucosa and its gastric pits. a) The stomach mucosa consists of the oxyntic mucosa, which lines the body and fundus, and the pyloric gland area, which lines the antrum. b) The stomach’s gland cells are located in deep invaginations, or gastric pits of the luminal surface of the stomach. c) The gland cells include mucous neck cells, which secrete mucus, chief cells, which secrete pepsinogen and parietal cells which secrete HCl and intrinsic factor. The surface epithelial cells also secrete mucus.

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i. Functions of HCl a. HCl participates directly in the breakdown of protein b. It provides an optimal pH for the action of pepsin c. It hinders the growth of pathogenic bacteria

ii. Mechanism of HCl secretion (complex pump actions of the parietal cells involving bicarbonate and carbonic anhydrase)

Although HCl can destroy many bacteria, some bacteria remain, including Helicobacter pylori which is now known to be responsible

for most ulcers. It is now becoming obvious that we know very little about GI bacteria/viruses. Recent new techniques have identifies1000 new GI viruses. Also, it’s been determined there are about 500 “singnature” bacteria in each person’s gut—unique to eachperson. What they do, etc has yet to be adequately understood. We do know that wiping some of them out (e.g., with antibiotics) cancause pathology.

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Mechanism of HCl secretion. The stomach’s parietal cells actively secrete H+ and Cl- by the actions of two separate pumps. The secreted H+ is derived from H2CO2 that is generated within the cell from CO2 that is either metabolically produced in the cell or diffuses from the plasma. The secreted Cl- is transported into the parietal cell from the plasma. The HCO3

- generated from H2CO3 dissociation is transported into the plasma in exchange for the secreted Cl-.

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3. Substances affecting HCl secretion (Figs 20-23)

i. Stimulation of HCl secretion. Ach, histamine, and gastrin act directly on the parietal cell to stimulate HCl secretion. In addition, Ach and gastrin may directly stimulate the mast cell to secrete histamine.

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a. ACh, a neurotransmitter, is released from nerve cells innervating the parietal cell.

b. Histamine is released from mast cells located within the corpus. 1) Histamine can stimulate HCl secretion directly or

can potentiate the secretion produced by ACh or gastrin.

2) Histamine is classified as a paracrine agent because it diffuses from its release site to the parietal cells (rather than traveling within the circulation as does a hormone).

3) The most commonly used anti-ulcer drugs (i.e. cimetidine and ranitidine) are histamine antagonists that block the H2 receptor on the parietal cell.

c. Gastrin is released from G cells in the distal stomach. Gastrin is classified as a hormone because it travels to its target cell through the circulation. A variety of substances affect gastrin secretion.

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ii. Inhibition of HCl secretion. Somatostatin inhibits HCl secretion by parietal cells and gastrin secretion by G cells. Somatostatin is released from interneurons within the enteric nervous system.

4. Regulation of gastric acid (HCl) secretion (Figs 21-23) Fig 21 Stimulation is highly integrated by ANS, hormones, and reflexes (local)

Fig 22 Inhibition is also highly integrated Fig 23

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a. Stimulation during the cephalic phase. The vagus nerve

stimulates the release of ACh and inhibits the release of somatostatin from interneurons within the enteric nervous system, thus enhancing the secretion of HCl.

b. Stimulation during the gastric phase. The amount of ingested protein is the most important determinant of acid secretion during the gastric phase. Amino acids and peptides directly stimulate parietal cells to secrete acid.

c. Inhibition during the gastric phase. The most potent inhibitor of HCl secretion during the gastric phase is the presence of acid in the stomach. If the pH of the stomach falls below 2, acid secretion stops. Acid secretion is inhibited by two mechanisms. 1) A low pH directly inhibits HCl and gastrin secretion. 2) Lowering the pH also releases somatostatin, which

inhibits the secretion of gastrin by the G cells and HCl by the parietal cells.

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d. Stimulation during the intestinal phase. The presence of protein digestion products within the duodenum causes an increase in HCl secretion.

e. Inhibition during the intestinal phase. The inhibition of HCl secretion is accomplished by the same mechanisms responsible for inhibiting gastric motility. 1) H+, fatty acids and increased osmolarity stimulate

the release of enterogastrones from the duodenum. 2) The most important of the enterogastrones may be

gastric inhibitory peptide (GIP), which inhibits both gastrin release and parietal cell secretion of HCl. GIP is thought to act by stimulating the release of somatostatin, which, in turn, inhibits the parietal and G cells.

5. Gastrin secretion i. Functions of gastrin

a. Gastrin stimulates HCl

b. Secretion c. It increases gastric and intestinal motility

Starvation reduces gastrin secretion and propermucosal growth (intestinal villi are involved too).These are factors to be considered with patientssuffering from anorexia-excessive initial feedings canpromote diarrhea/vomiting and make the conditionworse.

d. It increases pancreatic secretions. e. It is necessary for the proper growth of GI mucosa.

ii. Regulation of gastrin secretion a. In general of gastrin secretion is regulated by the

same mechanisms that regulate HCl secretion (i.e. vagal stimulation, pH, enterogastrones).

b. In addition, several foods and food breakdown products directly stimulate the release of gastrin. These include protein digestion products, alcohol, and coffee (both caffeinated and decaffeinated).

6. Pepsinogen secretion (Fig 24)

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Fig 24. Pepsinogen activation in stomach lumen. In the lumen, hydrochloric acid activates pepsinogen to its active form, pepsin, by cleaving off a small fragment. Once activated, pepsin autocatalytically activates more pepsinogen and begins protein digestion. Secretion of pepsinogen in the inactive form prevents it from digesting the protein structures of the cells in which it is produced. Its activation process does not commence until it reaches the lumen and comes into contact with CCl secreted by a separate cell in the gastric pit.

i. Function of pepsinogen. Pepsin, the active form of pepsinogen, is a proteolytic enzyme that begins the process of protein digestion.

ii. Regulation of pepsinogen secretion. Pepsinogen is released from the chief cells of the oxyntic glands during all three phases of digestion.

7. Intrinisic factor

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i. Definition. Intrinsic factor is a glycoprotein secreted by the parietal cells of the gastric mucosa, chiefly by those in the fundus.

ii. Function. Intrinsic factor is required for the absorption of vitamin B12. a. Intrinisic factor forms a complex with vitamin B12. b. The intrinsic factor B12 complex is carried to the

terminal ileum, where the vitamin is absorbed. D. The gastric mucosal barrier protects the gastric lining cells from

damage by intraluminal HCl or autodigestion. Its chief component is a thick viscous alkaline mucous layer that measures over 1 mm thick and is secreted by the mucosal cells. The mucosal cells cover the surface between the various gastric glands and outnumber all other cell types found in the gastric mucosa (Figs. 25-26).

Fig 25 Mucosal barrier

The gastric mucosal barrier encompasses the following factors that enable the stomach to contain acid without injuring itself: the gastric mucosal cells are joined by tight junctions that prevent HCl from penetrating between the cells (1), and the luminal membranes of these cells are impermeable to H+ so that HCl cannot penetrate into the cells (2). A mucous coating over the gastric mucosa offers further protection (3).

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Fig 26 Ulcer formation

1. The turnover rate of the gastric mucosa is extremely high; the entire mucosa is replaced in 1-3 days. Prostaglandins signal need for cell replacement. NSAIDs block prostaglandins, and his can result in ulcer formation with extended NSAID ingestion.

2. Mild injury results in increased mucus secretion and surface desquamation followed by regeneration.

3. More serious injury denudes the mucosal surface, forming an ulcer and produces bleeding. Ulceration results when damage to the mucosa (e.g. due to a highly concentrated HCl, 10% ethanol, salicylic acid, or acetylsalicylic

Aspirin (a weak acid) is easily absorbed in the low pH of thestomach--once absorbed it acts by acid stimulating histaminerelease and disruption of the local mucosa. Also suppressesprotective mucosal barrier production.

acid) allows acid to penetrate the mucosal barrier and destroy mucosa cells. This liberates histamine, which increases acid secretion and produces increased capillary permeability and vasodilation. The latter

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two effects lead to edema. It is the exposure of mucosal capillaries to the digestive process that leads to bleeding.

4. Additionally the class of drugs called non-steroidal anti-inflammatory agents (NSAIDS--and aspirin is an NSAID) inhibit COX-1 (cylco-oxygenase) which is necessary for the formation of GI prostaglandin, necessary for health stomach and duodenal blood flow, as well as mucus and bicarbonate secretion. COX-2 is responsible for inflammatory reactions, ergo selective COX-2 inhibitors would be preferred. (With Ibuprofen as a reference and GI complication risk of 1.0, Aspirin has a relative risk of 1.6, Naproxen 2.2, and Indomethacin 2.4)

E. Gastric digestion and absorption i. Digestion

a. Carbohydrate digestion in the stomach depends on the action of salivary amylase (minor).

b. Protein digestion. About 10% of ingested roteinis broken down completely in the stomach (HCl and pepsin).

c. Fat digestion is minimal, and is performed by gastric lipase produced by glands in the fundus.

ii. Absorption a. Nutrients. Very little

absorption of nutrients takes place in the stomach.

Aspirin and alcohol are the majorsubstances absorbed by thestomach.

b. Water moves in both directions across the mucosa. It does, however, follow osmotic gradients. Water-soluble substances, including Na+, K+, glucose, and amino acids, are absorbed in insignificant amounts.

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IV. Lecture 4: THE SMALL INTESTINE

Objectives: • 1. Describe exocrine secretions of pancreas and their function • 2. Describe factors regulating pancreatic secretion • 3. Describe components of bile and their regulation • 4. Describe carbohydrate, protein and fat digestion • 5. Describe small intestine secretions • 6. Describe motility in small intestine A. Anatomy

1. Small intestine i. The small intestine has three parts: the duodenum, the

jejunum, and the ileum. ii. Though the small intestine is approximately 5 m long, it has

an absorptive area of over 250 M2. a. Its large surface area is created by numerous folds of

the intestinal mucosa (valvulae conniventes); by densely packed villi, which line the entire mucosal surface; and by microvilli, which protrude from the surface of the intestinal cells.

b. The epithelial cells from which the microvilli protrude are called enterocytes.

c. The microvilli (about 1 micrometer long and 0.1 micrometer in diameter) give the intestinal mucosa its characteristic brush order appearance.

Much of actual digestion and absorption occurs at the brush border membrane.

iii. The blood supply of the villus is ideally organized to collect the nutrients after they are absorbed across the brush border appearance. a. Each villus is supplied by an arteriole, which gives

rise to a capillary tuft at the tip of the villus. The capillaries coalesce into venules, which drain into the protal vein. The portal vein carries the absorbed nutrients to the liver.

b. Branches of the lymphatics, called lacteals, also extend to the tip of the villus. These vessels carry absorbed fats to the thoracic duct from which they enter the general circulation.

2. The accessory organs involved in intestinal digestion and absorption are: the pancreas, the liver, and the gallbladder (Figs 27-29).

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Fig 27 Pancreas has both exocrine and endocrine portions

Schematic representation of exocrine and endocrine portions of the pancreas. The exocrine pancreas secretes into the duodenal lumen a digestive juice composed of digestive enzymes by the acinar cells and the aqueous NaHCO3 solution secreted by the duct cells. The endocrine pancreas secretes the hormones insulin and glucagons into the blood.

GI 30 Fig 28-blood from GI system is first "processed" by liver lobes before entering major circulation Fig 29

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B. Motility (Fig 30-32)

1. Contractile activity includes 2 types of movements Fig 30

GI 32 Fig 31 Pacing and Peristalsis and Mixing Fig 32

BER and Peristalsis

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a. Segmentation is the most common type of intestinal contraction. 1) During segmentation, about 2m of the intestinal wall

contracts, forcing the chyme back toward the stomach (oradly) and toward the colon (aboradly).

2) When the muscle relaxes, the chyme returns to the area from which it was displaced.

3) This back-and-forth movement enables the chyme to become thoroughly mixed with the digestive juices and to make contact with the absorptive surface of the intestinal mucosa.

4) Segmentation contractions occur about 12 times/min in the duodenum and 8 times/min in the ileum. The contractions last for 5-6 seconds.

5) Segmentation occurs throughout the digestive period. b. Peristaltic contractions also occur in the small intestine (see p.

8) 1) Although peristaltic contractions

occasionally propel food along the entire length of the intestine, they rarely involve more than a short segment of the intestine.

2) Peristalsis is not considered to be an important component of intestinal transit.

3) The relationship between segmentation and peristalsis has been poorly understood until recently, as the roles of excitatory and inhibitory neurons in the gut have been elucidated. (p. 29, Fig. 31).

c. The MMC spreads over the intestine during the interdigestive period. 1) The MMC's sweep out the chyme remaining in the small

intestine during interdigestive period. 2) MMC's occur every

60-90 minutes and last for about 10 minutes.

MMC's are important to preventbacterial overgrowth.

2. Propulsion of chyme. During the digestive period, the higher frequency of

segmentation in the proximal intestine (duodenum) than in the distal intestine (ileum) propels the chyme slowly toward the colon. Thus when chyme is pushed forward it is less likely to be forced back by a segmentation contraction. In contrast, when it is pushed backward, it will be quickly pushed forward again by a segmentation contraction.

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Fig 33 Bulk movements in intestines are controlled by reflexes, e.g., gastrocecal reflex

3. Control of intestinal motility. The frequency and strength of

segmentation contractions in the intestine are controlled by the slow waves. i. Generation. Segmentation contractions can occur only if the

slow waves produce spikes, or action potentials. Spikes appear on the slow waves when the membrane potential is sufficiently depolarized. (N.B. The "ileal break" (a reflex) stops propulsion if fatty acids present in intestines).

ii. Frequency of spikes related to frequency of slow waves iii. Strength

a. The strength of a segmentation contraction is proportional to the frequency of spikes generated by the slow wave. This frequency is controlled by the amplitude of the slow wave. Thus, the greater the

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slow wave amplitude, the greater the frequency of spikes generated and the greater the strength of the contraction.

b. Slow wave amplitude is also controlled by the hormones released during digestion. 1) Gastrin, CCK, motilin and insulin increase the

slow wave amplitude. 2) Secretin and glucagon reduce the slow wave

amplitude. C. Pancreatic secretions

1. Pancreatic cell types and their functions. The pancreas contains endocrine, exocrine, and ductal cells. i. The endocrine cells, arranged in small islets within the

pancreas, secrete insulin, glucagon, somatostatin, and pancreatic polypeptide directly into the circulation.

ii. The exocrine cells are Organized into acini that produce four types of digestive enzymes: peptidase

Various pancreatic inflammations can severely limitabsorption and cause diarrheas as well as fluid andelectrolyte disturbances by a failure of liberation ofappropriate enzymes.

lipases, amylases, and nucleases, which are responsible for digesting proteins, fats, carbohydrates, and nucleic acids, respectively. In their absence, malabsorption syndromes develop.

iii. Each day, the ductal cells secrete about 1200-1500 ml of pancreatic juice containing a high concentration of HCO 3-. The HCO3

- neutralizes gastric acid and regulates the pH of the upper intestine. Failure to neutralize the chyme as it enters the intestine will result in duodenal ulcers.

2. Composition of pancreatic secretions i. Electrolytes

a. Na+ and K+ concentrations in pancreatic juice are the same as those in plasma water (i.e., 142 mEq/L respectively).

b. HCO3- concentration in pancreatic juice is much

higher than it is in plasma water (100mEq/L as opposed to about 24 mEq/L).

c. Pancreatic juice also contains small amounts of other ions such as Ca2+, magnesium.

d. Mechanism of secretion of HCO3- by the ductal cells is

not well understood. ii. Enzymes. Three major types of pancreatic enzymes

(excluding nucleases) are secreted by the pancreas: amylases, lipases and proteases. a. Pancreatic alpha-amylase is secreted in its active

form. It hydrolyzes glycogen, starch, and most other complex carbohydrates, except cellulose, to form disaccharides.

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b. Pancreatic lipases (lipase, cholesterol lipase and phospholipase) are secreted in their active forms. The enzymes that hydrolyze water-insoluble esters require bile salts to work. Water-soluble esters can be hydrolyzed without the action of bile salts.

c. Pancreatic proteases (tyrosine and the chymotrypsins) are secreted in their inactive zymogen form (trypsinogen and the chymotrypsinogens, respectively). 1) Trypsinogen is converted to trypsin by

enterokinase or by trypsin itself (autocatalysis).

2) The chymotrypsinogens are converted

Part of the damage in pancreatitis is traced to autodigestion of the pancreas by its own enzymes.

to their active form by trypsin.

3) Trypsin inhibitor is secreted by the same cells and at the same time as the pancreatic proenzymes. Trypsin inhibitor protects the pancreas from autodigestion.

3. Control of pancreatic secretion. Like gastric secretion, pancreatic secretion is divided into the following three phases. i. Cephalic phase. The thought, sight, smell or taste of food

produces the cephalic phase of pancreatic secretion. Both acinar and ductal cell secretions are enhanced by vagal

stimulation. (Fig. 34).

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a. Enzyme secretion by the acinar cells is stimulated by enteric neurons that release ACh.

b. HCO3- secretion by ductal cells is stimulated by

enteric neurons that release a noncholinergic transmitter that is thought to be VIP.

ii. Gastric phase. Pancreatic secretion is enchanced during the gastric phase by distension and food breakdown products.

1) Distension of the antrum and corpus initiates a vago-vagal reflex resulting in a low volume of pancreatic secretion containing both HCO3

- and enzymes. ACh is the transmitter.

2) Food breakdown products (primarily amino acids and peptides) can stimulate pancreatic secretions because of their ability to cause the

G cells of the antrum to release gastrin. Gastrin produces a low volume, high enzyme pancreatic secretion.

iii. Intestinal phase. The major stimulants for pancreatic secretion are the hormones CCK and secretin. They are released from endocrine cells in the duodenum and jejunum during the intestinal phase of pancreatic secretion (fig. 35).

Fig 35

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a. CCK in addition to its effect on the gallbladder, is potent stimulant of pancreatic enzyme secretion.

b. Secretin was the first hormone ever discovered. Its primary effect is to increase HCO3

- secretion by the pancreas.

c. Control of CCK and secretin release. CCK and secretin are secreted from endocrine cells in response to the entrance of chyme into the small intestine. 1) Amino acids (primarily phenylalanine), fatty

acids (primarily phenylalanine), fatty acids, and monoglycerides

Pancreatic secretions are important not only fordigestion but also for control of pH in the duodenum.The enterogastrones are important for proper"timing" and orderliness of digestion.

are the major stimuli for CCK secretion. 2) Low pH (< 4.5), caused by the presence of

gastric acid (HCI) in the intestine, is a potent stimulus for the release of secretin.

D. Biliary secretions 1. General features of bile

i. Function. Bile is required for the disposal and absorption of fats and for the excretion of water-insoluble substances such as cholesterol and bilirubin.

ii. Formation. Bile is formed by liver epithelial cells, called hepatocytes, and by epithelial cells lining the bile ducts, called ductal cells. Between 250 and 1100 ml of bile are secreted daily.

iii. Storage. Although it is secreted continuously, bile is stored in the gallbladder during the interdigestive period.

iv. Release. Bile is released into the duodenum during the digestive period only after chyme has triggered the release of CCK, which then produces contraction of the gallbladder and relaxation of the sphincter of Oddi.

2. Composition of bile i. Bile acids (primarily from hepatocytes and secondary by

action of bacteria in intestine). ii. Bile pigments.

a. Bilirubin and biliverdin, the two principal bile pigments, are metabolites of hemoglobin formed in the liver and conjugated as glucuronides for excretion. They are responsible for the golden yellow color of bile.

b. Intestinal bacteria metabolize bilirubin further to urobilin, which is responsible for the brown color of stool--obstruction of the bile duct can cause clay colored stools.

GI 39 c. If bilirubin is not secreted by the liver, it builds up in

the blood and tissues, producing jaundice. iii. Phospholipids are 2nd most common constituent of bile,

after salts iv. Cholesterol --present in very small amounts. v. Electrolyte composition similar to that of plasma

3. Enterohepatic circulation -- recirculation of bile salts from liver to small intestine and back again due to limited amount of bile salts

Fig 36

i. Path of circulation. Bile salts travel from the liver to the duodenum via the common bile duct. When the bile salts reach the terminal ileum, they are reabsorbed into the portal circulation. The liver then extracts them from the portal blood and secretes them once again into the bile. a. Bile salts are reabsorbed only in the terminal ileum.

No reabsorption of bile salts occurs in the duodenum or jejunum.

b. From 90-95% of the bile salts that enter the small intestine are actively reabsorbed from the lower ileum back into the portal circulation.

c. The remaining bile salts are excreted into the feces. ii. Circulating pool. The total circulating pool of bile salts

(consisting of primary and secondary bile acids) is approximately 3.6 g. Because 4-8 g of bile salts are required to digest and absorb a meal (more if the meal is high in fat),

GI 40

the total pool of salts must circulate twice during the digestion of each meal. Consequently, the bile salts usually circulate 6-8 times daily.

iii. Bile salts synthesis and replacement. The rate of bile salt synthesis is determined by the rate of return to the liver. The usual rate is 0.2-0.4 g/day, which replaces normal fecal losses. The maximal rate is 3-6 g/day. If fecal losses exceed this rate, the total pool size decreases.

iv. Clinical implications: malabsorption syndromes and diarrhea often resulting in fat and fat soluble vitamin malabsorption, and/or fluid and electrolyte loss (e.g. Crohn's disease).

4. Control of biliary secretion. The volume of biliary secretion is controlled by secretin and the amount of bile in that secretion is dependent upon bile reabsorbed by the intestine (liver has limited synthetic ability--total amount tends to be constant).

5. Gallbladder i. Functions. The gallbladder stores and concentrates the bile

during the interdigestive period and empties its contents into the duodenum during digestion.

ii. Control. CCK is the major stimulus for gallbladder contraction and sphincter of Oddi relaxation. Vagal stimulation of the gallbladder also causes gallbladder contraction and sphincter of Oddi relaxation. Vagal stimulation occurs directly during the cephalic stage of digestion and indirectly via a vago-vagal reflex during the gastric phase of digestion.

iii. Effects of cholecystectomy. Bile, not the gallbladder, is essential to digestion. After removal of the gallbladder, bile empties slowly but continuously into the intestine, allowing digestion of fats sufficient to maintain good health and nutrition. Only high-fat meals need to be avoided.

6. Bilirubin metabolism (Fig 36) formation of bilirubin from hemoglobin catabolism--pathologies an result in jaundice from e.g. excessive RBC destruction or liver/bile duct obstruction.

E. Intestinal secretion 1. Mucus most likely serves a protective role, preventing HCI and

chyme from damaging the intestinal wall. 2. Enzymes capable of breaking down small peptides and

disaccharides are associated with the microvilli of the epithelial cells lining the intestine (brush borer enzymes). Although these enzymes are not secreted into the intestine, they are able to digest small peptides and disaccharides during the absorptive process.

3. Water and electrolytes are secreted by al the epithelial cell of the intestine.

i. The watery secretion provides a solvent into which the

products of digestion are dissolved.

GI 41

ii. If excessive amounts of fluid are produced (as happens when the enterotoxin responsible for cholera stimulates massive fluid secretion), potentially life-threatening watery diarrhea can result

F. Digestion and absorption (Figs 37-39) Fig 37

GI 42

Fig. 38

FIGURE 16-Small intestine absorptive (a) Gross structure of the small intestine. the circular folds of the small intestine collectively increase the absorptive surface area (c) Microscopic fingerlike projection known as a Collectively, the villi increase the surface area (d) Electron microscope view of a villus depicting the presence of microvilli on its luminal microvilli increase the surface area another 20-fold. These surface modifications increase the small absorptive surface area

GI 43 Fig 39

GI 44

1. Carbohydrate Digestion and Absorption (Fig 39)

i. Digestion. Carbohydrates must be digested into

monosaccharides before being absorbed from the GI tract. a. Although starch digestion, by salivary alpha-amylase,

begins in the mouth, almost all carbohydrate digestions occurs within the small intestine.

b. Pancreatic alpha-amylase digests carbohydrates into a variety of oligosaccharides.

c. The oligosaccharides are digested into monosaccharides by brush border enzymes such as maltase, lactase and sucrose.

d. The end products of carbohydrates are fructose, glucose and galaxies.

ii. Mechanisms of absorption (Fig 40-41) Fig 40

GI 45 Fig 41

a. Glucose and galactose are absorbed by a common Na+ dependent active transport system.

b. The carrier has two binding sites for Na+ and one to which either one molecule of glucose or galaxies can bind.

c. Because two Na+ are transported down their electrochemical gradient (established by Na+/K+ pump in basal membrane), a large amount of energy is available for transport; thus, almost all of the glucose and galactose present in the intestine can be absorbed.

iii. Fructose is absorbed by facilitated transport. Fructose absorption occurs readily because most of the fructose is rapidly converted into glucose and lactic acid within the intestinal epithelial cells, thus maintaining a high concentration gradient for diffusion.

iv. After being absorbed into the enterocytes, the monosachardies are transported across the basolateral membrane by facilitated diffusion. They then diffuse from the intestinal interstitium into the capillaries of the villus.

v. Absorption of monosaccharides is not regulated. The intestine can absorb over 5 kg of sucrose each day.

GI 46

vi. Failure to absorb carbohydrates results in diarrhea and intestinal gas. a. The unabsorbed carbohydrates act as osmotic

particles and draw excessive fluids into the intestine, which results in diarrhea.

b. The flora of the intestine and colon metabolize the unabsorbed carbohydrates producing a variety of gases [hydrogen (H2), methane (CH4), and CO2], as well as a variety of intestinal irritants.

c. Lactose intolerance is the most common cause of carbohydrate malabsorption. It results from the inability of the brush border cells to produce lactase. 1) Avoidance of milk or milk products prevents the

symptoms from developing.

Lactose “intolerance” is really not a“disease” but may be an evolutionaryvariant, devolving from cultures whichdid not consume much milk, but do eatcheese. There are other suchexamples: consider that Asianpopulations cannot “digest” alcoholwell, whereas Western populationscan. It has been suggested thatevolutionary wise, Western (European)populations developed this ability as aneed for drinking “safe” forms of water(e.g., wine, beers); whereas Asianpopulations “cleaned” their water withhot teas.

2) Lactose intolerance in adults, where it is common, is not usually a problem. However, in infants, the diarrhea- produced dehydration can be life threatening.

2. Proteins (Fig 42) i. Digestion. Proteins must be digested into small

polypeptides and amino acids before being absorbed. a. About 10 to 15% of the protein entering the GI tract is

digested by gastric pepsin secreted by chief cells. Protein digestion within the stomach is important primarily because the protein digestion products act as secretagogues, stimulating the secretion of proteases by the pancreas.

b. Pancreatic proteases play a major role in protein digestion. The proteases, such as trypsin, are secreted in an inactive form and must be converted into an active form within the intestine. 1) Enterokinase, an enzyme secreted by the

epithelial ells of the duodenum and jejunum, converts the inactive trypsinogen into trypsin.

2) Trypsin then autocatalizes the conversion of trypsinogen to trypsin as well as activating the other proteases.

c. Peptidases, secreted by the intestinal epithelial cells, continue the digestive process begun by the pancreatic proteases, eventually converting the ingested proteins to small polypeptides and amino acids.

ii. Mechanisms of absorption

GI 47 Fig 42

GI 48

A variety of Na+-dependent active transport systems have been identified for the transport of tripeptides, dipeptids, and amino acids. Polypeptides with more than three peptides are poorly absorbed.

1) Separate transporters are present for the absorption of basic, acidic, and neutral amino acids. At least two different polypeptide transporters exist.

2) Tripeptides and dipeptides are absorbed in greater quantities than amino acids.

a. Once inside the enterocytes, intracellular peptidases digest some of the polypeptides to amino acids.

b. Amino acids and the remaining polypeptides are transported across the basolateral membrane of the enterocytes by facilitated or simple diffusion. They then enter the capillaries of the villus by simple diffusion.

3. Fats (Fig 43)

GI 49

Fig 43

GI 50

i. Digestion. Although the serous glands of the tongue secrete lingual lipase, very little, if any, lipid digestion occurs in the mouth or stomach. Unlike carbohydrates and proteins, lipids are absorbed from the GI tract by passive diffusion. However, before the lipids can be absorbed, they must first be made soluble in water. Bile salts are required for the solubilization of lipids. a. Pancreatic lipases. The pancreas secretes three

different lipases. 1) Pancreatic lipase is a fairly specific lipase that

cleaves fatty acids from the 1 and 1' positions of triglycerides, leaving a 2-monoglyeride.

2) Cholesterol esterase cleaves the fatty acid from cholesterol esters, leaving free cholesterol.

3) Phospholipase A, cleaves the fatty acids from phospholipids such as phosphatidylcholine.

b. Emulsification of lipids. Lipids must be broke down into small droplets (less than 1 micrometer in diameter) or emulsified into fat globules by bile acids and lecithin (a component of bile) before being digested.

c. Fat digestion by the pancreatic lipases occurs very rapidly after emulsification because of the large surface-to-volume ratio of the small globules.

ii. Mechanism of absorption

GI 51

Fig 44

a. Micelle formation (Fig 44). The emulsified products of lipid digestion (e.., monoglycerides, cholesterol) must form micelles with bile salts before they can be absorbed. 1) Micelles are small (about 5 nm in diameter)

spherical aggregates containing some 20-30 molecules of lipids and bile salts.

2) The bile salts are on the outside of the micelle. The 2-monoglycerides and lysophosphatides have their hydrophobic chains facing the

GI 52

interior of the micelle and their polar ends facing the surrounding water phase. The cholesterol and fat-soluble vitamins are located within the fat-soluble interior of the micelle.

b. Absorption of lipids and bile salts from micelles. 1) The micelles move along the microvilli

surface allowing their lipids to diffuse across the microvilli membrane and into the enterocytes.

c. Formation of chylomyirons by enterocytes; digested lipids are reformed in the enterocytes and are termed chylomicrons. These leave the cells into lacteal by exocytocis--a process dependent upon a coating of beta lipoprotein (formed in the enterocytes).

4. Water and electrolyte secretion and absorption (Figs 45-46) i. Water (water tends to follow osmotic gradients reabsorption)

Fig 45 Most water in intestines (ingested or secreted) is absorbed

GI 53

Fig 46 There is a biochemical balance between secretion and absorption in GI tract

GI 54

ii. Vitamins and minerals a. Fat-soluble vitamins (A, D, E, and K) become part

of the micelles formed by bile salts and are absorbed along with other lipids in the proximal intestine.

b. Water-soluble vitamins (C, and the vitamins biotin, folic acid, nicotinic acid, B, or pyridoxine, B, or riboflavin, and/or thiamin) are absorbed by facilitated transport or a NA-dependent active transport system in the proximal small intestine.

c. Vitamin B12 absorption is more complex than other vitamins. 1) In the stomach, vitamin B12 is bound to an R

protein, which is a specific binding protein. 2) The gastric parietal cells secrete another

vitamin b-12-binding protein called intrinsic factor. However, the affinity of intrinsic factor for vitamin B-12 is less than that of R protein, so most of the B12 is bound to R protein in the stomach.

3) In the intestine, pancreatic proteases cleave vitamin B12 from the R protein, allowing it to bind to intrinsic factor.

4) The intrinsic factor-B12 complex binds to a receptor on ileal enterocytes. Absorption of the vitamin B12 from the intrinsic factor B12 complex can occur only after the complex binds to the receptor.

d. Ca+ absorption occurs via a membrane-bound carrier that is activated by vitamin D.

e. Iron absorption (Fig 47). Requires carrier proteins and storage.

Vitamin C enhances ion absorption. The ferrous form ofiron is more easily absorbed than the ferric. Nutrientscontaining phosphate and oxalate bind iron and preventabsorption,

GI 55

Fig 47

GI 56

V. THE COLON, OR LARGE INTESTINE

Objectives • 1. Identify nutrients absorbed in the large intestine • 2. Describe the function of large intestine • 3. Describe fluid and electrolyte balance in the large intestine • 4. Describe process of defecation

A. Anatomy (Fig 48) B. Motility designed to enhance water and electrolyte absorption and fecal

excretion-characterized by "haustra" Fig 48

GI 57

1. Function. (enhancement of absorption of water and electrolytes plus fecal elimination) i. Types of movements

a. Haustral shutting b. Bands of muscle

divide the large intestine into sac-like segments called haustrations. Although the haustrations are present when the colon is empty, the entry of food into the colon causes an increase in colonic contractile activity.

Bulk is necessary for proper functioning and prevention of diverticulosis (abnormal outpouching of the colon). Decreased mass forces increased contractions and pressure causing the diverticula .

c. The dynamic formation and disappearance of haustrations squeeze the chyme, moving it back and forth along in a manner similar to that described for the segmentation contractions in the small intestine.

ii. Peristalsis, here, as elsewhere in the gut, is a progressive contractile wave preceded by a wave of relaxation. Peristaltic-like segmentation contractions move the chyme very slowly (5 cm/hr) along the colon. It can take up to 48 hours for chyme to traverse the colon. Significance not well understood.

iii. Mass movements. Occasionally (three to four times daily) they chyme is swept rapidly along the colon by a peristaltic wave called a mass movement. The mass movement forces fecal material into the rectum.

iv. The frequency of contractions is greater in the rectum than in the sigmoid colon, causing retrograde movement of fecal material. Because of this orad movement of fecal material, the rectum is usually empty and material placed into it, such as a suppository, will be pushed up into the colon.

v. The overall effect of the neural input to the colon is inhibitory. Thus, elimination of the enteric nervous system, as occurs in Hircshsprung's disease, leads to a large increase in colonic tone.

2. Defecation (Fig 49)

GI 58 Fig 49

i.

C. Absorptio1. Wa

if mor ais n

2. Naesc

3. K+, secit's riseconthe

Fecal material entering the rectum is evacuated by defecation. During which:

Toilet training involves learning conscious control of the external sphincter. Initially with feces in the rectum, the internal sphincter relaxes but the external will remain closed if consciously controlled. After some minutes, if not expelled the pressure in the rectum decreases and the external sphincter returns to its normal tone. Prolonged fecal retention can be a factor in constipation. Excessive use of some laxatives can damage nerve plexuses and worsen the problem.

a. The smooth muscles of the distal colon and rectum contract, propelling the fecal material into the anal canal.

b. The internal and external sphincters both relax c. The abdominal and diaphragmatic muscles contract,

increasing intra-abdominal pressure and forcing the feces through the anal canal. Defecation involves both voluntary and reflex activity.

n, secretion, and gas production in colon ter. The colon is unable to absorb more than 2-3 L/day. Thus, ost of the 8-10 L entering the intestine (either as ingested water s gastric, pancreatic, or biliary secretions) ot absorbed in the small intestine, severe diarrhea can occur.

+ and Cl-. The colon absorbs most of the Na+ and Cl- that apes absorption in the small intestine. on the other hand, is reted by the colon. concentration typically s from its ileal centration of 9mEq/L to 75 mEq/L by the time the fluid reaches end of the large intestine.

Bicarbonate and chloride are also secreted (to balance charge and neutralize acid substances). Thus, if diarrhea ensues, sodium, potassium, bicarbonate, chloride and water may be lost depending upon the composition of the colonic fluid at the time.

GI 59

4. Aldosterone. While the small intestine has no way to regulate Na+ or K+ absorption, in the colon, the hormone aldosterone controls these processes. Aldosterone enables the colon to absorb all of the Na+ in the fecal fluid. However, in doing so, it causes significant amounts of K+ to be lost from the body.

5. Intestinal gas i. There are three sources of gas (flatus) in the GI tract.

a. Swallowed air, including air released from food and carbonated beverages, enters the stomach, from which it is removed by eructation or passed into the intestines with chyme.

b. Gas is formed by bacterial action in the ileum and large intestine.

c. Some gases diffuse into the GI tract from the bloodstream.

ii. Gas in the colon differs in volume and source from gas in the small intestine. a. Small intestine. The small amount of gas present is

usually the result of swallowed air. This gas most likely will be passed on to the colon.

b. Colon 1) Colonic gas,or flatus, is produced in Large

volumes up to 7-10 L/day. 2) The gas is produced chiefly through the

breakdown of undigested nutrients that reach the colon.

3) The main components of flatus are CO2, CH4, H2, and nitrogen gas (N2). Since all of these gases except N2 diffuse readily through the intestinal mucosa, the volume of flatus expelled is reduced to about 600 ml/day depending upon gender. Methane an also be produced.

Gender differences in gas production (men more; women less)is thought to be due to sex hormones which affect intestinalmotility: transit time in men is faster than women, thuspreventing absorption of gases. At the same time, it is thoughtthat this contributes to the greater instance of constipationamong women, by allowing for more water absorption.Excessive gas and liquid production immediately after GI (orother) surgery (resulting in absence of motility) can bedangerous. The pressures built up can overcome normalcapillary flow and cause ischemia. This is one reason whynasogastric tubes are used to decompress the GI tract aftersurgery.

GI 60

VI. REVIEW: INTEGRATION DESCRIPTION. (RESPONSE TO A MEAL)

A. INTERDIGESTIVE PERIOD Lasts twelve to fifteen hours per day. It is characterized by a low level of activity. At the salivary glands there is basal secretion of saliva. At the esophagus, low frequency waves, and some secondary peristaltic waves to clean up gastric reflux. At the stomach, low volume of very acidic fluid, low rate of secretion. Low level of circulating gastrin. Steady secretion of bicarbonate by surface epithelial cells penetrates jellified mucus and gives protection to the mucosa. Infrequent waves of contractile activity (Migrating Motor Complex). The pancreas is secreting at basal rate, enough to buffer small quantities of gastric contents that pass to the duodenum. In the liver, the concentration of bile salt in the protal blood is low, the synthesis of bile salt is high, most of it ends up in the gall bladder where water is being reabsorbed and bile is becoming highly concentrated. The high cholesterol/bile acid concentration ratio in the hepatic ducts determines higher risk of gallstone formation. The intestine is almost empty, some MMCs sweep the house infrequently to prevent bacterial overgrowth, these MMCs are determined by transient elevations of plasma motilin. The colon is absorbing water and storing feces. C. CEPHALIC PHASE Sight, smell and taste of food cause a large increase in parasympathetic activity. This stimulates digestive secretion at all levels. Salivary flow increases six to ten fold. Mastication is almost automatic, swallowing is initiated voluntarily, and then proceeds reflexly, and it includes oropharyngeal and esophageal phases. The esophageal phase starts with a general relaxation, which is most sustained at the lower esophageal sphincter. This relaxation is vagally mediated. The swallow, or primary esophageal peristalsis, brings food to the stomach. At the stomach, the cephalic phase includes direct vagal stimulation of oxyntic glands and indirect stimulation, mediated by gastrin. At the pancreas, the cephalic phase determines a characteristically concentrated secretion, rich in enzymes. Vagal influence relaxes the sphincter of Oddi and causes partial (up to 30%) emptying of the gallbladder. Blood flow to the GI tract increases. D. GASTRIC PHASE It overlaps in time with the cephalic phase to some extent. Food in the stomach has three effects: 1) it brings about an increase in the pH, releasing gastrin secretion from inhibition, 2) it causes distention, distention causes secretion of acid via vago-vagal (long) and local reflexes that act both directly on the parietal cells and indirectly via secretion of gastrin; finally, 3) the products of food digestion, and other constituents of food like Ca and alcohol promote secretin and movement, mainly indirectly by increasing gastrin. Gastrin dominates the gastric phase; it increases the motility and the tone of the LES and pylorus (retarding emptying). The increase in frequency and intensity of propagated gastric contractions is mediated mostly by aetylcholine and mechanical stimulation. In the gastric phase gastrin exerts stimulation of pancreatic secretion, the gallbladder continues to empty but a lower rate due to

GI 61

decreased vagal activity. The intestinal motility increases, a massive colonic movement may happen at this point, probably mediated by gastrin. D. EARLY INTESTINAL PHASE

The augmented motility of the stomach promotes emptying; with emptying a decrease in gastric pH ensues which starts to inhibit acid secretion. A lowered pH in the duodenum causes abundant secretion of pancreatic juice rich in HCO; this is mediated by release of secretion. Fats in the duodenum release CCK which stimulates release of pancreatic enzymes and zymogens. Distention and small peptides in the duodenum increase acid gastric secretion; secretin increases pepsonigen but not acid secretion; fats and aminoacids decrease gastric secretion and motility, mainly by promoting secretion of GIP. The intestinal phase thus has a subtle combination of excitatory and inhibitory actions on the stomach. Cholecystokinin causes intense gallbladder contraction and relaxation of the Oddi sphincter, the bile salt pool is now mostly in the intestine, bile salt recirculation increases, its synthesis decreases, bile becomes more diluted. The pattern of intestinal contractions changes to frequent segmentations. This favors digestion. Digestive enzymes enter the duodenum from the pancreas. The proteolytic enzymes come as zymogens and their conversion to enzymes, started by enterokinase, is autocatalytic. E. LATE INTESTINAL PHASE Carbohydrates are absorbed mainly as monosaccharides, their digestion starts in the mouth, continues in the stomach and is completed in the intestine by luminal and membrane bound enzymes. Their absorption is almost complete by the end of the jejunum. Proteins must be digested to aminoacids and oligopeptides, and most of the digestion takes place in the duodenum. There is luminal and brush border digestion of peptides. The digestion continues intracellularly on the absorbed oligopeptides. Most of the absorption takes place in the jejunum. Lipids are mostly absorbed as monoglycerides and fatty acids. Lipids are inherently permeable through membranes, the main barrier to their absorption is the unstirred layer, motility and miler formation are essential to their absorption; triglycerides are resynthesized in the enterocyte and packed in chylomicrons which circulate in the lymph. Most lipids are absorbed in the upper half of the small intestine. Cobalamin and bile salts are selectively transported by the lower ileum. Osmotic differences are equilibrated in the duodenum by passive flow of water. If the meal is carbohydrate-based (hypertonic) it will draw water into the lumen in the upper duodenum, but the fast digestion and absorption of carbohydrates will reverse the flow of water in the jejunum. Water continues to leave the lumen in the colon, where it follows absorbed NA and Cl. In the colon, the permeability of the paracellular pathway decreases greatly, permitting the storage of hyperosmotic feces. In the late intestinal phase gastric and small intestinal motility return to the interdigestive pattern. Chyme continues to enter the cecum. Colonic activity is enhanced resulting in continued accumulation of fecal material in the rectum. Rectal distention elicits reflex relaxation of the inner and sphincter and contraction of the striated sphincter.

GI 62

VII. REVIEW: MAJOR HORMONES (Fig 50) Fig 50