GASTROINTESTINAL PHYSIOLOGY

INTESTINAL & COLONIC

PHYSIOLOGY & BIOCHEMISTRY
PART 2: SECRETION, DIGESTION, ABSORPTION

Dr. Oleksii Hliebov, MD, PhD

Associate Professor, Department of Medical Foundations
[email protected]
Spring 2022
 Intended Learning Objectives

1. Draw and describe the general locations and mechanisms of secretion, mechanical digestion, chemical
digestion, and absorption within the GI tract.
2. List and describe the composition and functions of intestinal and colonic secretions. Describe the cellular
mechanism of this secretion and how it is controlled in each location.
3. List and describe the composition and functions of exocrine pancreatic secretions. Describe the cellular
mechanism of this secretion and how it is controlled. Differentiate between high-volume vs. low-volume
secretion.
4. Describe the structure of the intestinal villi and how their brush borders support absorption of materials from
the intestinal lumen.
5. For both carbohydrates and proteins, describe the mechanisms by which each are digested into component
parts and absorbed from the gut lumen into the bloodstream.
6. Describe the specific mechanisms by which water, sodium, chloride, potassium, cobalamin, and calcium are
processed and absorbed in from the intestinal or colonic lumen into the bloodstream. Describe the control
processes that affect the absorption of each in different regions of the lower GI tract.
7. Briefly describe several small intestinal pathophysiological conditions.
8. Briefly describe several colonic pathophysiological conditions.

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CASE SCENARIO
Case Scenario

A 23-year-old male college student presents to his primary care physician with abdominal pain, bloating, flatulence, and
diarrhea after eating ice cream. During the past 6 months, he experienced several bouts of severe abdominal bloating and
cramps, followed by diarrhea. He thought these episodes were caused by the stress of her demanding academic program.
However, he noticed that the symptoms occurred approximately 1 hour after he drank milk or ate ice cream. He denies fever,
sick contacts, or recent travel. His father has a history of similar symptoms. The patient is diagnosed with lactose intolerance
and is given medications to help him digest dairy products.

What products of carbohydrate digestion are absorbed in the small intestine?

Propose a mechanism for this patient’s lactose intolerance.

Why did his lactose intolerance cause diarrhea?

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INTESTINAL SECRETIONS
Small Intestinal Secretions

• Quantitatively very important, at approximately 1000 mL/day.

• Contains mucus.
• Aqueous component whose ion composition is essentially the same as
plasma (no ducts = no reprocessing).
• Some capability for secretion of bicarbonate.

Overall fluid balance in the human gastrointestinal tract. About 2 L of water is ingested and 7 L of various secretions enters the
gastrointestinal tract. Of this total, most is absorbed in the small intestine. About 2 L is passed onto the colon, the vast majority of which is
absorbed in health. (From Vander AJ et al: Human Physiology, 6th ed. New York, McGraw-Hill, 1994.)

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• Recap, that chemical digestion begun in the oral cavity continues in the stomach:
• Some pancreatic amylase and some lipases are active after swallowing, for a while.
• Most of the chemical digestion in the stomach is for protein using pepsin (optimum pH about 3).
• On a quantitative basis, most chemical digestion of macromolecules occurs in the duodenum and
jejunum.
• Very little absorption takes place in the stomach.

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Duodenum

I cells:
• Stimulated by fats and protein.
• Produces CCK -> stimulates pancreas & gallbladder,
slows gastric emptying, relaxes sphincter of Oddi.

S cells:
• Produce secretin -> pancreatic bicarbonate, decreases
gastric acid, and increases bile secretion.

K cells:
• Stimulated by fats, protein and glucose.
• Produces GIP -> decreases gastric acid & increases
insulin release.

Duodenal mucosa protection:

• Pancreatic bicarbonate.
• Brunner’s glands. Locations of gastrointestinal secretory cells.

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• Small intestine dominated by villi and crypts. Villus epithelial cells are generally absorptive. Villus crypt cells are more
secretive.
• Large intestine dominated by surface epithelium and crypts. No villi.
• Secretions of the mucosal epithelial cells have a dual purpose. They protect the surface epithelium and lubricate the
chyme. The secretion of water and electrolytes assist in the absorption of nutrients, in part, by driving secondary active
transport.
• Glucagon-like peptide-1 (GLP-1) is synthesized and secreted by intestinal L cells of the ilium and colon in response to
chyme. It is classified as an incretin because it binds to receptors on the pancreatic beta-cells and stimulates insulin
secretion.
• Peptide YY (PYY) is secreted by intestinal L cells following a meal. It decreases appetite by inhibiting ghrelin secretion,
and via a direct effect on the hypothalamus.
• The small intestinal mucosa is characterized by finger-like projections, the villi, and deep folds creating pits referred to
as crypts of Liberkuhn. Deep within the crypts, enterocytes secrete as electrolyte solution, similar to interstitial fluid.
Secretion is via a chloride pump is similar to that described for the acini of the salivary glands. This fluid along with
digested nutrients, is reabsorbed by the villi. Each cell of the villus has many microvilli, referred to as the brush border,
which future increases the surface area. This cycle provides a watery environments for the final digestion and
absorption of nutrients along the length of the small intestine.

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Brunner’s Glands

• Brunner’s glands secrete an alkaline mucous fluid.

• Stimuli for secretion:
• Irritation.
• Parasympathetic stimulation (occurs concurrently with gastric secretions, following a meal).
• Secretin.
• Inhibited by sympathetic stimulation (may provide this region with less protection from ulceration in
highly emotional individuals.).
• Secretions by Brunner’s glands along with pancreatic secretions and bile, which are high in HCO3-, protect
the small intestine lining from the caustic actions of acid and provide the necessary neutral environment for
intestinal digestion and absorption.
• A mucus-type secretion is maintained throughout the length of the small and large intestine from goblet
cells within the mucosa.

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• Located in the first part of the duodenum.

• Rapid neutralization of acids is important. Even with the secretions of Brunner’s glands, the lining of the duodenum does
not have the same level of protection against acid as the stomach.

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Secretion by the Crypts of Liberkuhn

• Located over the entire surface of the small intestine.

• Two types of cells:
• Goblet cells.
• Secrete mucus.
• Enterocytes.
• In the crypts secrete large quantities of water and
electrolytes.
• Reabsorb the water and electrolytes along with the end
products of digestion.
• pH is around 7.5 – 8.0
• Secretion involve at least two active secretory processes:
• Active secretion of chloride ions into the crypts.
• Active secretion of bicarbonate ions.

A crypt of Lieberkühn, found in all parts of the small

intestine between the villi, which secretes almost pure
extracellular fluid.

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• The secretion of both ions causes electrical drag of positively charged sodium ions through the membrane and into the
secreted fluid as well. Finally, all these ions together cause osmotic movement of water.

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 Na+, Cl-,HCO3- Secretion from Crypt Cells
1. Transcellular Cl- secretion is used to create the
electrochemical gradient to drive paracellular Na+ secretion.
Na+ secretion is low at all locations from duodenum to distal
colon.
2. HCO3- secretion primarily uses an apical exchanger with Cl-,
which thanks to Cl- secretion here and from the stomach,
pancreas, and liver/bile ducts should be in sufficient
quantity to activate this antiporter. The basolateral Na+/H+
exchanger is essentially the same as that in salivary ducts,
except here it is only on the basolateral side.
3. The net effect is an increase in HCO3- in the lumen and an
increase in by-product H+ in the venous blood, which will
mix with blood from the stomach within the hepatic portal
vein.
4. All of the intestinal crypt cells are secreting more Cl- and Na+
than HCO3- , which drives about 1 L of water per day into the
small intestine. The newly secreted HCO3- acts as a buffer to
neutralize stomach acid and create a weakly alkaline
environment in the duodenal and jejunal lumen in which
digestive enzymes can function at their peak function. Mechanism of Cl− secretion in the small Mechanism of bicarbonate secretion in the
and large intestines. duodenum. CA – carbonic anhydrase.

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• Early in the digestive tract of the small intestine there is sufficient pancreatic and biliary bicarbonate to neutralize
stomach acid. When later in the intestine there might be more need to buffer acids (e.g. from bacterial metabolism in the
colon), the epithelial cells have the capacity to produce bicarbonate and secrete it into the lumen. As with other sources
of acid or bicarbonate secretion, they are both produced at the same time using carbonic anhydrase then are secreted
out different membranes. In this case, bicarbonate crosses the apical membrane into the lumen and hydrogen crosses
the basolateral membrane into the blood.
• Hydrogen, the other component produced by carbonic anhydrase, is traded with sodium across the basolateral
membrane. This is secondary active transport because the sodium that comes into the cell is then pumped across the
basolateral membrane using the sodium-potassium pump. The hydrogen goes into the blood and eventually interacts
with blood bicarbonate which was itself a byproduct of gastric acid secretion.
• A limiting factor for this secretion is the availability of chloride ions in the lumen, as the cell uses a chloride/bicarbonate
antiport to achieve this apical bicarbonate secretion. In cystic fibrosis, the inability to secrete chloride anywhere using the
uniport CFTR results in a shortage of chloride ions in the intestinal tract, so this compromises the body’s ability to secrete
bicarbonate. In cholera, there is no such limitation so combined with the dehydration that already occurs, the high
bicarbonate secretion into the intestinal lumen has the side effect noted above, extra hydrogen in the blood. This could
produce an acidosis in severe secretory diarrhea.
• Transcellular chloride secretion is used to create the electrochemical gradient to drive paracellular sodium secretion.
Those two then create an osmotic gradient to drive water secretion. NaCl and water secretion can occur at low levels
through the length of the intestinal tract.
• Note that cystic fibrosis transmembrane regulator (CFTR) is the apical protein whose activity drives all the rest of the
crypt cell secretion. When not in use, most CFTR’s are stored in intracellular vesicles in an inactive state.
• Note too the role of the triple transporter NKCC1 in bringing in the chloride to be secreted across the apical membrane.
This is secondary active transport because the sodium-potassium pump is used to remove excess sodium back into the
ECF.

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• Bicarbonate secretion primarily uses an apical exchanger with chloride, which thanks to chloride
secretion here and from the stomach, pancreas, and liver/bile ducts should be in sufficient quantity
to activate this antiporter. This is essentially the same exchanger as that from the salivary and
pancreatic ducts. Similarly, the basolateral sodium-hydrogen exchanger is essentially the same as
that in salivary ducts, except here it is only on the basolateral side. Note: New data indicates that
some bicarbonate crosses with chloride using CFTR!
• The net effect is an increase in bicarbonate in the lumen and an increase in by-product hydrogen in
the venous blood, which will mix with blood from the stomach within the hepatic portal vein. It is
all secondary active transport because ultimately one must pump the sodium out of the cell which
had come in transporting chloride, potassium, and hydrogen across the basolateral membrane.
• In reality all of the intestinal crypt cells are secreting more chloride and sodium than bicarbonate,
which drives about 1 liter of water per day into the small intestine. The newly secreted bicarbonate
acts as a buffer to neutralize stomach acid and create a weakly alkaline environment in the
duodenal and jejunal lumen in which digestive enzymes can function at their peak function.
However, the relative contribution of crypt calls must be added to that of pancreatic ducts and bile
ducts; each only contributes a part to this pH modification. The pH of the intestinal lumen rises to
close to 8.0, which is close to the pH optimum of many pancreatic digestive enzymes.
• Intestinal HCO3- secretion is highest in the proximal colon, where many bacteria produce acid as a
fermentation waste product. No significant secretion from duodenum or jejunum.
Regulation of Crypt Cell Secretion

• Enteric neurons:
• Acetylcholine (phospholipase C, PLC).
• VIP (adenylyl cyclase, AC).
• Basolateral endocrine/paracrine agents and some toxins:
• Serotonin (5-HT) (+PLC).
• Prostaglandins (+AC).
• Histamine (in inflammation) (+AC).
• Certain toxins that cross cell to (+AC).
• Apical agents and some toxins:
• Minor hormone guanylin (+Guanylyl Cyclase, GC).
• Certain toxins that act at apical membrane (+GC).
• All increase CFTR activity!

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Colonic Potassium Secretion

• Potassium Secretion only occurs in the colon, typically during

dehydration.

• Passive secretion:
• Paracellular.
• Greatest in distal colon.
• Follows increased electrical gradient.

• Active secretion:
• Transcellular.
• More in proximal colon than in distal colon.
• Stimulated by aldosterone on surface epithelial cells.
• Stimulated by cAMP activation in intestinal crypt cells.
• Increased number/activity of apical potassium channels.

Cellular mechanisms of K+ secretion and absorption. Throughout the colon, passive

K+ secretion occurs via tight junctions, driven by a lumen-negative transepithelial
voltage. Throughout the colon, active K+ secretion is transcellular.
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• Colonic potassium secretion is rare in normal physiology. As in the kidney, active potassium secretion is often secondary
to trying to maximize sodium and water retention in the blood via the hormone aldosterone. But it can also be passive,
following an electrical gradient into the colon.
• In active secretion, aldosterone increases the number of apical potassium channels making it easier for potassium that
had been pumped into the cytoplasm with the basolateral sodium-potassium pump to cross the apical membrane into
the colonic lumen. This is a small amount compared to that happening in the kidney but it is still present.
• Passive secretion: increased sodium/water absorption has a side effect of making the colonic lumen more negatively
charged. If the electrical gradient between ECF and lumen fluid is large (-25 millivolts), paracellular potassium secretion
increases.

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PANCREATIC SECRETIONS
Overview of Pancreatic Secretions

• The pancreas is both an exocrine and endocrine gland.

• Its exocrine secretions flow through a series of ducts
into the duodenum, mixing with bile and then with
chyme.
• Acinar cells are the site of initial production and
secretion of pancreatic juice, including pancreatic
enzymes and proenzymes.
• Ductal cells are sites of modification of the primary fluid
such that the final fluid is high-volume when necessary
and rich in bicarbonate.

Pancreatic acinus and duct morphology. A, The fundamental secretory unit is composed of an acinus
and an intercalated duct. Intercalated ducts merge to form intralobular ducts, which in turn merge to
form interlobular ducts, and then the main pancreatic duct. B, The acinar cell is specialized for
protein secretion. Large condensing vacuoles are gradually reduced in size and form mature zymogen
granules that store digestive enzymes in the apical region of the acinar cell. C, The duct cell is a
cuboidal cell with abundant mitochondria. Small microvilli project from its apical membrane.

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• For purposes of exocrine secretions, it is helpful to think of the pancreas and the salivary glands as “siblings”– they are
not identical twins by any means, but they share more similarities than differences. The third member of this family of
related exocrine glands would be the lacrimal gland that secretes tears, but that gland and its functions are outside the
scope of digestive physiology.
• Like in salivary glands, most of the proteins found in pancreatic juice are secreted along with a primary salivary juice by
acinar cells.
• Like in salivary glands, there is extensive modification of this primary secretion by duct cells. Unlike salivary ducts,
pancreatic ducts can significantly increase bicarbonate and water secretion under the proper endocrine and nervous
signals.
• Unlike salivary glands, there is one final exit point for all pancreatic juice, the sphincter of Oddi at the duodenal wall. This
typically opens during periods of pancreatic and gallbladder secretion, which again is typically in the presence of
nutrients in the duodenum and jejunum.
• Pancreatic secretions that enter the duodenum have two main functions:
• They represent the largest contributor of digestive enzymes in the gut.
• They provide HCO3- to neutralize stomach acid entering the small intestine.
• Note: Pancreatic enzymes are required for the digestion of carbohydrate, fat, and protein, and their secretion is almost
entirely due to CCK.
• Clinical Correlate: cystic fibrosis, acute and chronic pancreatitis.

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Overview of Pancreatic Secretions
• Its exocrine secretions contain:
• Bicarbonates and water.
• Digestive enzymes:
• Pancreatic amylase.
• Trypsinogen (enterokinase in duodenum cleaves it
into trypsin which activates other zymogen
proteases).
• Chymotrypsin.
• Carboxypeptidases.
• Pancreatic lipase, cholesterol esterase,
phospholipas.
• It is stimulated to secrete by a numbers of hormones (e.g.
stimulated by CCK and secretin & inhibited by somatostatin)
and the autonomic nervous system.

Pancreatic acinus and duct morphology. A, The fundamental secretory unit is composed of an acinus
and an intercalated duct. Intercalated ducts merge to form intralobular ducts, which in turn merge to
form interlobular ducts, and then the main pancreatic duct. B, The acinar cell is specialized for
protein secretion. Large condensing vacuoles are gradually reduced in size and form mature zymogen
granules that store digestive enzymes in the apical region of the acinar cell. C, The duct cell is a
cuboidal cell with abundant mitochondria. Small microvilli project from its apical membrane.

Image source: Medical Physiology, 3rd ed. W. F. Boron, E. L. Boulpaep. ROSS UNIVERSITY SCHOOL OF MEDICINE
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• For purposes of exocrine secretions, it is helpful to think of the pancreas and the salivary glands as “siblings”– they are
not identical twins by any means, but they share more similarities than differences. The third member of this family of
related exocrine glands would be the lacrimal gland that secretes tears, but that gland and its functions are outside the
scope of digestive physiology.
• Like in salivary glands, most of the proteins found in pancreatic juice are secreted along with a primary salivary juice by
acinar cells.
• Like in salivary glands, there is extensive modification of this primary secretion by duct cells. Unlike salivary ducts,
pancreatic ducts can significantly increase bicarbonate and water secretion under the proper endocrine and nervous
signals.
• Unlike salivary glands, there is one final exit point for all pancreatic juice, the sphincter of Oddi at the duodenal wall. This
typically opens during periods of pancreatic and gallbladder secretion, which again is typically in the presence of
nutrients in the duodenum and jejunum.
• Pancreatic secretions that enter the duodenum have two main functions:
• They represent the largest contributor of digestive enzymes in the gut.
• They provide HCO3- to neutralize stomach acid entering the small intestine.
• Note: Pancreatic enzymes are required for the digestion of carbohydrate, fat, and protein, and their secretion is almost
entirely due to CCK.
• Clinical Correlate: cystic fibrosis, acute and chronic pancreatitis.

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Pancreatic Exocrine Secretions
• Secretion = ~ 1.5 L / day.
• Acinar:
• Enzymes and other proteins & peptides:
• Proteases, lipases, amylase, nucleases, trypsin inhibitors (prevent digestion of the
pancreas).
• Ductular epithelial cells:
• Ions and water - HCO3- - neutralizes gastric acid & creates optimal pH for digestive enzymes.
Pancreatic Enzyme Function Comments
Alpha-amylase Starch digestion Secreted in active form

Lipases Fat digestion Pancreatic lipase, cholesterol esterase,

phospholipase
Proteases Protein digestion Includes trypsin, chymotrypsin, elastase,
carboxypeptidases. Secreted as proenxymes,
also called zymogens.
Trypsinogen Converted to active anzyme trypsin -> activation of Converted to trypsin by
other proenzymes and cleaving of additional enterokinase/enteropeptidase, a
trypsinogen molecules into active trypsin (positive brush-border enzyme on duodenal and jejunal
feedback loop). mucosa.

Overall fluid balance in the human gastrointestinal tract. About 2 L of water is ingested and 7 L of various secretions enters the
gastrointestinal tract. Of this total, most is absorbed in the small intestine. About 2 L is passed onto the colon, the vast majority of which is
absorbed in health. (From Vander AJ et al: Human Physiology, 6th ed. New York, McGraw-Hill, 1994.)

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• The main function of the exocrine pancreas is to secrete a pancreatic juice that is rich in both bicarbonate (to neutralize
stomach acid) and in an assortment of active (e.g. lipases) and inactive (e.g. trypsinogen) digestive enzymes, along with
water and sodium chloride.
• The overall volume of secretion on average is about the same as that of salivary glands, perhaps 1.5 liters per day. The
highest rates of secretion tend to occur when there is chyme from the stomach in the duodenum. The content of this
chyme (e.g. acids and lipid molecules) can be detected through chemoceptors in the intestinal wall, leading to autonomic
reflexes and pancreatic responses to hormones secreted by the intestinal wall (e.g. secretin).
• The nature and control of pancreatic exocrine secretions is a particularly high-yield topic on board exams because its
failure either leads to or contributes to many pathologies of the digestive and endocrine systems.

Pancreatic secretion:
• Initial secretion into the acini is isotonic, with electrolyte concentrations similar to the interstitial fluid, plus a large
number of enzymes and proenzymes (proteases).
• Acini secretion is stimulated by parasympathetic acetylcholine and CCK.
• Duct cells are stimulated by secretin.
• Pancreatic enzymes include:
• Alpha-amylase – carbohydrates digest to mainly disaccharides.
• Lipase – triglyceride to fatty acids and monoglycerides.
• Cholesterol esterase – cholesterol hydrolysis.
• Phospholipase A2 – cleaves fatty acids from phospholipids.
• Proteases are secreted in the inactive form along with a trypsin inhibitor to prevent activation. Initially, trypsin
is activated by enterokinase/enteropeptidase, which is a brush border enzyme of the small intestine.
• When first synthesized in the pancreatic cells, the proteolytic digestive enzymes are in their enzymatically inactive forms
trypsinogen, chymotrypsinogen, and procarboxypolypeptidase.They become activated only after they are secreted into

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• the intestinal tract.
Steps of Sodium Bicarbonate Secretion in Pancreas

1. CO2 diffuses to the interior of the cell from the blood.

2. Carbonic anhydrase forms carbonic acid (H2CO3) from CO2 and water.
3. H2CO3 dissociates into HCO3− and H+.
4. Additional HCO3− ions enter the cell through the basolateral
membrane by co-transport with Na+ ions.
5. HCO3− ions are then exchanged for Cl− ions by secondary active
transport into the lumen of the duct.
6. H+ ions formed by dissociation of carbonic acid are exchanged for Na+
ions by secondary active transport. Na+ ions also enter the cell by
co-transport with HCO3− across the basolateral membrane. Na+ ions
are then transported across the luminal border into the pancreatic
duct lumen.
7. The negative voltage of the lumen also pulls the positively charged
Na+ ions across the tight junctions between the cells.
8. The overall movement of Na+ and HCO3− ions from the blood into the
duct lumen creates an osmotic pressure gradient that causes osmosis
Peristalsis. During peristalsis a contractile ring appears around the
of water also into the pancreatic duct, isosmotic bicarbonate
solution.

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Control of Secretion in Pancreatic Acinar & Duct Cells

Enteric neurons & n.vagus:

• Acetylcholine (stimulates phospholipase C (PLC) pathway).

Endocrine/paracrine agents:
• Secretin (basolateral, stimulates adenylyl cyclase pathway) is the most
important.
• There may be others (e.g., CCK binding with less affinity).
• There may also be some apical receptors (e.g. for ATP) but they too are
less important than secretin.
• All increase CFTR activity!

• ACh and CCK stimulate the acinar cells, causing production of large
quantities of pancreatic digestive enzymes with small quantities of water
and electrolytes.
• Without the water, most of the enzymes remain temporarily stored in
the acini and ducts until more fluid secretion comes along to wash them.
• Secretin stimulates secretion of large quantities of water solution of Na+
and HCO3- by the pancreatic ductal epithelium.

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• As in many other secretory cells of the gastrointestinal tract, secretion of chloride ions is followed by sodium and water,
and in this case is accompanied by exocytosis of many proteins including digestive enzymes.
• For both chloride secretion and exocytosis, the phospholipase C-induced pathway plays a larger role than does the
adenylyl cyclase-mediated pathway. And the two major signal molecules for these are the PNS neurotransmitter
acetylcholine, and the hormone cholecystokinin (CCK). However, for full stimulation of secretion, adenylyl cyclase must
also be activated, and this requires both PNS neurons using vasoactive intestinal peptide (VIP), and the hormone
secretin.
• When both second messenger systems are activated, they potentiate one another, producing levels of secretion greater
than that of just adding the levels produced by either AC or PLC pathways.
• Note the important role of CFTR in the bicarbonate secretion process of the pancreatic ducts. CFTR is activated by several
mechanisms including increased cAMP (secretin) and calcium (ACh). Another player in the process only found here, is the
ATP receptor on the apical lumen which increase calcium as well. When chloride is secreted, sodium and water follow in
a paracellular transport. But some of the chloride is also reabsorbed in an apical antiport with bicarbonate.
• As in so many other tissues, carbonic anhydrase is involved in producing the bicarbonate to be secreted plus a by-product
(hydrogen ion). Unlike many other tissues there is also a means to move bicarbonate into the cell across the basolateral
membrane using secondary active transport. At the end of the process, sodium bicarbonate and water are secreted into
the pancreatic duct lumen, increasing pressures to help “wash out” enzyme-rich acinar secretions.
• Clinical significance: hydrochloric acid is secreted/reabsorbed into the blood using a basolateral ATPase in sufficient
quantities to react with the stomach’s byproduct of bicarbonate within the hepatic portal circulation. In the end, both in
the intestinal lumen and in the portal blood, a normal nonacidic environment should be restored. Compromise of this
process either through vomiting or through taking antacid tablets will have a side effect within the blood, producing an
acidosis or alkalosis. Similarly, failure to secrete sufficient bicarbonate to neutralize stomach acid will result in the wrong
pH for optimal pancreatic enzyme activity and malabsorption may result.

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Composition of Pancreatic Juice

• Reflects changing proportions of acinar and ductal secretions.

• There is always a low basal secretion rate featuring mostly
acinar fluid rich in chloride and low in bicarbonate.
• At the highest flow rates pancreatic juice is mostly from ducts,
high in bicarbonate and low in chloride.
• The same hormone that promotes more flow (secretin) also
promotes more bicarbonate in the juice.

• Isotonic fluid.
• Low flow – high Cl-.
• High flow – high HCO3-.

Flow dependence of the electrolyte composition of pancreatic fluid.

Increasing secretin levels not only increases the secretory rate, but also
changes the composition of the fluid. (Data from Case RM, Harper AA,
Scratcherd T: The secretion of electrolytes and enzymes by the pancreas
of the anaesthetized cat. J Physiol 201:335–348, 1969.)
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• Similar to what happens in the stomach, at “rest” with no acid in the duodenum, there is no need to secrete either a
large volume of pancreatic juice or a great quantity of bicarbonate. The secretion that does take place is basal,
unstimulated, and containing almost plasma-equivalent levels of sodium chloride. It is functionally acinar cell primary
secretion alone with just enough ductal secretion to prevent inappropriate digestive enzyme activation in the ducts.
• When the secretory rate rises, acinar flow rises but ductal flow rises so much more that the chloride levels drop to one
third of the unstimulated level and the bicarbonate level rises to five times that of the blood. Both sodium and potassium
levels remain essentially unchanged.

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Phases of Pancreatic Secretion

• Cephalic phase – vagal control. % of

Regulatory Maximum
• Gastric phase – vagal control. Phase Stimuli
Pathway
Comments
Enzyme
• Intestinal phase – feedback control from Secretion
nutrients and acid in duodenum. Sight, smell, Vagal pathways Small amounts of water and
• Most pancreatic juice is secreted during Cephalic taste, (release electrolytes secreted, secrete 20-25
the intestinal phase as part of feedback. mastication acetylcholine) stays in pancreas
Small amounts of water and
Distention, Vagal-cholinergi
Gastric electrolytes secreted, secrete 5-10
gastrin c
stays in pancreas
Endocrine pancreatic secretions:
Response mainly to secretin,
• Pancreatic D cells -> somatostatin which acidic chyme stimulates
decreases all secretions. secretion of secretin, secretin
CCK, secretin,
• GIP -> beta-islet cells release insulin. Intestinal
Amino acids,
enteropancreati
stimulates secretion of large
50-80
fatty acids, H+ quantities of fluids with Na+,
c reflexes
HCO3- that neutralizes acidic
chyme. CCK stimulates enzymes
secretion, and less HCO3-.

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During the cephalic and gastric phases:

•Acetylcholine stimulates both acini and ducts to secrete .
•This prepares the duodenum to receive nutrient-rich acidic chyme and neutralize the acid when it arrives .
•This prevents any damage to duodenal wall when chyme first arrives - this protective mechanism is essential to prevent the
development of duodenal ulcers.

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 Cephalic, Gastric, and Intestinal Phase of Pancreatic Secretion

Intestinal phase.

• Lipid and protein is detected by I cells, secrete CCK.

Cephalic and gastric phases. • CCK stimulates vagal reflex (ACh) and stimulates acinar secretion.
• ACh stimulates acinar and duct cells.
• Acid is detected by S cells, they secrete secretin.
• Secretin stimulates duct cells.
Image source: Medical Physiology, 3rd ed. W. F. Boron, E. L. Boulpaep. ROSS UNIVERSITY SCHOOL OF MEDICINE
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• It helps sometimes to realize that as the pancreas is not the gut wall, it has no ENS. Vagal neurons directly interact with
target cells in the pancreas.
• Note the receptors on the luminal membrane of I cells that detect fat and protein in the duodenum. These cells secrete
CCK into the blood, and into the local environment where CCK stimulates autonomic sensory cells. The autonomic reflex
initiated by CCK causes a lot of acinar cell secretion using the PNS neurotransmitter acetylcholine, and a lesser amount of
stimulation of bicarbonate secretion from ducts. As fluid is secreted into the fixed-volume acinar lumen, its pressure will
rise and this will force fluid out of the acinus toward the lower-pressure duodenal lumen.
• The receptors on the luminal membrane of S cells detect acid, typically below pH of 4.5. When stimulated by acid, S cells
secrete the hormone secretin into the blood. Secretin has its most important effects at the pancreatic ducts, greatly
increasing both bicarbonate and fluid secretion into the ducts. This helps create a pressure gradient to “wash out” the
enzymes etc. from acinar fluid into the duodenal lumen. Ultimately when digestion and absorption remove the fat and
protein, and acid has been adequately neutralized by bicarbonate, both I cells and S cells will cease activity and the
intestinal phase will be over.

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COLONIC SECRETIONS
Colonic Secretions

• No digestive enzymes and transport proteins for absorbing the end products of carbohydrate or protein
digestion. If they are not digested and absorbed in the small intestine, they pass into the stool.
• Fermentation is present due to the colonic bacteria, as with lactose intolerant individuals.
• Distal colonic segments mainly serve a storage function.
• The colon has the crypts of Lieberkuhn, but there are no villi as in the small intestine. Villi have mucus cells
that secrete mucus. Secretion is normally a mucus-type high in HCO3- that is protective and acts as an
adherent for the fecal material. The rate of mucus secretion is regulated by direct tactile stimulation or by
parasympathetic ANS.
• There continues to be a net reabsorption of electrolytes, particularly in the ascending and transverse colon.
The colon is a target tissue for aldosterone, whose action is like that in kidney. It promises the reabsorption
of NaCl and water but a net secretion of K+. Some excess K+ is lost by the colon but the main route of K+
excretion is the kidneys.
• Irritation of the colon lining or excessive PNS stimulation (e.g. emotional state) often causes a much more
serious type of secretion. The result can be a diarrhea with the loss of a large amount of water and
electrolytes. Not only NaCl is lost, but K+ and HCO3- is lost as well. The lost of HCO3- promotes a metabolic
acidosis, which is often accompanied by a hyperkalemia. In this case, however, the washout of K+ promotes
hypokalemia.
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Colon:
• No digestive enzymes.
• Reabsorption of water and electrolytes.
• Net secretion of bicarbonate and potassium.
• Clinical correlate – Diarrhea.

23
 GENERAL PRINCIPLES OF DIGESTION AND
ABSORPTION OF MACRONUTRIENTS

• Except Lipids, covered in Hepatic/Biliary Physiology

24
Villus

• Intestinal cells “stick out” into the intestinal lumen,

increasing surface area.
• Cells change function as they ascend villus, from secretory
to absorptive.
• Absorptive cells have microvilli, folds that increase apical
membrane area still more.
• Deep to these cells are arterioles, venules, and both blood
capillaries and lymphatic capillaries (lacteals).
• The enterocytes of the villi & mucosa contain digestive
enzymes that digest specific food substances while they are
being absorbed through the epithelium:
• Peptidases for splitting small peptides into amino acids.
• Sucrase, maltase, isomaltase, lactase—for splitting Microcirculation pattern of the small intestine. Capillary plexuses arise from
arterioles in the villus and also in the crypt. Blood leaves the crypt via venules
disaccharides into monosaccharides. that enter the portal circulation. Lymphatic vessels (lacteals) originate within
the villus and eventually form a plexus at the base of the villus. (Redrawn from
• Small amounts of intestinal lipase for splitting neutral Kierszenbaum A: Histology and Cell Biology: An Introduction to Pathology.
fats into glycerol and fatty acids. Philadelphia, Mosby, 2002.)

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• The small intestine is a hollow tube 6-7 meters in length.

• The structure within the inner lining of the tube contains folds, villi, and microvilli that raise surface area 1000 times
higher than if they were not there. (appx. 200-250 square meters for the entire small intestine).
• This allows a much larger number of membrane-associated enzymes and transport proteins than would otherwise fit
along the length of the tube.
• The microvilli are collectively called “the brush border” because on microanatomy images they resemble the bristles in a
brush just surface to the main body of each cell. They are responsible for a great deal of the difference in surface area
over that of the tube proper.
• Clinical note: in celiac disease, there is a change in the structure of the inner lining of the tube such that the villi and the
brush border with it is significantly reduced in size. This leads to malnutrition as absorption of nutrients becomes less
optimal in proportion to the loss of surface area.

25
General Patterns of Digestion & Absorption

• The chemistry of digestion is simple - the same basic

process of hydrolysis is involved. The difference is in
the types of enzymes required to promote the
hydrolysis reactions for each type of food.
• All the digestive enzymes are proteins
• Monomer, no digestion required.
• Digestion in lumen into monomers.
• Digestion in lumen into oligomers. Further
digestion at brush border into monomers.
• Dimers and trimers absorbed into enterocyte,
digested into monomers inside cell.
• Digestion into monomers in lumen. Absorption
into enterocytes. Repackaged into larger
molecules before exiting enterocytes.
General mechanisms of digestion and absorption. Digestion-absorption can follow any of five patterns. First, the substance (e.g., glucose) may not require digestion; the intestinal cells may
absorb the nutrient as ingested. Second, a polymer (e.g., protein) may be digested in the lumen to its constituent monomers (e.g., amino acids) by pancreatic enzymes prior to absorption.
Third, an oligomer (e.g., sucrose) is digested into its constituent monomers (e.g., monosaccharides) by brush-border enzymes prior to absorption. When in free solution, fructose is present
primarily as the pyranose (6-membered ring) form and less so as the furanose (5-membered ring) form. Fourth, an oligomer (e.g., oligopeptide) may be directly absorbed by the cell and then
broken down into monomers (e.g., amino acids) inside the cell. Finally, a substance (e.g., TAG) may be broken down into its constituent components prior to absorption; the cell may then
resynthesize the original molecule.
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Digestion & Absorption of Most Water-Soluble Nutrients

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• In either a one-step or multi-step process, polymers that are digestible are broken down into a large number of
monomers, which are absorbed across the epithelial cells of the absorptive part of the villus. These then transit across
the basolateral membrane and are carried in the portal blood to the liver.
• Sometimes one must first digest polymers into dimers and trimers. Usually brush border enzymes then break the dimers
into monomers for absorption proper using special apical transport proteins. Many of these are secondary active
transporters in which the nutrient comes in with sodium.
• Some di-and-tri-peptides break the rule slightly and are absorbed into the cytoplasm prior to final digestion but the
picture shown above is by far the most common pathway.

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 DIGESTION & ABSORPTION OF CARBOHYDRATES

• Except Lipids, covered in Hepatic/Biliary Physiology

28
Digestion of Carbohydrates
• Complex carbohydrates consist mainly of the
linked monosaccharides, glucose, galactose,
and fructose.

Digestion process:
1. Saliva contains ptyalin (alpha-amylase
mainly form parotid glands):
1. Hydrolyzes starch into the disaccharide
maltose. Digestion of carbohydrates.
2. No more than 5% of starches will be
hydrolyzed in mouth cavity. 4. The enterocytes lining the villi of the small intestine contain four
2. In the stomach alpha-amylase inactivated by enzymes (lactase, sucrase, maltase, and α-dextrinase), which are
gastric juice (low pH), but around 30-40% of capable of splitting the disaccharides lactose, sucrose, and maltose,
starches will be hydrolyzed. plus other small glucose polymers, into their constituent
3. Digestion finished in small intestine with monosaccharides – disaccharides digested as they come in contact
help of pancreatic amylase (identical to the with brush border.
amylase in saliva, but more powerful).

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• Carbohydrate digestion begins in the mouth with salivary alpha-amylase and continues in the proximal stomach until acid
penetrates the bolus.
• Pancreatic alpha-amylase, a required enzyme, continues digestion in the small intestine with disaccharides (sucrose,
lactose) as the major end-products along with small-branched alpha-limit dextrins and trioses.
• Disaccharides cannot be absorbed by the small intestine. Enzymes on the enterocytes covering the villi (sucrase, lactase,
isomaltase) complete the digestion to the absorbable monosaccharides (only glucose, galactose, fructose are absorbed).

29
Digestion of Carbohydrates
• Lactose splits into a molecule of galactose and a molecule of
glucose.
• Sucrose splits into a molecule of fructose and a molecule of
glucose.
• Maltose and other small glucose polymers all split into multiple
molecules of glucose.
• Thus, the final products of carbohydrate digestion are all
monosaccharides.

• Lactase can show a decline in some individuals after weaning,

which results in lactose intolerance. As such, lactose continues
to the colon, where it ferments and causes abdominal cramps, Sites of nutrient absorption. The entire small intestine absorbs carbohydrates,
proteins, and lipids. However, the absorption is greatest in the duodenum, somewhat
gas, and diarrhea. A bacterial-derived lactase can be taken in less in the jejunum, and much less in the ileum. The thickness of the arrows indicates
tablet form before ingesting dairy products. the relative magnitude of total absorption at the indicated site in vivo (see inset). The
maximal absorptive capacity of a specific segment under optimized experimental
conditions (e.g., substrate concentrations) may be greater.

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• On a quantitative basis, most carbohydrates and proteins are digested, and their pieces absorbed in the duodenum and
into the jejunum. Given that intestinal motility keeps moving materials in an anal direction, the longer it takes to fully
digest a given type of food, the further along the digestive tract it will be absorbed. There is also a significant surface area
for absorption in the early part of the small intestine.
• Some substances, like fructose in high-fructose corn syrup can be absorbed as soon as it enters the duodenum, because
it requires no digestion at all. Other materials like disaccharides (e.g. table sugar, sucrose) require very little digestion and
can also start having their component parts absorbed early rather than late. However, some substances such as
triglycerides often require considerably more processing or multiple steps of enzymatic degradation before all their parts
can be absorbed, and their absorption often starts in significant quantities in the jejunum and still have some absorption
even within the ileum.
• Still other substances, like cellulose (dietary fiber), cannot be digested by humans at all and are supposed to pass
unchanged into the colon to help maintain the correct balance between solid and liquid in stools.
• Normally, only a trace quantity of nutrients make it into the proximal colon, which support a certain number of colonic
bacteria but with certain digestive disorders (e.g., pancreatitis), absorption will not be complete by the time materials
reach these living beings who naturally take advantage with major growth and waste production. The combination of
unabsorbed foods tuffs and bacterial metabolic waste products can produce soft stools or even diarrhea, and infringe on
body water balance from the intake side.
• Most carbohydrate absorption takes place in the duodenum and early jejunum, but there are transport proteins for
carbohydrate absorption all the way into the ileum.

30
Absorption of Carbohydrates

• Monosaccharides do not diffuse across cell membranes -

protein carriers are required.
• On the luminal membrane, glucose and galactose are
transported by secondary active transport driven by the large
sodium gradient, established by the Na+/K+-ATPase pump.
• Electrolyte secretion by the enterocytes in the crypts maintains
a constant delivery of sodium to drive the monosaccharide
across the luminal membrane. As stated previously, luminal
Na+ stimulates the uptake of galactose and glucose. Fructose
uptake is not linked to Na+.
• The preceding is utilized in a simple treatment for the cholera
toxin, which acts to increase the electrolyte secretion by the
crypt enterocytes. Oral administration of an electrolyte
solution with glucose will accelerate the reuptake of fluid,
Digestion of carbohydrates to monosaccharides. SGLT1 is the Na+ - coupled
reducing the associated diarrhea. transporter that mediates the uptake of glucose or galactose from the lumen of
• Once across the luminal membrane, the high concentration of the small intestine into the enterocyte. GLUT5 mediates the facilitated diffusion of
fructose into the enterocyte. Once the monosaccharides are inside the enterocyte,
monosaccharides within the cell drives the passive facilitated GLUT2 mediates their efflux across the basolateral membrane into the interstitial
transport (GLUT2) across the basolateral membrane. space.

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• Note that glucose and galactose compete for the same apical transporter, SGLT-1 (Na+ dependent). Fructose is taken up
via facilitated diffusion by GLUT5. All are transported to blood by GLUT2.
• Clinical correlation: D-xylose test – simple sugar that is passively absorbed in the proximal small intestine; blood and
urine levels will be decreased with mucosal damage; but will be normal in case of pancreatic insufficiency.

31
Digestion of Carbohydrates

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• Humans consume a larger variety of carbohydrates than can be adequately digested. Chief among the indigestible
carbohydrates is cellulose, which goes undigested by humans and is used as a physiological stool softener, providing a
surface area with which water molecules can associate. Adequate “dietary fiber” of this kind ensures that stools will not
be too hard to easily pass (constipation).
• For the rest, the sequence of carbohydrate digestion starts in the mouth with salivary amylase breaking down starch. This
continues in the stomach until stomach acid renders these higher-pH enzymes inactive. Pancreatic amylase performs
most of the digestion of starch into smaller units, mostly maltose (disaccharide) units. These maltoses are broken down
by maltase into two absorbable glucose molecules. The same process occurs for sucrose (using sucrase to produce
glucose + fructose units) and lactose (converted by its enzyme into glucose + galactose).
• Clinical: Not all humans express a functional lactase enzyme in adulthood. These people are susceptible to lactose
intolerance in which bacteria complete the digestive process and in so doing produce acid, gas, and many osmotic
components that result in diarrhea. Lactase pills are sold in every pharmacy so this is a preventable condition.

32
 DIGESTION & ABSORPTION OF PROTEINS

• Except Lipids, covered in Hepatic/Biliary Physiology

33
Digestion of Proteins

• Protein digestion begins in the stomach with pepsin.

• Like salivary alpha-amylase, it is not a required enzyme and it
only functions in the acid medium of the stomach. End products
would include intact protein, polypeptides, and few
amino-acids.
• Pepsin only initiates the process of protein digestion (covers
10-20 % of protein digestion).
• Digestion continues in the small intestine, with the pancreatic
proteases, which are required enzymes:
• Trypsin. Peristalsis. During peristalsis a contractile ring appears around the
• Chymotrypsin.
• Carboxypolypeptidase.
• Elastase.
• End-products include short peptides and individual amino acids.

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• One of the important features of pepsin digestion is its ability to digest the protein collagen, an albuminoid type of
protein that is affected little by other digestive enzymes. Collagen is a major constituent of the intercellular connective
tissue of meats; therefore, for the digestive enzymes to penetrate meats and digest the other meat proteins, it is
necessary that the collagen fibers be digested.
• Both trypsin and chymotrypsin split protein molecules into small polypeptides; carboxypolypeptidase then cleaves
individual amino acids from the carboxyl ends of the polypeptides. Proelastase, in turn, is converted into elastase, which
then digests elastin fibers that partially hold meats together.
• Only a small percentage of the proteins are digested all the way to their constituent amino acids by the pancreatic juices.
Most remain as dipeptides and tripeptides.

34
Mechanism of Amino Acid and Peptide Absorption

• As with carbohydrates, final digestion is accomplished on the enterocytes of

the villi, which express peptidases. The end products include individual
amino acids and very short peptides (di and tripeptides), which are all
readily absorbed.
• The initial uptake of amino acids across the luminal membrane is, as with
glucose and galactose, a secondary active transport linked to sodium.
Because of the great variety of amino acids, the carriers tend to be
nonspecific.
• Di- and tripeptides are also readily absorbed but by a slightly different
mechanism. Again, it is a symporter, but in conjugation with H+ rather than
with Na+. Within the cell the peptides are digested to amino acids. The
basolateral membrane has additional transporters for the amino acids.

Action of luminal, brush-border, and cytosolic peptidases. Pepsin from the stomach and the five pancreatic proteases
hydrolyze proteins—both dietary and endogenous—to single amino acids, AA, or to oligopeptides, (AA)n. These
reactions occur in the lumen of the stomach or small intestine. A variety of peptidases at the brush borders of
enterocytes then progressively hydrolyze oligopeptides to amino acids. The enterocyte directly absorbs some of the
small oligopeptides via the action of the H/oligopeptide cotransporter PepT1. These small peptides are digested to
amino acids by peptidases in the cytoplasm of the enterocyte.

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• In digestion of proteins and oligopeptides, the usual products that reach the apical membranes of enterocytes are
single amino acids, dipeptides, and tripeptides.
• Unlike with carbohydrates, it is not necessary to digest the trimers and dimers before absorption across the apical
membrane, because there is a transporter, that with hydrogen as a cotransporter can carry these into the cell for final
digestion inside the enterocyte.
• The peptide dimers and trimers will compete for this transporter.

35
 SMALL INTESTINAL AND COLONIC ABSORPTION OF
SODIUM, CHLORIDE, POTASSIUM AND WATER

Except Lipids, covered in Hepatic/Biliary Physiology

36
Small Intestinal Water Absorption

• Quantitatively very important, at approximately 6.5 - 7 L/day.

• Still leaves around 2 L/day presented to colon.
• Most nutrients are absorbed here as are most of the fluids supporting
the digestion and absorption of these nutrients.
• Both active and passive mechanisms are involved.
• Fluid movement is always coupled to solute movement. Water
reabsorbed by osmosis (diffusion).

Overall fluid balance in the human gastrointestinal tract. About 2 L of water is ingested and 7 L of various secretions enters the
gastrointestinal tract. Of this total, most is absorbed in the small intestine. About 2 L is passed onto the colon, the vast majority of which is
absorbed in health. (From Vander AJ et al: Human Physiology, 6th ed. New York, McGraw-Hill, 1994.)

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Absorption of Electrolytes

• Hypertonic gastric chyme enters the duodenum and,

with a net movement of water into the lumen, it
becomes isotonic and it remains isotonic throughout
the small and large intestine.
• Throughout the duodenum and jejunum there is a net
secretion of water and electrolytes by the crypt cells
and a net reabsorption at the villi tips.
• Most of the iron (Fe2+) is absorbed in the duodenum,
but Ca2+ is also absorbed along the jejunum.
• Absorptive mechanisms (including the products of
digestion) are similar to the mechanisms of the
proximal tubule of the kidney.
• Unlike earlier sections, the ileum demonstrates a net Fluid movement across the gut is a balance.

secretion of bicarbonate.

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• To a large extent, fluid secretion is driven by secretion of chloride and bicarbonate ions (or chloride and hydrogen in the
gastric pits). Sodium follows chloride and bicarbonate, and water follows. Since they are regulated independently, the
balance of which one has greater flux determines the net movement of fluid into the lumen (secretory) or into the blood
(absorptive).

38
Four Modes of Sodium Absorption by the Intestine

Cotransport with monosaccharides and amino acids (symports):

• e.g., SGLT-1 symport with glucose.
• Sodium-potassium pump moves sodium into interstitial fluid (active part
of secondary active transport).
• Mainly in the jejunum and ileum.
• Associated with absorption of carbohydrates and amino acids.
Na+/H+ exchanger (antiport):
• Mainly in the duodenum and jejunum.
• Associated with absorption of dipeptides and tripeptides.
Parallel Na+/H+ and Cl-/HCO3- exchangers (twin antiports):
• Mainly in the ileum and proximal colon.
• Associated with mass absorption of NaCl and water.
Epithelial Na+ channel (ENaC):
• Mainly in the distal colon.
• Associated with finer control of plasma sodium and potassium.

• Aldosterone greatly enhances Na+ absorption! Absorption of sodium, chloride, glucose, and amino acids through
the intestinal epithelium. Note also osmotic absorption of water
(i.e., water “follows” sodium through the epithelial membrane).

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• A large amount of water reabsorption is secondary to absorption of ions, particularly Na+ and Cl-.
• Normally, less than 0.5 percent of the intestinal sodium is lost in the feces each day because it is rapidly absorbed
through the intestinal mucosa.
• Unlike in secretion where for most purposes Cl- secretion led to Na+ following the chloride, in absorption it is more
common for sodium to be absorbed/reabsorbed and then the chloride and water follow the sodium in.
• There are exceptions such as the cotransporter with hydrogen and dipeptides/tripeptides, but generally water follows
sodium.
• It is possible to bring in both sodium and chloride across the apical membrane, so long as there is a carbonic anhydrase
available on the luminal side of the apical membrane to turn H+ and HCO3- back into H20 and CO2.
• On rare occasions like severe dehydration, the colon becomes involved in aldosterone-associated absorption of sodium
and water to complement that occurring in the kidney. There is a special Electrogenic Na Channel (ENaC) associated with
this.

39
Three Modes of Chloride Absorption by the Intestine

Passive reabsorption:
• Paracellular, following sodium electrochemically.
• Greatest in jejunum, distal colon, and ileum.
• Associated with nutrient absorption and fine control of plasma volume.
Chloride-bicarbonate exchanger:
• Secondary active transport (for hydrogen, the byproduct of carbonic anhydrase).
• Greatest in proximal colon, ileum, and distal colon.
• Associated with bicarbonate secretion (crypt cells).
Parallel Na+/H+ and Cl-/HCO3- exchangers:
• Brings in both sodium and chloride into the cell.
• In the lumen the secreted HCO3- and H+ are converted back into CO2 and water.
• Greatest in ileum and proximal colon.
• Associated with mass absorption of NaCl and water.

Modes of Cl− absorption by the intestine. A, In voltage-dependent Cl− absorption, Cl− may passively diffuse from lumen to blood across
tight junctions, driven by a lumen-negative transepithelial voltage (paracellular route). Alternatively, Cl − may diffuse through apical and
basolateral Cl− channels. B, In the absence of a parallel Na+/H+ exchanger, electrogenic Cl-/HCO3- exchange at the apical membrane
results in Cl− absorption and HCO3- secretion. C, Electroneutral NaCl absorption can mediate Cl− absorption in the interdigestive period.
Intracellular pH may couple the two exchangers. The thickness of the arrows in the insets indicates the relative magnitudes of Cl −
absorptive fluxes in different segments. CA, carbonic anhydrase.

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• Sodium, chloride, and water absorption are tied together. Shown above are the three mechanisms by which chloride is
absorbed.
• Voltage-dependent passive absorption, which occurs in every location which sodium is absorbed, is chloride ions
following the more actively-absorbed sodium ions either across the cell (transcellular) or between cells (paracellular).
Classic examples are following sodium and glucose in carbohydrate absorption, and sodium and amino acids.
• •The chloride-bicarbonate exchanger can be used in the ileum or colon, particularly in locations where bacteria are
producing excess acid, to better neutralize that osmotic agent and also bring chloride and water into the blood. It is most
active where there is both a lot of water and a lot of colonic bacteria, the proximal (ascending) colon.
• The chloride-bicarbonate exchanger, #3 of the sodium absorption modes, lets both sodium and chloride into the cell for
absorption and both hydrogen and bicarbonate out for processing by carbonic anhydrase. Either way water tends to
follow the sodium and chloride into the blood.

40
Absorption of Bicarbonates

• Absorbed indirectly:
• When sodium ions are absorbed, moderate amounts of hydrogen ions are secreted into the lumen of
the gut in exchange for some of the sodium.
• These hydrogen ions, combine with the bicarbonate ions to form carbonic acid (H2CO3), which then
dissociates to form water and carbon dioxide.
• The water remains as part of the chyme in the intestines, the carbon dioxide is readily absorbed into
the blood and subsequently expired through the lungs.

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• To a large extent, fluid secretion is driven by secretion of chloride and bicarbonate ions (or chloride and hydrogen in the
gastric pits). Sodium follows chloride and bicarbonate, and water follows. Since they are regulated independently, the
balance of which one has greater flux determines the net movement of fluid into the lumen (secretory) or into the blood
(absorptive).

41
Two Modes of Potassium Absorption

Passive absorption:
• Paracellular.
• Carried with water in bulk processing (solvent drag).
• Greatest in jejunum and ileum.

Active absorption:
• Involves exchange with hydrogen at surface epithelial cells.
• Only occurs in distal colon.
• Most typically with dietary K+ depletion.

• Note: The distal colon can either secrete or absorb potassium

depending on body needs for potassium.

Cellular mechanisms of K+ secretion and absorption. A, In the small intestine, K+ absorption occurs via solvent
drag. B, In the distal colon, active K+ absorption is transcellular. The thickness of the arrows in the insets indicates
the relative magnitude of K+ flux in different segments.

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• Potassium absorption is critical for maintenance of homeostasis, but it does not have many active transport
mechanisms.
• Most potassium absorption takes place in the jejunum and ileum, through passive means, particularly paracellular. This is
not so much diffusion as “bulk processing”, in which the potassium ions are carried along with water from the lumen to
the blood, like a stick carried down a river.
• Active absorption is typically only found in the most distal colon, as part of the fine control of correcting a hypokalemia in
the plasma. If one is short on potassium in the plasma, and cardiac arrhythmias might occur.

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FORMATION OF FECES

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Formation of Feces

• Less than 100 ml of fluids are excreted with feces.

• Only 1 to 5 mEq each of sodium and chloride ions to be lost in the feces.
• Proximal one half of the colon is absorbing colon, the distal colon functions
principally for feces storage - storage colon.
• The feces are composed of:
• 30 % percent dead bacteria.
• 10 – 20 % percent fat.
• 10 – 20 % percent inorganic matter.
• 2 - 3 % protein.
• 30 % % undigested roughage from the food and dried constituents of
digestive juices (bile pigment, sloughed epithelial cells).
• The brown color of feces is caused by stercobilin and urobilin, derivatives of
bilirubin. The odor is caused principally by products of bacterial action.

Overall fluid balance in the human gastrointestinal tract. About 2 L of water is ingested and 7 L of various secretions enters the
gastrointestinal tract. Of this total, most is absorbed in the small intestine. About 2 L is passed onto the colon, the vast majority of which is
absorbed in health. (From Vander AJ et al: Human Physiology, 6th ed. New York, McGraw-Hill, 1994.)

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• The large intestine can absorb a maximum of 5 to 8 liters of fluid and electrolytes each day. When the total quantity
entering the large intestine through the ileocecal valve or by way of large intestine secretion exceeds this amount, the
excess appears in the feces as diarrhea.
• Toxins from cholera or certain other bacterial infections often cause the crypts in the terminal ileum and large intestine
to secrete 10 or more liters of fluid each day, leading to severe and sometimes lethal diarrhea.
• Numerous bacteria, especially colon bacilli, are present even normally in the absorbing colon. They are capable of
digesting small amounts of cellulose, in this way providing a few calories of extra nutrition for the body. In herbivorous
animals, this source of energy is significant, although it is of negligible importance in human beings.
• Other substances formed as a result of bacterial activity are vitamin K, vitamin B12, thiamine, riboflavin, and various
gases that contribute to flatus in the colon, especially carbon dioxide, hydrogen gas, and methane. The bacteria-formed
vitamin K is especially important because the amount of this vitamin in the daily ingested foods is normally insufficient to
maintain adequate blood coagulation.

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 SMALL INTESTINAL ABSORPTION OF IRON,
COBALAMIN (VITAMIN B12), AND CALCIUM

Except Lipids, covered in Hepatic/Biliary Physiology

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Location for Micronutrient Absorption

• Iron: duodenum.

• Folic acid: mainly jejunum.

• Calcium: duodenum, jejunum, and ileum

(regulated by PTH and vit. D).

• Cobalamin: terminal ileum.

• Bile salts and intrinsic factor bound to B12:

reabsorbed only in distal ileum.

Sites of nutrient absorption. A, The entire small intestine absorbs carbohydrates,

proteins, and lipids. However, the absorption is greatest in the duodenum,
somewhat less in the jejunum, and much less in the ileum. The thickness of the
arrows indicates the relative magnitude of total absorption at the indicated site in
vivo. The maximal absorptive capacity of a specific segment under optimized
experimental conditions (e.g., substrate concentrations) may be greater. B, Some
substances are actively absorbed only in the duodenum. C, Bile acids are
absorbed along the entire small intestine, but active absorption occurs only in the
ileum. D, The vitamin cobalamin is absorbed only in the ileum.

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Mechanism of Iron Absorption

• Iron ions come in two main forms, Ferric (Fe3+)

and Ferrous (Fe2+).
• Only the Fe2+ form can be absorbed from the
intestine, mostly duodenal.
• In contrast, Fe3+ is the usual storage form and
the form transported in the blood.
• Ferritin is used to store iron in iron excess.
• Iron-binding proteins help process Fe3+ and
deliver it to the blood protein transferrin.
• Liver releases hepcidin that inhibits ferroportin
channels and reduces Fe2+ absorption.

Absorption of nonheme and heme iron in the duodenum. The

absorption of nonheme iron occurs almost exclusively in the form
of Fe2+, which crosses the duodenal apical membrane via DMT1,
driven by a H+ gradient that is maintained by Na+/H+ exchange.
Heme enters the enterocyte by an unknown mechanism. Inside
the cell, heme oxygenase releases Fe3+, which is then reduced to
Fe2+. Cytoplasmic Fe2+ then binds to mobilferrin for transit across
the cell to the basolateral membrane. Fe2+ probably exits the
enterocyte via basolateral ferroportin. The ferroxidase activity of
hephaestin converts Fe2+ to Fe3+ for carriage in the blood plasma
bound to transferrin.
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• Like calcium ion, absorption of ferrous iron from the lumen to the enterocyte cytoplasm is limited by its transport
maximum. Excess iron in the intestinal lumen will pass into feces.
• Unlike calcium, once absorbed into the enterocyte, ferrous iron is converted to ferric iron and stored within the cell, such
that passage across the basolateral membrane into the blood is also subject to control.
• Remember that the cells doing the absorption have a limited lifespan of only a few days. If Iron ions stay within the cell
too long, the cell will die and the iron will be re-released back into the intestinal lumen again.

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Cobalamin (Vitamin B12) and Intrinsic Factor

• Vitamin B12 is required for proper blood synthesis.

• Intrinsic factor, secreted by parietal cells, protects this peptide
from digestion.
• Once past the digestive enzymes in the terminal ileum, the
complex is absorbed through endocytosis.
• Vitamin B12 enters portal blood, intrinsic factor is degraded.

Normal absorption of vitamin B12. Dietary vitamin B12 (cobalamin, CBL) is food protein (P) bound. In the
stomach, pepsin and hydrochloric acid (HCl) secreted by parietal cells release CBL from P. CBL then binds
haptocorrin (R protein, R), released from salivary glands, and remains bound until intestinal pancreatic
proteases, including trypsin, catalyze its release. Parietal cells secrete intrinsic factor (IF), which binds CBL
in the duodenum. Cubilin-amnionless (cubam) and megalin receptors in ileal enterocytes bind CBL-IF and
release the CBL. Enterocytes produce transcobalamin (TC), which binds CBL and transports it through the
portal circulation. Bone marrow pronormoblast membrane TC receptors (TC-R) bind CBL-TC and release
the CBL, which is converted to methylcobalamin (methyl-CBL). Methyl-CBL is a coenzyme that supports
homocysteine-methionine conversion. Hepatocyte TC-R receptors bind CBL-TC and release the CBL, which
is moved to storage organelles or excreted through the biliary system.

The absorption of vitamin B12 can be impaired by (1) failure to separate vitamin B12 from food proteins in
the stomach, (2) failure to separate vitamin B12 from haptocorrin in the intestine, (3) lack of intrinsic
factor, (4) malabsorption, and (5) competition for available vitamin B12.

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Mechanism of Intestinal Calcium Absorption

• Paracellular transport is not very substantial. Nearly all

of the calcium that enters the body goes through the
cell (transcellular) in a highly regulated fashion.
• Like other divalent ions, calcium’s usual absorption is
limited not by the quantity in the diet but by the
number and activation state of transporters at the
absorptive cells.

Active Ca2+ uptake in the duodenum. The small intestine absorbs Ca2+ by two
mechanisms. The passive paracellular absorption of Ca2+ occurs throughout the small
intestine. This pathway is the predominant one but is not under the control of vitamin
D. The second mechanism - the active transcellular absorption of Ca2+ - occurs only in
the duodenum. Ca2+ enters the cell across the apical membrane via a channel. Inside
the cell, the Ca2+ is buffered by binding proteins such as calbindin and is also taken up
into intracellular organelles such as the endoplasmic reticulum. The enterocyte then
extrudes Ca2+ across the basolateral membrane via a Ca2+ pump and an Na+/Ca2+
exchanger. Thus, the net effect is Ca2+ absorption. The active form of vitamin D (1,25
dihydroxyvitamin D) stimulates all three steps of transcellular Ca2+ absorption. NCX1,
Na+/Ca2+ exchanger 1.

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• Once inside the cell much of the calcium is temporarily held in place by a protein called calbindin before it is finally
transported across the basolateral membrane by either primary active transport (calcium-hydrogen antiport pump), or
secondary active transport like that seen in the heart (sodium-calcium antiport with a sodium-potassium pump).

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SELECTED PATHOLOGIES

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Selected Pathologies

• Disorders of the Oral Cavity, Pharynx, and • Disorders of the Small Intestine:
Esophagus: • Cholelithiasis (Gallstones).
• Dysphagia. • Malabsorption secondary to pancreatic
• Achalasia. failure (e.g., pancreatitis).
• Gastroesophageal Reflux Disease. • Malabsorption by the small intestinal
• Barrett Esophagus. mucosa.
• Excess secretion of intestinal fluids.
• Disorders of the Stomach:
• Gastric Injury leading to Gastritis. • Disorders of the Large Intestine:
• Peptic Ulcers. • Inflammatory Bowel Disease (Ulcerative
• Pernicious Anemia. Colitis or Crohn’s Disease).
• Vomiting. • Constipation.
• Congenital Megacolon.
• Acute Diarrhea.
• Diverticulosis/ Diverticulitis.

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Biliary, Pancreatic, and Small Intestinal Disorders

• Increased small intestinal motility in response to irritants or intestinal blockage:

• Antiperistalsis.
• Power propulsion.
• Gallstones and cholecystitis.
• Malabsorption of nutrients secondary to insufficient secretion of pancreatic enzymes (exocrine pancreatic insufficiency).
• Acute & chronic pancreatitis.
• Malabsorption of nutrients from failure of either enzymes or transport proteins on the apical (brush border)
membranes of intestinal enterocytes.
• Sprue.
• Excess secretion of fluids from small intestine:
• Discussed under diarrhea, large intestinal disorders.
• Obstructions.

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• Note that antiperistalsis is not a disorder per se, but it is often associated with vomiting. Similarly a power propulsion
might be associated with diarrhea or an external cause but it is not a disorder itself. They are listed here as
consequences/effects of other conditions which are disorders, such as intestinal obstruction, gastric inflammation, etc.
• As before, you should focus first on the conditions listed in RED.

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Two Ways to Clear the Small Intestine

• Antiperistalsis - forcing duodenal contents into the stomach for subsequent vomiting. This is controlled in the same way
that antiperistalsis occurs in the stomach and the distal 2/3 of the esophagus. Depending on the source of the irritant in
the intestinal tract (proximal or distal to sphincter of Oddi) either metabolic alkalosis or acidosis might occur.

• Power propulsion is strong, long-lasting contractions of the circular muscle that propagate for extended distances along
the small and large intestines. These “giant” propulsive contractions are considerably stronger than the propulsive
circular muscle contractions during the MMC or fed pattern. They last for 18–20 s and rapidly strip the lumen clean as
they travel at about 1 cm/s over long lengths of intestine.

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Pancreatitis and Exocrine Pancreatic Insufficiency

• Inflammation of the pancreas can lead to many problems.

• One of these is exocrine pancreatic insufficiency, an inability to secrete enough fluid (digestive enzymes) to properly
digest the variety of nutrients in the small intestinal lumen.

• There are several possible causes which include cystic fibrosis and gallstone blockage of the pancreatic duct.

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Cystic Fibrosis

• Cystic fibrosis is a genetic disorder that affects mostly

the lungs, but also the pancreas, liver, kidneys, and
intestine.
• Long-term issues include difficulty breathing and
coughing up mucus as a result of frequent lung
infections.
• Other signs and symptoms may include sinus
infections, poor growth, fatty stool, clubbing of the
fingers and toes, and infertility in most males.

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Steatorrhea

• Steatorrhea is an increase in fat excretion in the

stools.
• Steatorrhea is one of the clinical features of fat
malabsorption and noted in many conditions such as
exocrine pancreatic insufficiency (EPI), celiac disease,
and tropical sprue.
• An increase in the fat content of stools results in the
production of pale, large volume, malodorous, loose
stools.

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Lactose Intolerance

• Lactose intolerance is a clinical syndrome that manifests with characteristic signs and
symptoms upon the consumption of food substances containing lactose, a disaccharide.
• Normally upon the consumption of lactose, it is hydrolyzed into glucose and galactose by
lactase enzyme, which is found in the small intestinal brush border. Lactose intolerant
persons can neither digest lactose, nor absorb its component monosaccharides.
• Deficiency of lactase due to primary or secondary causes results in clinical symptoms.
Disease severity varies among individuals.
• Lactose is present in dairy, milk products, and mammalian milk. It is also sometimes
referred to as lactose malabsorption.
• There are 4 main causes of lactase deficiency:
• Primary lactase deficiency (hereditary cause).
• Secondary lactase deficiency (injury to intestinal mucosa due to several infectious,
inflammatory, or other diseases (e.g. gastroenteritis, Chron disease, etc).
• Congenital lactase deficiency (there is a decrease or absence of lactase enzyme
activity since birth due to autosomal recessive inheritance. It is a rare cause of the
deficiency.)
• Developmental lactase deficiency (it is seen in premature infants born at 28 to 37
weeks of gestation: the intestine of the infant is underdeveloped, resulting in an
inability to hydrolyze lactose; this condition improves with increasing age due to
the maturation of the intestine, which results in adequate lactase activity).

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Secretory Diarrhea

• Secretory diarrhea is usually associated with large volumes of

watery stools and persists during fasting. Consequently, it is
helpful to assess the effects of fasting on stool output.
• Pure secretory diarrheas are uncommon, but can occur in the
setting of certain enteric infections.
• Secretory diarrhea occurs in 80 percent of patients with carcinoid
syndrome and is often the most debilitating component of the
syndrome.
• Stools may vary from few to more than 30 per day, are typically
watery and nonbloody, and can be explosive and accompanied by
abdominal cramping. The abdominal cramps may be a
consequence of mesenteric fibrosis or intestinal blockage by the
primary tumor. The diarrhea is usually unrelated to flushing
episodes.
Action of secretagogues. Secretagogues (agents that stimulate the net secretion of fluid and electrolytes
into the intestinal lumen) act by any of the mechanisms numbered 1, 2, or 3. AC, adenylyl cyclase; CaM,
calmodulin; DAG, diacylglycerol; ER, endoplasmic reticulum; Gq and Gs, α-subunit types of G proteins;
GPCRs, G protein–coupled receptors; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A;
PKC, protein kinase C; PKG, cGMP-dependent protein kinase; PLC, phospholipase C.

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• Chloride secretory diarrhea works at the crypt cells.

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Disorders of the Large Intestine

• Inflammatory bowel disease (IBD) secondary to either ulcerative colitis or Crohn’s disease.
• Constipation.
• Congenital megacolon (Hirshprung’s Disease).
• Diarrhea.
• Irritable bowel syndrome (IBS).
• Diverticulosis/diverticulitis.

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Inflammatory Bowel Disease

• Inflammatory bowel disease (IBD) is comprised of two major disorders:

ulcerative colitis and Crohn disease.
• Ulcerative colitis affects the colon. It is a chronic inflammatory
condition characterized by relapsing and remitting episodes of
inflammation limited to the mucosal layer of the colon.
• Crohn disease is characterized by transmural inflammation and by
skip areas of involvement (ie, segments of normal-appearing
bowel interrupted by areas of disease). The transmural
inflammatory nature of Crohn disease may lead to fibrosis and
strictures and to obstructive clinical presentations that are not
typically seen in patients with ulcerative colitis. Transmural
inflammation may also result in sinus tracts, giving rise to
microperforations and fistula formation. Crohn disease most
commonly involves the ileum and proximal colon; however, any
part of the gastrointestinal tract may be affected.

• These disorders have somewhat different pathologic and clinical

characteristics, but with substantial overlap.

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Constipation

• Constipation is a common complaint that may be due to a variety of causes.

• Constipation is not a disease.
• There are specific criteria for a clinical diagnosis of constipation.
• Excess absorption of water and/or inadequate motility of the colon leads to stools that are excessively dry and often
difficult to pass.
• Can be associated with other conditions such as congenital megacolon or colonic diverticulitis, neurogenic and
non-neurogenic disorders, drugs.

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Congenital Megacolon

• Hirschsprung disease (HD) is a motor disorder of the gut, which is caused by

the failure of neural crest cells (precursors of enteric ganglion cells) to
migrate completely during intestinal development during fetal life.
• The resulting aganglionic segment of the colon fails to relax, causing a
functional obstruction.

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Acute Diarrhea

• Like constipation, diarrhea is a symptom/sign, not a disease.

• Diarrhea implies an increase in stool volume and diminished stool
consistency.
• Excessive secretion of water and/or excess motility of the colon
leads to stools that are excessively wet and high in volume and/or
frequency.
• Can be associated with other conditions such as inflammatory
bowel disorder or certain gastrointestinal infections, particularly
those with toxins.

Action of secretagogues. Secretagogues (agents that stimulate the net secretion of fluid and electrolytes
into the intestinal lumen) act by any of the mechanisms numbered 1, 2, or 3. AC, adenylyl cyclase; CaM,
calmodulin; DAG, diacylglycerol; ER, endoplasmic reticulum; Gq and Gs, α-subunit types of G proteins;
GPCRs, G protein–coupled receptors; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A;
PKC, protein kinase C; PKG, cGMP-dependent protein kinase; PLC, phospholipase C.

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• Chloride secretory diarrhea works at the crypt cells.

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Irritable Bowel Syndrome

• Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by chronic abdominal
pain and altered bowel habits.
• Chronic abdominal pain - abdominal pain in IBS is usually described as a cramping sensation with variable intensity
and periodic exacerbations. The location and character of the pain can vary widely. The severity of the pain may
range from mild to severe. The pain is frequently related to defecation.
• Altered bowel habits - symptoms of IBS include diarrhea, constipation, alternating diarrhea and constipation, or
normal bowel habits alternating with either diarrhea and/or constipation.
• Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Bowel movements
generally occur during waking hours, most often in the morning or after meals. Most bowel movements are
preceded by lower abdominal cramping pain, urgency, and a sensation of incomplete evacuation or tenesmus.
• Constipation - stools are often hard and may be described as pellet-shaped. Patients may also experience tenesmus
even when the rectum is empty.

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CASE ANSWERS
Case Scenario: Lactose Intolerance

A 23-year-old male college student presents to his primary care physician with abdominal pain, bloating, flatulence, and diarrhea after
eating ice cream.
• What products of carbohydrate digestion are absorbed in the small intestine?
• Propose a mechanism for this patient’s lactose intolerance.
• Why did his lactose intolerance cause diarrhea?

What products of carbohydrate digestion are absorbed in the small intestine?

• Glucose, galactose, and fructose.

Propose a mechanism for this patient’s lactose intolerance.

• Lactose cannot be absorbed by intestinal epithelial cells. It must first be digested to the absorbable monosaccharides glucose and
galactose. So, lactose intolerance can result from a defect in lactose digestion to monosaccharides (e.g., lactase deficiency) or from a
defect in one of the monosaccharide transporters. Note, that a defect in the glucose or galactose transporter would create nonspecific
intolerance to di- and monosaccharides. Our patient has lactase deficiency (either too little lactase or none at all). Because of this
deficiency, he cannot digest dietary lactose in milk products to the absorbable monosaccharides glucose and galactose.

Why did his lactose intolerance cause diarrhea?

• Lactose intolerance causes diarrhea because undigested lactose is not absorbed. Some of the lactose is fermented by colonic bacteria to
lactic acid, methane, and H2 gas. Undigested lactose and lactic acid then behave as osmotically active solutes in the lumen of the
gastrointestinal tract. These solutes draw water isosmotically into the intestinal lumen and produce osmotic diarrhea.

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 Questions?

Dr. Oleksii Hliebov, MD, PhD

Associate Professor, Department of Medical Foundations
[email protected]
Spring 2022