Download Large chemical concentration gradient Small electric

Cell Bio 7- Secretory Functions of Alimentary Tract
•
•
•
•
•
•
•
The present lecture looks at the movement of intestinal fluid and electrolytes, which mainly involves two
general activities of the intestines
– Secretion
– Absorption
Intestinal Secretions
The intestines have two general types of secretions—as in other parts of the GI tract
– Serous : These watery secretions are largely devoid of digestive enzymes, but contain many electrolytes
and hormones
– Mucous : Mucus is important for lubrication of chyme, which protects the mucosa and aids in propulsion
of the bolus
When secretions of the small intestine are collected without cellular debris, they have almost no enzymes
– Enzymes of the small intestine are found along the microvilli—and are thus referred to as brush border
enzymes—and digest molecules as they are being absorbed
• Note that the large intestine does not secrete digestive enzymes
Water and all manner of solutes (nutrients) are absorbed by the small intestine
– In contrast, only water and electrolytes are absorbed by the large intestine
The absorption and secretion of water and electrolytes are the main focus of this lecture
The intestines are presented with ~9L of fluid per day
– ~2L comes from dietary intake, while the remaining 7L results from various secretions of the tract and
associated organs
~7 of the 9L are reabsorbed by the small intestine, and ~2L passes on to the large intestine
– Of this, only 100-200mL is excreted in the feces
•
•
Substantial secretions into the
intestines (and the entire GI tract)
ensure a watery milieu, which is
important for many reasons
– Lubrication of the bolus
– Necessary environment for
biochemical reactions
• In chemical
digestion, water
molecules
themselves are
necessary for
hydrolysis reactions
– Necessary environment for
effective diffusion of
nutrients, which travel to
the gut wall for absorption
– Secretions are thought to
dilute and wash out
pathogens
In an average adult, the 9L of fluid presented to the small intestine represents a large portion of the body’s
entire extracellular fluid content
– Any disturbance in absorptive mechanisms in the intestines can lead to excessive discharge from the
bowels (diarrhea), and consequently, the potential for life-threatening losses of water and electrolytes
Cell Bio 7- Secretory Functions of Alimentary Tract
Functional Anatomy
• The absorptive surface of both the small and large intestine is amplified by structural specializations of the
mucosa and submucosa
• Three anatomical specializations maximize the absorptive area of the small intestine (~600 fold increase in
surface area)
• Circular folds
• These permanent, circular folds are ~10 mm high and extend one-half to two-thirds around the
lumen
• Villi (and associated crypts of Lieberkühn)
• These finger-like projections are ~1 mm high
• Microvilli
• These tiny projections on the apical surface of most cells of the intestinal mucosal epithelium
are ~1 µm high (~3000 microvilli per absorptive cell)
• Three anatomical specializations maximize the absorptive area of the large intestine
• Colonic folds
• These folds are similar to circular folds of the small intestine, although they are created by
muscular contractions
• Crypts (of Lieberkühn)
• Villi are absent in the large intestine, but crypts are present
• Microvilli
• The two primary functions discussed herein—absorption and secretion—generally occur in discrete locations
within the intestines
• Absorption
• In the small intestine, absorption occurs in columnar epithelial cells lining the villi
• In the large intestine, absorption occurs in surface epithelial cells
• Secretion
• In both small and large intestine, secretion occurs in the crypt cells
•
•
•
General Principles of Water and Electrolute Movement in Intestines
In the intestine, water and electrolyte absorption and secretion involve paracellular and transcellular routes
– In paracellular movement, the solute moves passively between adjacent epithelial cells through tight
junctions
– In transcellular movement, two membranes must be crossed, and active transport is generally required
in at least one membrane
The movement of water is always coupled to the movement of solute
– The absorbed or secreted fluid is always isosmotic, meaning that solute and water absorption and
secretion occur in proportion to each other
Fluid movement is driven by one of two forces
– Actively transported solute pulls water by osmosis
– Bulk movement of the solvent (water) pulls along the solute—something known as solvent drag
• Occurs only in paracellular route
Cell Bio 7- Secretory Functions of Alimentary Tract
•
•
Many different types of ions (electrolytes is a general term applied to ions) are secreted and absorbed by the
small intestine
– Sodium (Na+), chloride (Cl-), potassium (K+), and bicarbonate ion (HCO3-) are the most important
As well, many other ions are absorbed in the intestines
– Calcium (Ca++), iron (Fe++), magnesium (Mg++), and phosphate (PO3-) are examples
• Note that most of the above ions are bivalent, and tend to be absorbed in proportion to the
body’s needs
• Monovalent ions are absorbed with ease and in great quantities (sodium is a good example)
Na+, Cl-, K+, HCO3• The following four ions have important general functions
– Sodium, potassium, and chloride participate in overall body fluid balance
– Sodium and potassium produce cell membrane potentials
– Bicarbonate ion is a buffer
• In the digestive system all of these ions help govern the movement of water by osmosis
– In addition, bicarbonate ion is important in the intestines as a neutralizer of stomach acid
• The small intestine absorbs net amounts of Na+, Cl-, K+, and secretes net amounts of HCO3• The large intestine absorbs net amounts of Na+, Cl-, and secretes net amounts of K+, and HCO3– Note that all of the above ions can be secreted or absorbed in the intestines
•
•
Intestinal Absorption
Recall that the small intestine is presented with ~9L of fluid per day, nearly all of which must subsequently be
absorbed by the small intestine and the colon (100-200 mL is excreted in feces)
– The first step in this process is electrolyte absorption
The basis for much electrolyte transport across the intestinal epithelium is the Na+-K+ pump (Na+-K+-ATPase)
located on the basolateral membrane of the epithelial cells
– 3 Na+ for 2 K+ exchange creates both electrical and chemical gradients, which subsequently allows the
movement of various ions across the cell membrane
Cell Bio 7- Secretory Functions of Alimentary Tract
•
In the postprandial state, the jejunum and ileum have large quantities of glucose and amino acids in the lumen
– The epithelium takes advantage of the presence of these nutrients by activating Na+/glucose and
Na+/amino acid co-transporters to get sodium into the cells
• Sodium is subsequently pumped into the interstitium by the Na+/K+ ATPase
•
In the duodenum and jejunum only, where alkalinity is high—the result of HCO3- secreted by the pancreas,
gallbladder, and duodenum—a pH gradient is established, and H+ is drawn out of the cell
– The Na+-H+ exchanger can then drive sodium into the cell
– The exchange of Na+ for H+ enhances cellular production of HCO3-, which pulls luminal CO2 into the cell
• Removal of luminal CO2 is an indirect method of clearing HCO3- from the lumen (if necessary)
During the interdigestive period, when nutrients are not readily available, the uptake of Na+ occurs by
cooperative interaction of Na+-H+ and Cl--HCO3- antiporters (main mechanism for ileum and proximal colon)
– Note that chloride is absorbed in this process
– The source of both H+ and HCO3- is cellular water and carbon dioxide
•
•
•
In the distal colon, sodium is very efficiently absorbed by highly specific sodium channels
– This process is a last-line defense to prevent excessive loss of water in the stool
– Note that chloride ions follow passively through tight junctions to maintain electric neutrality
The GI tract participates in overall K+ balance, but the role of the kidneys is much greater
– In the jejunum and ileum, K+ absorption occurs passively, likely from solvent drag
– Active K+ absorption is confined to the distal colon
• Use of K+-H+ pump
Cell Bio 7- Secretory Functions of Alimentary Tract
•
•
Intestinal Secretion
Recall that intestinal secretion, though representing only about 1L, is important in lubricating the food bolus and
maintaining a liquid environment
As with absorption, water follows an ionic gradient
– The secretion of chloride and bicarbonate ion are of greatest importance
Chloride Secretion
• The majority of intestinal secretion of fluid is driven by the active secretion of chloride ions
– Cl- is secreted by the crypts of both the small intestine and the colon
• In addition to the Na+-K+-ATPase already described, crypt epithelial cells also contain a basolateral Na+-K+-Cl- cotransporter, which brings these ions into the cells from the blood (interstium)
– The Cl- then moves into the lumen through apical Cl- channels
– Na+ follows Cl- passively, and in turn draws out water
• The apical Cl- channels are usually closed, but respond to binding of various hormones and neurotransmitters
along the basolateral membrane
– ACh, and VIP, for example, bind to receptors and activate adenylyl cyclase, increasing cAMP levels, thus
opening Cl- channels
•
•
In some segments of the intestines, secretion of bicarbonate ion is important
– Secretion of HCO3- in the duodenum is necessary to counter the acidity of chyme coming from the
stomach
– Secretion of HCO3- in the colon is important in the neutralization of acids formed by bacteria
The secretion of K+ in the distal colon goes hand in hand with the absorption of Na+
– Under the influence of aldosterone, many Na+ channels are synthesized, allowing more and more
luminal Na+ to enter epithelial cells
– These large quantities of Na+ are then pumped out of the basolateral cell in exchange for K+, by the Na+K+ ATPase
• K+ then follows its concentration gradient and is secreted from the apical cell membrane
Cell Bio 7- Secretory Functions of Alimentary Tract
•
•
•
Regulation of Intestinal Ion Transport
Both secretion and absorption occur in response to two general activities
– Mechanical distortion of the gut lumen
– Chemical status of the gut lumen (presence, or absence, of food)
There are three types of controlling responses to these chemical and/or mechanical signals
– Endocrine, neurocrine, and paracrine
The chemical mediators of these responses are termed agonists
– They cause either secretion (secretagogues) or absorption (absorbtagogues)
Secretagogues
• In addition to the normal body secretagogues just mentioned, there are may exogenous types of secretagogues
• Grouped according to type, the secretagogues fall into four categories
– Hormones and neurotransmitters
– Products of immune cells
• Regardless of 2nd messenger system activated,
– Bacterial exotoxins (enterotoxins)
secretagogues have a similar end effect
– Laxatives
– They stimulate active Cl- secretion by
opening Cl- channels in the apical
membrane
– They inhibit NaCl absorption on the
apical membrane
• The cholera toxin—which we will see shortly—
is a secretagogue
Cell Bio 7- Secretory Functions of Alimentary Tract
Absorptagogues
• Only a few agonists enhance water and electrolyte absorption, and these work by a paracrine or endocrine
mechanism
– Corticosteroids are the primary hormones that enhance absorption
– Somatostatin, the enkephalins, and norepinephrine are also known to act as asborptagogues
• As mentioned previously, the mineralocorticoid aldosterone stimulates Na+ absorption and K+ secretion in the
distal end of the colon
– Aldosterone does not affect ion transport in the small intestine
• The glucocorticoids stimulate Na+ and Cl-absorption throughout the small and large intestine
Diarrhea
• The term diarrhea refers to an abnormally frequent (and urgent), and abnormally loose (fluid, semi-fluid)
discharge of feces
– The term means “to run through”
• Dia, through (Gr.)
• Rheum, mucous or watery discharge (from Gr., rheuma, a flux)
• Diarrhea has many causes and can be classified in many ways
• The main causes of diarrhea include the following
– Decreased surface area for absorption
• Secondary to disease processes that reduce intestinal surface area
– Osmotic diarrhea
– Secretory diarrhea
• Osmotic diarrhea is caused by the presence of non-absorbable solutes in the lumen
– In lactase deficiency—where lactose is not digested to the absorbable molecules glucose and
galactose—the lactose accumulates in the lumen and retains water, leading to osmotic diarrhea
• Bacteria may degrade the lactose to smaller (non-absorbable) molecules, thus increasing
osmosis
Secretory Diarrhea
• While other forms of diarrhea are caused by inadequate absorption, secretory diarrhea is caused by excessive
secretion of fluid by crypt cells
– The major cause of secretory diarrhea is overgrowth of enteropathic bacteria, such as E. Coli, or Vibrio
cholerae, which secretes the cholera toxin
• The cholera toxin binds to adenylyl cyclase-containing protein complexes of the basolateral membrane of
intestinal crypt cells
– The toxin causes permanent activation of adenylyl cyclase, drastically raising intracellular cAMP levels,
and leading to open Cl- channels through which intracellular Cl- flows
• Large quantities of Na+ and water follow, overwhelming absorptive capacity, and leading to
heavy fluid loss
• Despite the massive fluid loss in cholera, intestinal morphology and nutrient-coupled Na+ absorption remain
normal
– Toxin-induced upregulation of cAMP does not affect Na+-glucose or Na+-amino acid co-transporters
• Therapeutically increasing the concentration of glucose and amino acids in the lumen enhances Na+ absorption
– Oral rehydration solution is very effective in treating many diarrheal diseases