Secretions of the Intestines/Ion Transport

Question 1

Brunner’s Glands

Answer 1

• Brunner’s glands are small glands found in the proximal duodenum close to the pyloric sphincter that secrete mucus and HCO3 - .
• Secretions from these glands are important for protecting the proximal duodenum from acid loads in chyme moving out of the stomach prior to the Sphincter of Oddi where pancreatic secretions emerge.

Question 2

Intestinal Villi

Answer 2

•Intestinal Villi refers to the extensive foldings observed in the surface of the small intestine. The villi are covered by a layer of epithelial cells with only a few other cell types interspersed (ex. Immune M-cells, endocrine cells). This folding arrangement dramatically increases surface area providing an optimal situation for absorption.

Question 3

Crypts of Lieberkuhns

Answer 3

• Crypts of Lieberkuhn are extensive pits found between villi at their base, which extend to the submucosa and are found in all parts of the intestine.
• The crypts contain pluri-potential cells, which can differentiate into absorptive epithelial cells as they migrate towards the villus tip. In addition to these precursor cells, a large variety of mucus secreting goblet cells, and endocrine cells are found in the crypts.
• Many of the nutrient sensing endocrine secreting cells are located in the crypts.

Question 4

Cell Growth and Differentiation

Answer 4

• Stem cells are located in the crypts. Epithelial cell turnover at the tip of a villus is high (3-6 day cycle), so a significant rate of migration of cells from the crypts is necessary to replace lost cells.
• As cells move from the crypts, changes in cell function occur: the absorptive capacity and the level of brush border enzymes both increase dramatically. Therefore, any process that increases cell death at the tip or slows differentiation in the crypts will reduce absorptive capacity and may lead to diarrhea due to malabsorption.
• Since mucosal stem cells divide rapidly, interventions that alter the cell cycle can lead to absorptive abnormalities.
• It is important to recognize that CCK is a primary stimulator of cell differentiation and turnover thereby promoting epithelial recovery.

Question 5

Water Secretion in the Small and Large Intestine

Answer 5

• Continuous secretion of water is observed from the crypts of both the small and large intestine. Since the area of the small intestine is far great than the colon, the bulk amount of fluid secretion is from small intestine crypts.
• The mechanism for active water secretion depends on activation of a cAMP activated Cl- channel (CFTR).
• VIP is the enteric neurotransmitter that ‘normally’ activates water secretion by elevating cAMP within colonic and small intestinal crypts.
• Inflammation or introduction of noxious compounds into the intestine also may cause elevation of cAMP within crypt cells due to local histamine release (from immune cells) which elicits an acute secretory response promoting flushing of the crypt.
• Similarly, enterotoxins released by infiltrating bacteria such as cholera can cause profound diarrhea via direct activation of adenylyl cyclase or other components of the cAMP signaling pathway

Question 6

[…] is the enteric neurotransmitter that ‘normally’ activates water secretion by elevating cAMP within colonic and small intestinal crypts.

Answer 6

VIP is the enteric neurotransmitter that ‘normally’ activates water secretion by elevating cAMP within colonic and small intestinal crypts.

Question 7

Inflammation or introduction of noxious compounds into the intestine also may cause elevation of cAMP within crypt cells due to local […] release (from immune cells) which elicits an acute secretory response promoting flushing of the crypt.

Answer 7

Inflammation or introduction of noxious compounds into the intestine also may cause elevation of cAMP within crypt cells due to local histamine release (from immune cells) which elicits an acute secretory response promoting flushing of the crypt.

Question 8

Similarly, enterotoxins released by infiltrating bacteria such as cholera can cause profound diarrhea via direct activation of […] or other components of the […] signaling pathway. Mucus secreting Goblet cells also are found throughout the intestine

Answer 8

Similarly, enterotoxins released by infiltrating bacteria such as cholera can cause profound diarrhea via direct activation of adenylyl cyclase or other components of the cAMP signaling pathway.

Question 9

Mucus secreting […] also are found throughout the intestine.

Answer 9

Mucus secreting Goblet cells also are found throughout the intestine.

Question 10

[…] are present but less extensive in the colon.

Answer 10

Crypts are present but less extensive in the colon.

•In the colon, crypts contain more goblet cells and stem cells than the small intestine, whereas fewer endocrine cells are observed. Mucus represents the largest component of colonic secretions acting to protect the colon wall and cause fecal material to adhere together.

Question 11

Normally there is net water […] together with […] secretion to the lumen in exchange for Cl- .

Answer 11

Normally there is net water absorption together with HCO3 - secretion to the lumen in exchange for Cl- .

•Simultaneously, a low rate of water secretion at an alkaline pH protects the colon walls from acid produced by bacteria.

Question 12

Absorption of Ions and Water

Answer 12

• Water movement follows the movement of osmolytes including ions and nutrients.
• In general, there is net fluid secretion from cells located within intestinal crypts, while there is net fluid absorption by enterocytes lining the villi.
• The surface area of the villi is massive compared to the crypts such that net water absorption is normally favored.
• However, continuous secretion of water, and therefore osmolytes is required to maintain the intestine moist particularly during fasting/resting (inter-digestive) periods.

Question 13

Sodium Absorption

Answer 13

• Na+ is absorbed along the entire intestine with most absorbed in the jejunum (~80%). Na+ moves into epithelial cells from the lumen through the apical membrane (down its electrochemical gradient) by co-transport with nutrients (small intestine), via Na+ /H+ exchange (primarily proximal intestine) or through Na+ channels (primarily in colon).
• Na+ absorption is dependent on the Na+ gradient generated by the basolateral Na-K ATPase that actively transports it across the basolateral membrane to the interstitial space.
• Since there is net movement of positive charge from the lumen to the blood (3 Na+ to blood for 2 K+ into cell), the lumen is more negative with respect to the interstitial space (15-25 mV). H2O follows NaCl down the osmotic gradient toward blood, therefore H2O movement is critically linked to Na+ absorption.

Question 14

Chloride Absorption

Answer 14

•The absorption of Cl- is passive in the proximal intestine where junctions between cells are leaky.

-In the jejunum, Cl- moves passively via paracellular pathways to offset net positive charge movement caused by rapid Na+ absorption.

•However, as the epithelia become less leaky in the distal intestine, electroneutral Cl- transport across the lumenal membrane becomes important for its absorption to the blood.

• In the ileum and colon, uptake of Cl- across the lumen membrane occurs through Cl/HCO3 - coupled antiport, which also provides for buffering bacterial H+ production.
• Carbonic anhydrase has been found in colonic enterocytes, and is likely important in facilitating HCO3 - production, and thereby a favorable chemical gradient for HCO3 movement to the lumen coupled to Cl- absorption into the cells.

Question 15

Na+ Channels

Answer 15

•most important in distal colon

Question 16

Na+ - Substrate Transporters

Answer 16

•decreases from proximal intestine to ileum

Question 17

Na+/H+

Answer 17

•high is proximal intestine, low in colon

Question 18

Aldosterone

Answer 18

•Increases number of Na+ channels and NKA and thus increases Na+ absorption which is particularly important for regulating water absorption in the colon.

Question 19

Cl- Absorption

Answer 19

• paracellular in the proximal intestine
• Cl-/HCO₃ - in the distal intestine/colon

Question 20

The largest fraction of Na+ is absorbed into the […] through Na+ - coupled co-transporters.

Answer 20

The largest fraction of Na+ is absorbed into the small intestine villus enterocytes through Na+ - coupled co-transporters.

•The Na-K ATPase removes this “absorbed” Na+ load to the blood. Cl- moves to the blood via paracellular pathways to maintain electroneutrality.

Question 21

Why does K+ absorption follow via a paracellular route in the small intestine?

Answer 21

•K+ follows via a para-cellular route most likely due to the large concomitant fluid flux (via solvent drag); the large paracellular fluid flux in the upper small intestine carries the relatively high K+ in the lumen to the blood where K+ is relatively low (5 mM).

Question 22

[…] uptake is the driving force for water reabsorption in the colon.

Answer 22

Na+ uptake is the driving force for water reabsorption in the colon.

•Na+ coupled cotransporters are much lower or non-existent in the colon while apical Na+ channels provide the primary route for movement into enterocytes. Apical Cl- / HCO3 -exchange is relatively more important due to the need for net HCO3 - secretion to neutralize H+ production by bacteria.

Question 23

K + absorption along the entire small intestine is […].

Answer 23

K + absorption along the entire small intestine is passive.

•Absorption in the jejunum is primarily via paracellular pathways. K+ is low in the intercellular space and the large paracellular fluid flux during active transcellular salt (NaCl) absorption is believed to drive passive paracellular K+ absorption via solvent drag.

Question 24

In the colon, […] K+ uptake is a slow process, but the driving force (lumen to cell/blood) is […] because the luminal K + concentration becomes elevated as fluid is removed.

Answer 24

In the colon, passive K+ uptake is a slow process, but the driving force (lumen to cell/blood) is increased because the luminal K + concentration becomes elevated as fluid is removed.

• However, under conditions where colonic transit increases (diarrhea), passive K + is greatly reduced such that net K + is lost in the stool.
• In addition to passive K+ uptake, there is an apical H+ /K+ antiport (ATPase) that also promotes K+ absorption in the colon, though a role for this transporter in overall K+ balance has not been established.

Question 25

Absorption of Water

Answer 25

• About 90 - 95% of water (re)absorption takes place in the small intestine in association with Na+ coupled nutrient and H+ absorption.
• Intestinal water flux occurs via both paracellular and transcellular pathways (aquaporin dependent).
• In the duodenum, chyme is quickly brought to isotonicity. Ingestion of a hypotonic meal actually leads to rapid movement of water to the blood with isotonicity of the chyme reached prior to the jejunum.
• Water permeability decreases from proximal to distal small intestine, and the colon has the lowest permeability. The driving force for H2O absorption is the Na+ that is pumped into the lateral extracellular space by the Na+ -K + ATPase. Cl- follows Na+ by diffusion through intercellular junctions, or via Cl- /HCO3 - antiport in the colon.
• These ion movements create hypertonic fluid near the lumenal end of the lateral intercellular space providing a gradient for water movement.
• The remaining 1-2 L/day is absorbed in the colon where water permeability is low.
• However, it is in the colon that regulation of stool water content takes place. A normal colon can reabsorb a up to ~4.5 liters of H2O per day.
• Aldosterone increases colonic water absorption by increasing expression of apical Na+ channels, basolateral the Na+ - K + ATPase and potentially specific aquaporins, as it does in the kidney.

Question 26

Diarrhea can be based on defects in […] which often are interrelated depending on the primary insult.

Answer 26

Diarrhea can be based on defects in Motility, Absorption or Secretion which often are interrelated depending on the primary insult.

•For example, normal motility keeps bacteria restricted mostly to the colon. Significant decreases in Motility in the small intestine that occurs after surgery (use of anti-cholinergics) can lead to migration of bacteria into the small intestine, and this in turn can lead to a decrease in enterocyte viability and absorptive diarrhea. Furthermore, patients using H2 antagonists or other inhibitors of HCl secretion are susceptible to parasitic and bacterial infections, which can lead to absorptive problems

Question 27

Motility

Answer 27

• Factors that alter the normal transit of a meal through the alimentary canal will affect the consistency of the fecal contents.
• Therefore, decreases in propulsion (colonic transit time) are correlated with constipation (more time for water removal), whereas increases in propulsion are correlated with (low grade) diarrhea.
• Sedatives (codeine) and pregnancy (progesterone) elicit increases in sphincter tone and are associated with constipation.

Question 28

Since intestinal contents are relatively high in […] , profound diarrhea often is associated with […].

Answer 28

Since intestinal contents are relatively high in K+ , profound diarrhea often is associated with hypokalemia.

Question 29

Absorptive

Answer 29

•Any treatment or infection that alters the viability and/or function of enterocytes of the small intestine will lead to elevated water ‘dumping’ into the colon due to accumulation of non-absorbed osmolytes in the lumen. If the fluid flux into the colon is greater than 4.5 L/day, diarrhea will ensue. Generally, the volume of diarrhea is only moderate with absorptive disorders, occurs only following ingestion of a ‘meal’, and is diminished upon fasting.

• lactase deficiency
• ileal resection, terminal ileal disease
• celiac disease

Question 30

Lactase Deficiency

Answer 30

• Absorptive diarrhea
• Lactose in dairy products is not digested, and therefore, cannot be absorbed leading to an osmotic diarrhea.

Question 31

Ileal resection, Terminal Ileal Disease

Answer 31

• Absorptive diarrhea
• elevated bile salts and their metabolites (bacterial produced) in the colon are strong osmotic agents and also stimulate crypt derived fluid secretion into the colon.

Question 32

Celiac Disease (Sprue)

Answer 32

• Absorptive diarrhea
• Wheat flour contains gluten. In the absence of gluten hydrolase, gluten is converted to a metabolite gliadin which initiates an adaptive immune response. This response causes the destruction of enterocytes, and endocrine cells which can severely limit absorption

Question 33

Secretory

Answer 33

• The primary mechanism for active secretion of water into the colon is coupled to the opening of apical Cl- channels. This is the “cystic fibrosis” channel. In addition, digestive (bacterial) products of bile salts act as secretagogues, though their mechanism of action is as yet unknown.
• Specific effectors that alter cAMP in crypt enterocytes lead to enhanced secretion of fluid throughout the intestine and thereby water flux into the colon. cAMP regulates (opens) the Cl- channel in the crypt enterocyte luminal membrane.
• VIP is known to elevate cAMP in these cells during the postprandial period. For this reason, VIP-oma’s are correlated with massive secretory diarrhea.
• Cholera toxin and other enterotoxins stimulate intestinal secretion through the same mechanism, i.e., elevating cAMP mediated pathways.

Question 34

Laxatives (also known as purgatives or evacuants) can be effective by either initiating […] or […].

Answer 34

Laxatives (also known as purgatives or evacuants) can be effective by either initiating fluid secretion or inhibiting absorption (retention of osmotic agents in the intestine).

• Secretory
• Osmotic
• Bulk Forming Agents

Question 35

Secretory Laxatives

Answer 35

•Secretory agents increase secretion of fluid and electrolytes into the lumen of the bowel, thereby causing fluid accumulation and a watery luminal content that flows rapidly through the small and large intestines.

• castor oil
• cascar and senna (anthraquinone derivatives)
• phenolphthalein and bisacodyl

Question 36

Castor OIl

Answer 36

• laxative - secretory agent
• The classic secretory laxative is castor oil, a natural fat obtained from beans of the castor plant. One of the fatty acids esterified with glycerin in castor oil is ricinoleic acid, a hydroxylated analog of oleic acid. Liberation of ricinoleic acid requires hydrolysis of castor oil triglyceride in the stomach and small bowel.
• Ricinoleic acid in high or frequent doses leads to generalized intestinal inflammation that can damage the intestinal mucosa.
• In low doses, ricinoleic acid probably activates crypt cell adenylyl cyclase and opens chloride channels.

Question 37

Cascara and Senna

Answer 37

• laxatives - secretory agents
• anthraquinone derivatives, cascara and senna, popular as lay remedies

Question 38

Phenolphthalein and Bisacodyl

Answer 38

• laxatives - secretory agents
• Synthetic agents include phenolphthalein (e.g. Ex-Lax®) and bisacodyl (Dulcolax®).
• However, in 1997 the FDA banned the use of phenolphthalein due to potential “carcinogenic activity” in rodents at high doses.

-Ex-Lax® now contains senna as the active ingredient.

Question 39

Osmotic Laxatives

Answer 39

• Osmotic laxatives contain a cation (e.g. magnesium) or anion (e.g., sulfate or phosphate) that is not absorbed well and thereby causes water to be retained in the intestinal lumen promoting flow through the bowel.
• Examples include magnesium hydroxide (“milk of magnesia”), which is also an antacid, sodium phosphate and Magnesium sulfate (Epsom Salts).
• The major disadvantage of saline cathartics is that they often produce explosive, watery bowel movements.

Question 40

Bulk Forming Laxatives

Answer 40

• The safest and preferred laxatives are the bulk-forming agents.
• Examples include bran, methylcellulose, and psyllium.
• Bulk-forming laxatives consist of nondigestable cellulose fibers that become hydrated in the intestine, and swell to provide bulk to activate general motility and the defecation reflex. The bulk-forming agents are essentially innocuous, are relatively inexpensive, and can satisfy the psychological needs of nearly all patients.

Question 41

Excess USe of Secretory or Osmotic Laxatives Can Lead to…

Answer 41

• nutritional imbalance
• abdominal cramps,
• fluid and electrolyte disturbance
• reliance on laxatives for any bowel movements.
• Constipation can usually be corrected by dietary adjustments or use of high-residue, bulk laxatives.

Question 42

The best way to manage diarrhea is to remove the cause: […].

Answer 42

The best way to manage diarrhea is to remove the cause: eliminate the infection, remove the secretagogue-producing tumor, or cure the inflammation.

•Diarrhea can be acute, often secondary to an enteric bacterial or viral infection, or chronic, often secondary to inflammatory or functional bowel disease.

Question 43

A major sequelae of diarrhea is […] and […].

Answer 43

A major sequelae of diarrhea is loss of fluid and electrolytes.

Question 44

The most effective nonspecific antidiarrheal drugs are […], and […].

Answer 44

The most effective nonspecific antidiarrheal drugs are natural opioids, and synthetic agents loperamide and diphenoxylate.

• In humans, opioids increase sphincter tone and segmenting contractions of the small and large intestines, thereby increasing resistance to flow through the lumen and promoting absorption of fluid and electrolytes.
• In addition, increased segmenting contractions in the duodenum and s decreased gastro-duodenal pressure gradient required for gastric emptying, coupled with increased tone of the pyloric sphincter, delays gastric emptying.
• These drugs do not alter secretion, and therefore are not effective against enterotoxin mediated secretory diarrhea.
• Morphine, codeine, and related agents can be used orally or by injection as antidiarrheal drugs.
• Opioids are effective against diarrhea resulting from almost any cause other than secretory diarrhea.
• Paregoric is effective in the therapy of diarrhea because it contains morphine.
• However, even natural opioids possess abuse potential and, in overdose, can exert serious extension effects characteristic of this class of drugs.

Question 45

Diphenoxylate

Answer 45

• Diphenoxylate is a synthetic compound sold commercially as a mixture with atropine (Lomotil®). The atropine content is subtherapeutic and serves mainly as a deterrent to abuse.
• Diphenoxylate exerts typical opioid effects on the digestive tract and, in high doses, on the central nervous system.
• It is an orally effective antidiarrheal, but in overdose diphenoxylate can cause respiratory depression, which can be reversed by naloxone.

Question 46

Loperamide

Answer 46

• Loperamide (Imodium®) is an effective antidiarrheal with the advantage of poor penetration across the blood-brain barrier and therefore virtually no central nervous system effect.
• Loperamide is essentially devoid of opioid subjective effects when taken orally and possesses virtually no abuse potential.

Question 47

When are opiod anti-diarrheals contraindicated?

Answer 47

•Opioid antidiarrheals should not be employed in symptomatic treatment of diarrhea induced by enteric infections with invasive organisms, especially species of Shigella and Salmonella. Diarrhea in these infections may be protective and help to flush organisms from the gut; the delay in transit of gut contents induced by opioids can exacerbate the infection.

Question 48

Other Anti-Diarrheal Agents

Answer 48

• bismuth subsalicylate
• gel forming substances
• cholestyramine

Question 49

Bismith Subsalicylate

Answer 49

• When taken prophylactically, Bismuth subsalicylate (Pepto-Bismol®) has been shown in several clinical trials to be an effective antidiarrheal; especially effective against enterotoxigenic strains of E. coli.
• The mechanism of action is uncertain, but bismuth subsalicylate may bind bacterial produced toxins thereby inhibiting toxin-induced formation of prostaglandins and/or cAMP in the intestinal mucosa.

Question 50

Gel Forming Substances

Answer 50

• Gel-forming substances, such as attapulgite and kaolin (clay) and pectin (citrus rinds) offer more psychological benefit than reversal of pathophysiological processes.
• These substances form semisolid gels when hydrated by the watery luminal contents, reduce the number of stools, and increase their firmness.
• However, they do not reduce the volume of fluid excreted and thus have little therapeutic benefit other than promoting formed stools.

Question 51

Cholestyramine

Answer 51

• Cholestyramine (Questran®) is strongly basic anion exchange resin that binds bile acids because they are negatively charged acids.
• Although used in medicine primarily as a lipid lowering agent, cholestyramine can be used in management of diarrhea caused by excessive secretion, or inadequate reabsorption, of bile acids (“bile acid catharsis”).
• Chronic therapy with cholestyramine can interfere with fat digestion, resulting in excess fat in stools (steatorrhea), because it binds the bile acids necessary for proper digestion/absorption of fats.
• The excess fats in the intestinal lumen can dissolve fat-soluble vitamins (A, D, E, K) and reduce their absorption as well.