PHYSIOLOGY OF GASTROINTESTINAL SECRETIONS

Factual Data used in making presentation are taken from books written by foreign authors, which might vary in indian scenario

Sincere attempt by Mayank Agarwal (JR I)

Under guidance of Dr. N.S. Verma

In a typical day, 9 liters of fluid pass through the lumen of an adult’s gastrointestinal tract.

Average 2-4 liters of that volume enter the GI system through the mouth.

The remaining 7 liters of fluid come from body water secreted along with enzymes and mucus.

About half of the secreted fluid comes from accessory organs and glands such as the salivary glands, pancreas, and liver. The remaining 3.5 liters are secreted by epithelial cells of the digestive tract itself.

SALIVA : FORMATION & SECRETION

Saliva is formed by three major glands:

i) the parotid (mainly serous secretion)

ii) submandibular (mixed secretion),

iii) and sublingual glands (mainly mucinous secretion)*.

In addition there are many tiny buccal glands which secretes only mucous

In the resting state, salivary secretion is low, amounting to about 30 ml/hr or 0.5 ml/min.

The submandibular glands contribute about two thirds of resting salivary secretion, the parotid glands about one fourth, and the sublingual glands the remainder.

Stimulation increases the rate of salivary secretion, most notably in the parotid glands, up to 400 mL/hr

The primary secretion of the salivary acinar cell is isotonic has the same Na+ ,K+ ,Cl- ,and HCO-

3 concentrations as plasma, which results largely from the basolateral uptake of Cl-

through Na+/K+/Cl- cotransporters, working in conjunction with Na+-K+ ATPase pumps and basolateral K+ channels.

Cl- & HCO3- leave the acinar cell and enter the lumen via an anion channel located in the

apical membrane of the acinar cell.

Na+ and some water reach the lumen through paracellular routes (leaky tight junctions) and aquaporin 5 water channel

Reabsorption of Na by salivary duct cells is a two-step transcellular process : i) First, Na+ enters the cell from the lumen through apical epithelial Na+ channels (ENaCs).ii) Second, the basolateral Na+-K+ pump extrudes this Na+

Elevated [Na+] provides feedback inhibition by downregulating ENaC activity, presumably through the ubiquitin-protein ligase Nedd4

Reabsorption of Cl- is also a two-step transcellular process:i) Entry of Cl- across the apical membrane occurs through a Cl--HCO3

- exchangerii) Duct cells have basolateral Cl- channels that provide an exit pathway for Cl-

Secretion of HCO3- occurs through the apical Cl--HCO3

- exchanger mentioned earlier

Secretion of K+ occurs through the basolateral uptake of K+ through the Na+-K+ ATPase pump. The mechanism of the apical K+ exit step is not well established, but it may involve K+-H+ exchange or other pathways.

Aldosterone acts on the ductal cells to increase the reabsorption of Na+ and the secretion of K+ (analogous to its actions on the renal distal tubule).

Saliva becomes hypotonic in the ducts because the ducts are relatively impermeable to water. Because more solute than water is reabsorbed from the ducts, the saliva becomes dilute relative to plasma.

REGULATION OF SALIVARY SECRETION

The composition of saliva varies with the salivary flow rate :

At the lowest flow rates, saliva has the lowest osmolarity and lowest Na+, Cl- and HCO-

3 concentrations, but has the highest K+

concentration.

At the highest flow rates (up to 4 mL/min* or 1 mL/min/g of gland# , the composition of saliva is closest to that of plasma.

SALIVA CONSTITUENTS AND FUNCTION

Saliva is characterized by:

i. High volume (relative to the small size of the salivary glands, 800 and 1500 millilitres+)

ii. High K+ (about 30 mEq/L, seven times as great as in plasma) and HCO-3 concentrations (50 to 70

mEq/L, about two to three times that of plasma)+

iii. Low Na+ and Cl- concentrations (about 15 mEq/L each, about one-seventh to one-tenth their concentrations in plasma)+

iv. Fluoride can be secreted in saliva, and fluoride secretion forms the basis of oral fluoride treatment for the prevention of dental caries#

v. pH between 6.0 and 7.0+

vi. Hypotonicity : Recent research has indicated that the hypotonic property of saliva protects against certain infections. Hypotonic saliva has been shown to kill the human immunodeficiency virus (HIV)-infected mononuclear leukocytes to prevent further transmission of the virus$

GASTRIC SECRETION

In addition to mucus-secreting cells that line the entire surface of the stomach, the stomach mucosa has two important types of tubular glands:

i) oxyntic glands (also called gastric glands) : located on the inside surfaces of the body and fundus of the stomach, constituting the proximal 80 percent of the stomach. These glands secrete hydrochloric acid, pepsinogen, intrinsic factor, and mucus, gastric lipase

ii) and pyloric glands : are located in the antral portion of the stomach, the distal 20 percent of the stomach. These glands secrete mainly mucus for protection of the pyloric mucosa from the stomach acid. They also secrete the hormone gastrin.

A typical stomach oxyntic gland is composed of :

i. mucous neck cells, secrete mainly mucus

ii. peptic (or chief) cells, secrete large quantities of pepsinogen and gastric lipase*

iii. parietal (or oxyntic) cells, secrete hydrochloric acid and intrinsic factor.

iv. Some endocrine cells like Enterochromaffin-like (ECL) cells secrete histamine

The antrum of the stomach contains the pyloric glands, which are configured similar to the oxyntic glands but with deeper pits.

The pyloric glands contain two cell types i. The G cells secrete gastrin, not into the pyloric ducts but into the circulation.ii. The mucous neck cells secrete mucus, HCO-

3 and pepsinogen

PEPSINOGEN SECRETION and ACTIVATION

Pepsins are endopeptidases

Pepsinogen secretion in the basal state is ~20% of its maximal secretion *

Zymogen granules release their contents by exocytosis when chief cells are stimulated

Between pH 5.0 and 3.0, spontaneous activation of pepsinogen is slow, but it is extremely rapid at a pH that is less than 3.0 (optimum pH 1.8 to 3.5*)

pH values higher than 3.5 reversibly inactivate pepsin, and pH values higher than 7.2 irreversibly inactivate the enzyme

MUCOSAL BARRIER

PHASES OF GASTRIC JUICE SECRETION

Cephalic Phase

Gastric phase

Intestinal Phase

Rate of secretion affects the compositionof the gastric juice.

Secretion from non-parietal cells is probably constant; therefore, it is parietal secretion (HClsecretion) that contributes mainly to the changes in electrolyte composition with higher secretion rates.

PANCREATIC SECRETION

The exocrine pancreas secretes approximately 1 L* - 1.5 L# of fluid per day into the lumen of the duodenum. The secretion consists of an aqueous component that is high in HCO3

- (approximately 113 mEq/L vs 24 mEq/L in plasma#) and an enzymatic component with pH 8.3*

As in the salivary glands, the pancreas has a structure that consists of ducts and acini. $

The acinus, which is the blind end of a branching duct system, is lined with acinar cells that secrete the enzymatic portion of the pancreatic secretion. The ducts are lined with ductal cells. $

At the junction between acinar and duct cells in the pancreas are small cuboidal epithelial cells known as centroacinar cells. These cells express very high levels of carbonic anhydrase and presumably play a role in HCO3

− secretion+

Enzymes are secreted by the acinar cells, and the aqueous component is secreted by the centroacinar cells and then modified by the ductal cells

PANCREATIC SECRETIONS : FORMATION AND CONSTITUENTS

Aqueous component of pancreatic secretion (centroacinar and ductal cells) : bicarbonate secretion Centroacinar and ductal cells produce the initial aqueous secretion, which is isotonic and

contains Na+, K+, Cl-, and HCO3-.

This initial secretion is then modified by transport processes in the ductal epithelial cells

i. A Na+/H+ exchanger is located in the basolateral cell membrane. The energy required to drive the exchanger is provided by the Na+/K+- ATPase generated Na+ gradient.

ii. CO2 diffuses into the cell and combines with H2O to form H2CO3, a reaction catalyzed by carbonic anhydrase, which dissociates to H+ and HCO3

-.

iii. The Na+/H+ exchanger extrudes the H+, and HCO3- is exchanged for luminal Cl- via a

Cl-/HCO3- exchanger.

iv. Also located in the luminal cell membrane is a protein called cystic fibrosis transmembrane conductance regulator. It is an ion channel belonging to the ABC (adenosine triphosphate [ATP] binding cassette) family of proteins. Regulated by ATP, its major function is to secrete Cl- ions out of the cells, providing Cl- in the lumen for the Cl-/HCO3

- exchanger to work.

v. The Na+/K+- ATPase removes cell Na+ that enters through the Na+/H+ antiporter.

vi. Na+ from the interstitial space follow secreted HCO3- by diffusing through a paracellular

path (between the cells).

vii. Movement of H2O into the duct lumen is passive, driven by the osmotic gradient.

The net result of pancreatic HCO3- secretion is the release of H+ Into the plasma; thus,

pancreatic secretion is associated with an acid tide in the plasma.

Effect of Flow Rate on Composition of Pancreatic Juice

In pancreatic juice, there is a reciprocal relationship between the Cl- and HCO-

3 concentrations, which is maintained by the Cl-/HCO-

3 exchanger in the apical membrane of ductal cells

Enzymatic component of pancreatic secretion (acinar cells)

The pancreatic enzymes are synthesized on the rough endoplasmic reticulum of the acinar cells. They are transferred to the Golgi complex and then to condensing vacuoles, where they are concentrated in zymogen granules. The enzymes are stored in the zymogen granules until a stimulus (e.g., parasympathetic activity or CCK) triggers their secretion

Mechanisms protecting the pancreas from autodigestion

PHASES OF PANCREATIC SECRETION

Effect of Other harmones on pancreatic secretion

BILIARY SECRETION

1. Bile is secreted by liver normally between 600 and 1000 ml/day

2. Bile is secreted continually by the liver cells, but most of it is normally stored in the gallbladder until needed in the duodenum. The maximum volume that the gallbladder can hold is only 30 to 60 milliliters. Nevertheless, as much as 12 hours of bile secretion (usually about 450 milliliters) can be stored in the gallbladder because water, sodium, chloride, and most other small electrolytes are continually absorbed through the gallbladder mucosa, concentrating the remaining bile constituents that contain the bile salts, cholesterol, lecithin, and bilirubin. Bile is normally concentrated in this way about 5-fold, but it can be concentrated up to a maximum of 20-fold

3. CCK stimulus that itself is initiated mainly by fatty foods causes gallbladder contraction and relaxation of sphincter of oddi . The gallbladder is also stimulated less strongly by acetylcholine-secreting nerve fibers from both the vagi and the intestinal enteric nervous system. the gallbladder normally empties completely in about 1 hour

4 and 5 . Entero-hepatic Circulation of Bile Salts About 94 percent of the bile salts are reabsorbed into the blood from the small intestine,

about one half of this by diffusion through the mucosa in the early portions of the small intestine and the remainder by an active transport process through the intestinal mucosa in the distal ileum

On the average these salts make the entire circuit some 17 times before being carried out in the faeces. The small quantities of bile salts lost into the faeces are replaced by new amounts formed continually by the liver cells. This recirculation of the bile salts is called the enterohepatic circulation of bile salts

The quantity of bile secreted by the liver each day is highly dependent on the availability of bile salts—the greater the quantity of bile salts in the enterohepatic circulation (usually a total of only about 2.5 grams), the greater the rate of bile secretion.

COMPOSITION OF BILE

The total bile flow is composed of the ductular secretion and the canalicular bile flow.

The ductular secretion is from the cells lining the bile ducts. These cells actively secrete HCO3

- into the lumen, resulting in the movement of water into the lumen of the duct. Secretin increases ductular secretion. Another mechanism that may contribute to ductular secretion of fluid is the presence of a cAMP-dependent Cl- channel that secretes Cl- into the ductile lumen.

Canalicular bile flow can be conceptually divided into two components: i. bile acid-dependent secretion ii. bile acid–independent secretion

(1) Na+/K+ - ATPase. (2) Bile salt-sodium symport. (3) Canalicular bile acid carrier. (4) Na+/H+ exchanger.(5) HCO3

- transport system

SUMMARY

SECRETIONS OF SMALL INTESTINE

IN DUODENUM

• the mucus secreted by Brunner’s glands protects the duodenal wall from digestion by the highly acidic gastric juice emptying from the stomach

• Brunner’s glands are inhibited by sympathetic stimulation; therefore, such stimulation in very excitable persons is likely to leave the duodenal bulb unprotected and is perhaps one of the factors that cause this area of the Gastrointestinal tract to be the site of peptic ulcers in about 50 percent of ulcer patients

Secretion of Intestinal Digestive Juices by the Crypts of Lieberkühn

The intestinal secretions are formed by the enterocytes of the crypts at a rate of about 1800 ml/day. These secretions are almost pure extracellular fluid and have a slightly alkaline pH in the range of 7.5 to 8.0

Mechanism of Cl secretion in the small and large intestines

Mechanisms of bicarbonate secretion inthe duodenum

MUCOUS SECRETION BY LARGE INTESTINE

The mucosa of the large intestine, like that of the small intestine, has many crypts of Lieberkühn; however, unlike the small intestine, there are no villi. The epithelial cells secrete almost no digestive enzymes. Instead, they contain mucous cells that secrete only mucus

The rate of secretion of mucus is regulated principally by direct, tactile stimulation of the epithelial cells lining the large intestine and by local nervous reflexes to the mucous cells in the crypts of Lieberkühn.

Stimulation of the pelvic nerves from the spinal cord, which carry parasympathetic innervation to the distal one half to two thirds of the large intestine, also can cause marked increase in mucus secretion

SECRETORY DIARRHEA

The cellular mechanism of K+ secretion in the colon

Aldosterone increases Na+ ch. Causing increased Na+ entry across the apical membrane, increased Na+ pumped out across the basolateral membrane by the Na+

K+ ATPase, increased K+ pumped into the cell, and, finally, increased K+ secretion across the apical membrane.

Even the flow-rate dependence of K+ secretion is present in the colon; for example, in diarrhea, the high flow rate of intestinal fluid causes increased colonic K+ secretion, resulting in increased K+ loss in feces and hypokalemia.