GI 6 - Bile acids, Small Intestine (+ absorption)

Bile acid recycling

20 to 40g of bile acids are released into the intestine each day. Only 0.5g are lost in feces (95% recovered)

Where does bile acid recycling ocur

Enterohepatic circulation

Movement of bile in GI system

1. Bile acid produced by hepatocytes, and secreted into the canalicular networks (increasing size) until it reaches common bile duct

2. Bile acids are stored in the gall bladder, or secreted into the duodenum

3. Bile acids move through the SI to the ileum

4. Ileum absorbs bile acids, portal vein brings them back to the liver

Why is bile acid reabsorbed and not just completely excrete?

Having a pool ready to secrete allows for a better secretion rate

Step 1: Transport of bile acids from hepatocyte to bile

Bile synthesized in hepatocytes, moves across apical surface, and is secreted into canalicular networks, becoming bile ducts. Bile then goes into the SI or is stored in the gall bladder

Mechanism of bile acid movement from hepatocytes into canalicular surface

Primary active transporter - ATP hydrolysis allows bile acid to move up concentration gradient. Canalicular networks have a high concentration of bile acid

Step 2: Bile acid reabsorption from the Ileum

Bile acids secreted into duodenum, digest fats, then move to ileum. The ileum reabsorbs bile acids into portal circulation by enterocytes

Mechanism of bile acid movement from lumen to enterocytes

Bile acid enters enterocytes via a secondary active transporter. Reabsorption is coupled to sodium movement into enterocyte

Mechanism of bile acid movement from the enterocyte into portal blood

Facilitated transport

Step 3: Transport of bile acids from blood into hepatocyte

Bile acids move in portal blood, and return to the hepatocytes. The bile acid secretion cycle can begin again

Mechanism of bile acid movement from portal blood into hepatocyte

Bile acid enters hepatocytes via a secondary active transporter. Movement is coupled to sodium movement into enterocyte

Summary of bile acid recycling (photo)

Role of dietary fiber

Sequesters bile acids, preventing them from cycling back to the liver (lost through feces). More bile acids have to be synthesized, lowering cholesterol levels in the blood

What would be the use if a drug entered the enterohepatic circulation?

Drug that effects enzyme would work well, as the whole dose is concentrated to the enterohepatic circulation

How is hepatobiliary secretion regulated during the intestinal phase?

By bile salts, secretin, and CCK

How does bile salts regulate hepatobiliary secretion?

As more bile salts are absorbed from ileum and return to liver, more will be secreted back into the bile. Bile salt synthesis is reduced when enterohepatic circulation is working well

How does secretin regulate hepatobiliary secretion?

Secretin is produced and released in duodenum S cells in response to acid. Secretin increases HCO3- secretion by bile duct cells (and the pancreas)

How does CCK regulate hepatobiliary secretion?

Fats and proteins in upper small intestine stimulate CCK release by I cell. CKKs increases gallbladder contraction and relaxes the sphincter of Oddi (hepatopancreatic sphincter), allowing for bile release into the duodenum

What are gallstones caused by

Excess cholesterol

How do gallstones form

Cholesterol is water insoluble - only kept in solution by micelles with bile acids and PLs

- If [cholesterol] > [bile acids], cholesterol precipitates out to form stone

What does cholesterol require to become a gallstone

A nucleating agent (protein, bacteria)

Pigment stones

Stones caused by excessive hemolysis, increasing bile pigment concentration in bile. Pigments precipitate with Ca2+

Consequences of gallstones

Depends on location - can cause obstruction, infection of gall bladder, liver pancreas.

Clinical manifestations of gallstones

Pain, nausea, jaundice, malabsorption of fats and fat-soluble vitamins

Treatment of gallstones

- Cholecystectomy (remove gall bladder): requires a reduction of fat in diet

- Removal of gallstones

- Drugs to dissolve gallstones

Location of small intestine

Between the stomach and large intestine

Shape of small intestine

Tube of 2.4 cm in diameter, 3m in length

Why does the SI increase in size in autopsy

Loss of muscle tone

Sections of the small intestine

Duodenum (30cm), Jejunum (1m), Ileum (1.7m)

Functions of the duodenum

- Mixes pancreatic digestive enzymes and bile with food

- Absorption of nutrients, iron, calcium

- Release of endocrine hormones secretin and CCK

Functions of the jejunum

digestion and absorption. Most of the chyme entering SI is digested and absorbed within first 25% of intestine

Functions of the ileum

Digestion and absorption - absorbs bile acids (secondary transporter) and vitamin B12

Pyloric sphincter

Controls passage of food from stomach to small intestine

How is SA increased in small intestine

SI has circular folds - layers of intestine that fold on itself. The circular folds are covered in villi: projection of tissue into the lumen.

- SI also has crypts, whcih increases surface area

- Villi covered in epithelial cells with microvilli projections for increased SA

Total surface are of small intestine

Around 1-2 million cm^2

Structure of the villus

- Apical layer consists of brush-border epithelial cells

- Crypts are invaginations of the epithelium - stem cells in crypts divide into epithelial cells, allowing top layer of cells to slough off

Cells that arise from small intestine crypts

Enterocytes, Goblet cells, enteroendocrine cell, paneth cell

Enterocyte function

Absorptive cell - contains microvilli on lumen (brush border with brush border enzymes)

Goblet cell function

Secretes mucus for food lubrication, and acts as buffer for amount of acid entering SI from stomach

Enteroendocrine cell function

Reease secretin and CCK - are either S or I cells (respectively)

Paneth cells function

Secrete antibacterial proteins to protect GI tract from bad bacteria

Brush border

small projections (microvilli) of epithelial cells covering the villi of the small intestine; major absorptive surface of the small intestine

Brush border enzyme

Enzyme anchored to the brush b order with catalytic activity in the lumen - used to break down carbs and peptides into sugars and amino acids prior to transport across the enterocyte

Initial breakdown of starch

Starch (amylose and amylopectin) are broken down into maltose, maltotriose, a-limit dextrin by salivary and pancreatic amylases. Need further digestion to monosaccharides for absorption

Small intestine breakdown of starch

Brush border enzymes break down maltose, maltotriose, and a-limit dextrin into glucose

Brush border enzymes that break down polysaccharides

Maltase, Sucrase, a-dextrinase

What enzyme(s) breaks down maltose or maltotriose

Either maltase, sucrase, or a-dextrinase break them down to glucose, cleaving the alpha 1-4 bond

What enzyme breaks down a-dextrin

a-dextrinase breaks it down to glucose, cleaving the alpha 1-6 bond

Other sugars in diet other than starch

Sucrose (table sugar), lactose

Enzyme to break down sucrose

Sucrase breaks sucrose into glucose and fructose (brush border enzyme)

Enzyme to break down lactose

Lactase breaks lactose into glucose and galactose (brush border enzyme)

What causes lactose intolerance

Lower amount of lactase enzymes in small intestine

How does the small intestine absorb glucose/galactose

- Carried into enterocyte by sodium dependent glucose transporter (SGLT)

- Secondary active transport pathway - uses sodium gradient to drive glucose absorption

- Sodium gradient facilitated by Na+/K+ ATPase

- Sodium moves into basolateral surface by GLUT transporter

How does the small intestine absorb fructose

- Enter cell via facilitated carrier GLUT5

- At basolateral surface, leave via facilitated carrier GLUT2

- Enters blood

Full overview of carbohydrate absorption

• Pancreatic amylase breaks down polysaccharides into 3 products (maltose, maltotriose, a-limit dextrins)

• Brush border enzymes break down polysaccharides down into glucose, fructose, galactose

○ Fructose carried by GLUT

○ Glucose and galactose carried by SGLT transporter (secondary active transport)

• Move through basolateral membrane of enterocyte by GLUT transporter

Initial digestion of proteins in stomach

Proteins are broken into peptides by stomach. They are further broken down into amino acids by pancreatic proteases

What enzymes break down peptides to amino acids?

- Carboxypeptidase (pancreatic protease)

- Aminopeptidase (brush border enzyme)

- Other brash border enzymes

How are free amino acids absorbed into enterocytes

Secondary active transport coupled to Na+ (multiple transport prtoeins)

Peptide absorption into enterocytes

Small peptides are absorbed by different secondary active transport proteins coupled to H+. Peptidases intracellularly will break down product

General pathway of protein digestion and absorption

• Pepsin in stomach starts acting on proteins

○ Pepsinogen released by chief cells, activated by acidic environment

• Pancreatic proteases continues to break down peptides into amino acids and peptides

• Brush border peptidases cleave peptides into AA's

• AA's can be taken up into enterocytes via Secondary active transport coupled to sodium

• Alternatively - small peptides are taken into cell via secondary active transport coupled to protons

○ Small peptides are cleaved by intracellular peptidases into amino acids

• Amino acids leave enterocyte via facilitated diffusion into interstitial space for bloodstream absorption