GASTROINTESTINAL SYSTEM

MAJOR ORGANS OF DIGESTIVE SYSTEM

• Oral cavity

• Pharynx

• Oesophagus

• Stomach

• Small intestine

• Large intestine

ORAL CAVITY

• 30-40s transport

• mechanical digestion (teeth), mix with saliva

PHARYNX

• propels food towards oesophagus

OESOPHAGUS

• 4-10s transport

• propels food towards stomach

STOMACH

• 1-4 hours transport

• chemical and mechanical digestion

SMALL INTESTINE

• Duodenum, jejenum, Ileum

• 4-6 hours transport

• Enzymatic digestion, absorption of water, vitamins, ions

LARGE INTESTINE

• Colon, appendix, rectum, anus

• 7-15 hours

• Absorption of water

• Compaction of indigestible material before excretion

ACCESSORY ORGANS IN DIGESTIVE SYSTEM

• Teeth

• Tongue

• Salivary glands

• Liver

• Gall-bladder

• Pancreas

TEETH

Mechanical digestion

TONGUE

• Assists mechanical digestion

• Taste

SALIVARY GLANDS

• Secrete lubricating fluid with enzymes to break down carbs

LIVER

• Secretes bile

• Stores nutrients

GALL BLADDER

• Storage and concentration of bile

PANCREAS

Exocrine = secrete buffers and digestive enzymes

Endocrine = secrete insulin + glucagon

FOOD TERMINOLOGY

Food → Bolus → Chyme → Faeces or Nutrients

UPPER OESOPHAGEAL SPHINCTER

• between pharynx and oesophagus

• opens to let bolus enter oesophagus

LOWER OESOPHAGEAL SPHINCTER

• between oesophagus and stomach

• lets air escape when burping

PYLORIC SPHINCTER

• End of stomach

• Controls chyme entering the duodenum

ILEOCECAL SPHINCTER

• Between small and large intestine

• Controls content entering large intestine

INTERNAL ANAL SPHINCTER

• Involuntary

• Prevents stool leakage

EXTERNAL ANAL SPHINCTER

• Voluntary

• Controlled excretion of stool

SPHINCTER OF ODDI

• Where common bile duct and pancreatic duct join before opening into the duodenum

When closed:

• Bile/pancreatic juice can’t enter duodenum

When open:

• Bile/pancreatic juice can enter, ensuring the right amount is released when food arrives.

GI TRACT WALL

1. Mucosa

• Epithelial layer with connective tissue, capillaries, neurons, immune cells, and smooth muscle.

2. Submucosa

• Loose connective tissue, larger blood vessels, may have glands.

3. Muscle Layer

• Two smooth layers (inner circular, outer longitudinal) with neurons between

4. Serosa

• Outer connective tissue with squamous epithelial cells.

6 STEPS OF GI TRACT

Ingestion → (Secretion + Digestion + Absorption + Motility) → Defecation

4 PROCESSES OF GI TRACT

1. Secretion

• Moving of material from cells into lumen or ECF

2. Digestion

• Mechanical and chemical breakdown of food into absorbable units

3. Absorption

• Movement of material from GI lumen into ECF (blood)

4. Motility

• Movement of material through the GI tract via muscle contractions

MACROMOLECULES AND THEIR BUILDING BLOCKS

Large macromolecules generally can’t cross GI wall and must be broken down into building blocks.

Macromolecule → Building blocks:

Proteins → Amino acids

Fats → Glycerol + fatty acids

Carbs → Monosaccharides

Nucleic acids → Nucleotides

DIGESTIVE ENZYMES

Enzymes are biological catalysts that accelerate reactions without being consumed.

• Substrate-specific

• Work mostly by hydrolysis (adding water to break a bond, releasing smaller absorbable units)

MACROMOLECULE → ENZYME CLASS → PRODUCT

Proteins/peptides → Proteases, peptidases → Amino acids, peptides

Fats → Lipases → Fatty acids + glycerol

Carbs → Amylase → Disaccharides, monosaccharides

Nucleic acids → Nucleases → Nucleotides

SUBSTRATE → WHERE DIGESTION MAINLY OCCURS

Proteins → Stomach + small intestine

Fats → Oral cavity + stomach + small intestine (mainly)

Carbs → Oral cavity + stomach + small intestine (mainly)

Nucleic acids → Small intestine

SALIVARY GLANDS TYPES

• Parotid glands

• Submandibular glands

• Sublingual glands

DIGESTION IN ORAL CAVITY

Digestion = carbs, Absorption = none.

In the mouth:

• Saliva contains salivary amylase mainly from parotid glands

• Amylase starts starch breakdown into maltose

• Only 5% starch is hydrolysed before swallowing

In the stomach:

• Salivary amylase becomes inactive in acidic conditions (pH < 4)

• Digestion continues 1hr until food mixes with gastric acid

• 30% of starches are digested

STOMACH SECTIONS

Cardia = nearest oesophagus/heart

Fundus = upper dome

Body = largest section

Antrum + Pylorus = leads into duodenum

STOMACH MAIN FUNCTIONS

1. Temporarily hold food

2. Partially digesting food into chyme

3. Denaturing proteins via HCl

4. Digesting proteins via pepsin

Digestion = proteins + fats

Absorption = lipid-soluble substances only

GASTRIC SECRETIONS

Secretion → Role

1. Acid (HCl) → Decreases pH to 1-1.5, kill pathogens/bacteria, denature proteins, activates pepsinogen → pepsin

2. Mucus → Secretion of water, bicarbonate and mucus, protects wall from acid by buffering

3. GI Hormones → Gastrin = stimulates acid production + stomach contractions, somatostatin = inhibits acid secretion, suppresses other GI hormones

4. Digestive enzymes → Pepsin = converts proteins to peptides, Gastric lipase = removes one fatty acid from each triglyceride.

STOMACH CELL TYPES

Mucuous cells → secrete mucus

Parietal cells → secrete HCl

Gastric chief cells → secrete pepsinogen, gastric lipase

Enteroendocrine cells → secrete G cells (gastrin), D cells (somatostatin)

PHASES OF GASTRIC SECRETION

1. Cephalic phase

2. Gastric phase

3. Intestinal phase

CEPHALIC PHASE

Triggered by:

• sight, smell, taste or thought of food

Mechanisms:

• the hypothalamus and medulla stimulates the vagus nerve, signalling to the stomach to begin secreting gastric juices + gastrin

Outcome:

• Prepares stomach for digestion

• Accounts for 10-20% of gastric secretion

GASTRIC PHASE

Triggered by:

• presence of food in the stomach

• Causes stretching and the presence of proteins/amino acids

Mechanisms:

• Stretch activates stretch receptors, stimulating gastrin release

• pH > 4 = increase in gastrin release

• pH < 3 = decrease in gastrin release

• More gastrin = more gastric juice = more stomach contractions

Outcome:

• 60-70% of gastric secretion

NOTE: parasympathetic = increase gastric secretion; sympathetic = decrease gastric secretion.

PANCREAS

Endocrine:

• Islets of Langerhans

• Secrete insulin and glucose

• Regulate blood glucose

Exocrine:

• Acinar cells = secrete digestive enzymes

• Ductal cells = secrete bicarbonate rich fluid

PANCREATIC JUICE

• watery, alkaline solution (pH 8)

• neutralises stomach acid entering duodenum

• 1200-1500mL per day produced

ENZYME → FUNCTION

Proteases → convert proteins to peptides

Carboxypolypeptidase → convert peptides to amino acids

Pancreatic lipase → Convert triglycerides to monoglycerides + fatty acids

Pancreatic amylase → convert starch to maltose

Nucleases → Convert DNA/RNA to nucleotides

GALLBLADDER

• small pear-shaped sac on the underside of the liver

• Stores and concentrates bile by absorbing water and electrolytes

• Honeycomb folds allow it to expand as it fills

BILE RELEASE

Stimulated by hormone CCK →

Gallbladder contracts →

Bile flows into cystic duct →

Common bile duct →

Duodenum

BILE

• Produced in the liver

• Contains bile salts, which are amphipathic

Emulsification:

• Bile salts surround large fat deposits, breaking them into smaller emulsion droplets

Increased surface area:

• Lets pancreatic lipase act more efficiently

Micelle formation:

• Bile salts package digested fats into micelles for transport to the intestinal epithelial cells where they’re absorbed

SMALL INTESTINE INPUT INTO LUMEN

9L per day

• Food and drink = 2L

• Saliva = 1.5L

• Bile = 0.5L

• Gastric secretions = 2L

• Pancreatic secretions = 1.5L

• Intestinal secretions = 1.5L

SMALL INTESTINE REMOVAL FROM LUMEN

9L per day

• Absorbed in small intestine = 7.5L

• Absorbed in large intestine = 1.4L

• Lost in faeces = 0.1L

Via homeostasis, output must = input → mass balance

SMALL INTESTINE FUNCTIONS

• Chemical digestion

• Nearly all nutrient absorption

• Chyme mixes with digestive juices slowly, allowing time for absorption

• Undigested materials passed on to large intestine

SMALL INTESTINE STRUCTURE

1. Same four layers as the rest of GI tract

• mucosa (SA x3 larger than stomach for greater absorption)

• submucosa

• muscularis externa

• serosa

2. Villi

• finger-like projections

3. Crypts

• Invaginations between villi

4. Microvilli

• Brush border on villi

SMALL INTESTINE SECRETIONS (PROTEASES + PEPTIDASES)

Enterokinase

• located at duodenal brush border

• activates pancreatic zymogen → trypsinogen → trypsin

Peptidases

• located in enterocytes

• peptides → amino acids

SMALL INTESTINE SECRETIONS (DISSACHARIDASES)

Maltase

• Located at brush border

• Maltase → glucose

Sucrase

• Located at brush border

• Sucrose → glucose + fructose

Lactase

• Located at brush border

• Lactose → glucose + galactose

SUMMARY OF ENZYME SECRETIONS

GLP-1 EFFECTS

Effects:

• More insulin, less glucagon from pancreas

• slower gastric emptying

• Less acid secretion

• Less appetite and higher satiety

Type 2 diabeties:

• Slower emptying flattens glucose peak after meal

• extra insulin decreases blood glucose

• effective in regulating

GLP-1 CHALLENGES

Challenges:

• Half life of 1-2 minutes

• useless as an injection

Solutions:

• modify with amino acids

• can last up to a week

THE INTESTINAL PHASE OF GASTRIC SECRETION

Triggered by:

• entry of partially digested chyme entering duodenum

Mechanism:

• Hormones released to inhibit further gastric secretion and slow gastric emptying

• Secretin = stimulates bicarbonate secretion and flow of bile from liver → gallbladder

• CCK = triggers gallbladder + pancreas to contract and release bile + enzymes into duodenum to aid digestion

• GIP + GLP-1 = stimulate insulin secretion

LARGE INTESTINE FUNCTIONS

• Digestion of remaining food

• absorb remaining water, electrolytes (salt) and vitamins

• Secretes mucus to ease passage of faeces

• Contractions propel faeces towards rectum

• Temporarily stores waste until defecation

  • Defecation is a reflex triggered by rectal dystension

THE COLON AND FAECAL CONSISTENCY

1. Ascending = fluid/semi-fluid

2. Transverse = mush

3. Descending = semi-mush/semi-solid

4. Sigmoid + rectum = solid

Poor motility = sits longer, increased water absorption → hard faeces → constipation

Excess motility = decreased absorption → faeces don’t solidify → diarrhea

MICROBIOTA

Community of microorganisms on multicellular organisms (ex. bacteria, fungi).

• Around 3.9 × 10^13 cells of microorganisms

• 95% found in GI tract

  • 70-80% in large intestine

FACTORS AFFECTING MICROBIOTA

• Diet

• antibiotics

• lifestyle (stress, sleep, exercise)

• Cohabituation (shared living environment is more important than genetics)

• Dysbiosis (imbalance - obesity, diabetes, mental health disorder, IBD)

FUNCTIONS OF MICROBIOTA

• Digestion (of fibres we cant digest ourselves)

• Vitamin synthesis (B and K)

• Immune support (train and regulate immune system)

• Protection (competes with harmful pathogens for resources)

• Signalling molecules (that interact with the host)

• Secondary bile acid production

• Drug metabolism

PERISTALSIS OF OESOPHAGUS

1. Contraction behind the bolus

• Circular muscles contract behind the bolus, squeezing it forward

2. Relaxation in front of the bolus

• Longitudinal muscles infront of bolus contract to shorten the oesophagus and circular muscles relax to create space for bolus to move forward

3. Sequential waves

• This wave like motion continues down oesophagus in coordinated manner

*gravity helps but not necessary

PERISTALSIS OF STOMACH

1. Gastric emptying

• Antral contractions propel chyme forward and grinds it

• Partly open pyloric sphincter lets some chyme through

• Stronger contraction = empties more

2. Gastric mixing

• When wave reaches pyloric sphincter it closes tightly

• Chyme hitting closed sphincter is tossed back into antrum

• Retropulsion = chyme mixes with gastric secretions

Wave starts at upper fundus → pyloric sphincter → antrum.

SEGMENTATION

Short segments of the intestine alternately contract and relax, churning the chyme.

• slow, short lived contractions

• mainly in small intestine

• triggered by filling of stomach and local stretch in small intestine

• does not produce much propulsion

MIGRATING MOTOR COMPLEX

• Occurs between meals

• Peristalsis starts in stomach and travels through small intestine

• one cycle = 2 hours

• Propels undigested food residue, dead cells, bacteria

  • ‘interdigestive housekeeper’

• stimulated by hormone motilin from small intestine

MASS MOVEMENTS

Slow, powerful peristalsis contractions in large intestine that moves waste to rectum.

• Occurs 3-5x per day for 10-15 minutes, during or after meals

• Triggers:

  • Stretch of colon wall

  • Irritants such as chemical or ulcers

  • Gastrocolic reflex

DEFECATION STEPS

1. Faeces enters and stretches the sigmoid colon and rectum, triggering the reflex

2. Stretch receptors activate sensory nerve fibres that signal the spinal cord

3. Parasympathetic efferent motor fibres are activated and CNS sends signals back to colon and rectum

4. Sigmoid colon and rectum contract, pushing faeces into anus

5. Internal sphincters relax in response to parasympathetic activation, letting faeces into anal canal

6. External sphincters stay closed, holding back faeces

7. When deciding to defecate, impulses from cerebral cortex relax external sphincter and faeces are expelled.

ENTERIC NERVOUS SYSTEM

• The GI tracts own nervous system

• 100 million neurons

• Enteric neurons communicate with each other and work autonomously, but also exchange info with the CNS

• Major nerve supply to GI wall and controls motility (including peristalsis)

ENTERIC NERVOUS SYSTEM STRUCTURE

Confined within the GI tract wall from start of oesophagus to internal sphincter and consists of two interconnected nerve plexus:

1. Submucosal nerve plexus

• In the submucosa

• Controls local secretions, blood flow and contractions or smooth muscle in mucosal layer

2. Myenteric nerve plexus

• In the muscularis externa

• Coordinates motility and peristalsis

ENTERIC NS NEURONS

Intrinsic neurons

• Short reflexes

  • ex. gastrin secretion triggered by stomach stretch

• in enteric plexus

• allows local reflexes to start, be integrated, and finish inside GI tract

• ‘little brain’

Extrinsic neurons

• Long reflexes

  • ex. defecation reflex

• autonomic neurons that carry signals from CNS to GI tract

• respond to stimuli inside or outside of gut

AUTONOMIC CONTROL AND DIGESTIVE SYSTEM

Parasympathetic activation

= enhances digestion

= relaxes sphincters so contents can move through

Sympathetic activation

= inhibits digestion

= contracts circular muscles and keep sphincters closed

LIVER FUNCTIONS

1. Regulates blood glucose levels

• stores glucose as glycogen

• synthesises glucose through gluconeogenesis

2. Vitamin storage

• A, D, E, K, B12

3. Bile production

4. Nitrogen excretion

5. Acts as an endocrine organ

• releases hormones

6. Waste management

• degrades old/damaged proteins

7. Iron metabolism

8. Protein synthesis of various plasma proteins for blood functions

9. Detoxification

• of foreign chemicals

10. Fat metabolism

• Break down of fatty acids and distributes lipoproteins

LIVER ARTERIAL BLOOD SUPPLY

• 25%

• delivered via hepatic artery

• O2 rich blood

LIVER VENOUS BLOOD SUPPLY

• 75%

• Delivered via hepatic portal vein, carrying blood from digestive tract

• 02 poor blood

• Blood contains

  • nutrients, drugs, hormones, pathogens, toxins

• Blood leaves via hepatic vein

LIVER LOBULES

Liver is organised into hexagonal units called liver lobules

• Portal vein + hepatic artery supply blood to portal venuoles + hepatic arterioles which converge at the corners of the lobule

PORTAL TRIAD

Found at each lobule corner, consists of:

• a portal vein branch

• a hepatic artery branch

• a bile duct that drains bile from hepatocytes via bile canaliculi

BLOOD FLOW IN LIVER

• Portal vein and hepatic artery empties blood into a shared capillary network known as liver sinusoids

• Blood from sinusoids is collected by central veins which drain into larger hepatic veins

• Hepatic veins then empty filtered blood into inferior vena cava

LIVER LOBULE CELLS

Hepatocytes (80% of all liver cells)

• main functional cells of the liver that are responsible for metabolism, detoxification, protein synthesis, and bile production

Liver endothelial cells (LEC)

• line the blood vessels (sinusoids) and facilitate exchange of substances between blood and hepatocytes

Stellate cells

• Store vitamin A and plays a role in liver fybrosis when activated

Kupffer cells

• specialised macrophages that are responsible for phacocytosing pathogens, erythrocytes, dead cells and debris

LIVER ZONATION

• Blood flow along lobules radial axis creates gradients of oxygen, nutrients and hormones

• Spatial variability results in non-uniform expressions of key liver functions

Ex.

Periportal (zone III)

• cholesterol biosynthesis

• protein secretion

Pericentral (zone I)

• drug detoxification

• bile acid production

LIVER PROTEIN SYNTHESIS OF PLASMA PROTEINS

ALBUMIN

• 60% of secreted/synthesised plasma proteins

• maintains osmotic pressure

• transports substances in blood

CARRIAGE PROTEINS

• Transferrin, ceruloplasmin, transcortin

BLOOD COAGULATION FACTORS

ANTI-CLOTTING PROTEINS

HORMONES

APOLIPOPROTEINS

IMMUNE PROTEINS

LIPOPROTEINS

Essential for transport of lipids in the blood or ECF and are produced by small intestine and liver.

CHYLOMICRONS

• located in small intestine

• transport dietary fats + cholesterol from gut → lymphatics → blood → muscle

VeryLowDensityLipoprotein

• located in liver

• Delivers triglycerides synthesised+packaged by liver to peripheral tissue

IntermediateDL

• formed from VLDL after TG (triglyceride) offloading

LowDL

• formed from IDL

• transports cholesterol back to liver

HighDL

• reverse cholestryl transport

FAT ABSORPTION + CHYLOMICRON FORMATION

Large fat droplets (from stomach) → emulsified by bile salts → miscelles → pancreatic lipase breaks down fats → fatty acids enter enterocytes → absorbed fats combine with cholesterol + proteins = chylomicron → exported in interstitial fluid → blood → used as energy source.

CHYLOMICRON METABOLISM IN CIRCULATION

At capillary beds of muscles LPL strips out TG → releasing fatty acids + glycerol for tissue uptake → chylomicron returns to liver for further processing,

LIPOPROTEIN CASCADE

Liver releases VLDL → LPL strips triglycerides → IDL → further TG loss → LDL → LDL receptor uptake by liver → cholesterol back to liver

CHOLESTEROL ELIMINATION

In the liver cholesterol is:

• re-secreted as VLDL or

• converted into bile acids

Bile acids secreted into:

• Bile → gut → excretion

• to maintain homeostasis

Cholesterol absorbed in intestine:

• liver → remainder is excreted as poo

IRON METABOLISM IN LIVER

Sources of iron:

• uptake of dietary iron

• recycling of haemoglobin via Kupffer cells

Iron transport + metabolism:

• Fe2+ leaves cells via ferroportin

• in blood, fe2+ binds to ferroportin in plasma

• Tf-bound iron can be taken up by cells via TfR1

• in the liver iron is stored as ferritin

HEPCIDIN

The liver secretes hepcidin which is a regulator of iron metabolism

• an increase in iron levels and storage stimulates hepcidin production

• suppressed hepcidin production in iron deficiency

• its target is ferroportin

• hepcidin binding to ferroportin = degredation = less iron released in blood = decreased iron availability

DETOXIFICATION IN THE LIVER

Xenobiotics = any compound foreign to the organism.

Compounds not taken up by hepatocytes undergo biotransformation:

• Phase 1: Modification

• Phase 2: Conjugation

• Phase 3: Secretion/excretion

PHASE 1 - MODIFICATION

• Chemical modification of compounds

• Cytochrome P450 enzymes add or expose reactive groups making the molecule more hydrophilic and reactive for phase 2

• reactions = oxidation, reduction, hydrolysis

PHASE 2: CONJUGATION

• The functional groups introduced in phase 1 are conjugated with polar molecules

• this process makes metabolites more hydrophilic, facilitating their excretion

PHASE 3 - EXCRETION/SECRETION

• Hepatocytes excrete phase 1 and 2 products into bile or blood

• Metabolites actively transported out of hepatocytes using membrane transport proteins

Excretion:

• most drugs excreted via kidneys

• Larger metabolites excreted into bile and out via faeces

SUPRACHIASMATIC NUCLEUS

• The central clock resides in the suprachiasmatic nucleas (SCN) of the hypothalamus

• Light is the dominant signal - detected by the retina and relayed to SCN

PERIPHERAL TISSUE CLOCKS

• SCN synchronises peripheral clocks present in most cells/organs

• peripheral clocks are influenced by feeding

SCN + peripheral clocks + feeding = rhythmic physiology

CIRCADIAN CLOCKS

• Humans intrinsic clock is approx 24.5 hours

• all known carcadian oscillators are built from negative feedback loops of gene expression

CIRCADIAN RHYTHM - LIVER BLOOD FLOW

• Peaks in early phases (2-8 hours)

• Trough mid-way through rest phase

CIRCADIAN RHYTHM - BILE SECRETION/EXCRETION INTO GALLBLADDER/DUODENUM

Bile secretion into gallbladder

• accumulation rises while fasting

Bile excretion into duodenum

• release rises around/after feeding

CIRCADIAN RHYTHM - BASAL GASTRIC ACID SECRETION

• Lowest around midday

• Rises towards evening/night

CIRCADIAN RHYTHM - SMALL INTESTINE MOTILITY

• peaks around midday

• Lowest during night/rest phase