Course Code: MEDF 1012B
Foundation Course for Health Sciences II
2017 - 2018
Integration of Body Functions:
Food Intake & Waste Elimination –
DIGESTIVE SYSTEM
Po Sing Leung
Room 609A, Lo Kwee-Seong Integrated Biomedical Sciences Building
School of Biomedical Sciences, Faculty of Medicine
The Chinese University of Hong Kong
Tel: 3943 6879; Fax: 2603 5123; E-mail: [email protected]
Learning Objectives
1. To have an overview of the digestive system
2. To understand the general mechanisms involved in the regulation
and integration of gut functions
3. To understand various types of gut hormones and neurotransmitters
4. To appreciate the importance of gut regulatory peptides and
structure-activity (function) relationship (SAR) of each peptide family
5. To further appreciate the physiological significance of region-specific
distribution of gut endocrine cells
6. To apply this basic knowledge for the study of GI physiology course
Overview of the Digestive System
Gastrointestinal (GI) System: GI sphincters
• Luminal GI: GI/digestive tract or alimentary canal • These structures are made of GI smooth muscle
• Hepato-biliary-pancreatic GI: its associated organs • They separate the GI segment from each other
• Dysregulation of sphincters leads to GI diseases
GI motility disorder:
e.g.
pressure in the LES is too much, the food bolous is pushed to the stomach
Transit time and function
pressure in LES is too low, the food bolus is pushed back to the esophagus
Upper Esophageal
Sphincter
Esophagus: (UES)
- 10 s (25 cm)
- Conduit * Lower Esophageal
Sphincter
Stomach: (LES)
- 1 to 3 h
- Storage; partial digestion of protein * the gastric sphincter
help to determine the
& absorption of alcohol/aspirin * time food bolus stay inPyloric
the stomach:
affect the time for
digestion
Sphincter
Small Intestine:
- 7 to 9 h
- Digestion & absorption of nutrients Sphincter of Oddi
Large Intestine:
- 25 to 30 h Ileocecal
- Absorption of water from Sphincter
undigested food
Rectum: Internal/External
Anal Sphincter
- 30 to 120 h
- Storage of feces before defecation
Exocrine Secretions of GI System
Site of Exocrine Secretory
Secretion Secretory Cell Component
Entire All cells Water
GI System Inorganic salts
Salivary Glands Serous Amylase
Mucous Mucin
Esophagus Mucous Mucin
Stomach Parietal HCl & IF intrinsic factor for
absorping vit.
B12
Chief Pepsin
Mucous Mucin
Pancreas Acinar Amylase
Protease
Lipase
Others
-
Duct cells HCO3
Liver Hepatocytes Bile salts
-
Duct cells HCO3
Small & Large Mucous Mucin
Intestine Mucous Mucin
_______________________________________________________________________________
Note: Underlined indicate the associated glands/organs of the GI system; IF=Intrinsic factor
Four Primary Functions of GI System
primary function of GI tract:
digestion, then absorption, then assimilation
but require secretion to do so
Among them, only absorption is central to the functioning of
GI system, whereby nutrients can be assimilated by the body
3 2
4 While digestion, secretion & absorption are taking place,
food contents are mixed & conveyed from oral to anal regions by GI movement
These 4 physiological functions are highly coordinated and integrated in order to optimize digestion and absorption,
thus assimilation of nutrients
Integration of GI System
• The digestive system is massive in size compared to all other organ systems, consisting of
esophagus, stomach, small intestine, large intestine, gallbladder, liver and pancreas
• After a food bolus is swallowed into our GI tract, numerous events are set into play that involve
complex digestive, absorptive, and excretory processes
• Because of the complexity of function of each organ and the interaction among different
parts of the GI tract, an intricate Neural-Hormonal System is required for the
integration of GI functions; otherwise, GI disorders ensue
Regulation and integration of gut
functions are complex
NEURAL: PEPTIDES HORMONAL:
and
Extrinsic (ANS) • Endocrine
Non-Peptides
Intrinsic (ENS) • Paracrine
local GI system
• Autocrine
• Neurocrine
can work totally independent from ANS and CNS
ANS=Autonomous nervous system
• Juxtacrine
ENS=Enteric nervous system
Gut Functions:
(I) • Motility (II)
Enteric • Secretion Gut
Nervous • Digestion Endocrine
System • Absorption System
• Blood Flow/Growth
Types of peptides acting as gut neuro-hormonal
regulators: major gut peptide families
Gastrin-Cholecystokinin Family Tachykinin/Bombesin Family
Gastrin Substance P
Gastric releasing peptide (GRP)
Cholecystokinin (CCK)
Bombesin
Secretin Family
Secretin Pancreatic Polypeptide Family
Vasoactive intestinal polypeptide (VIP) Pancreatic polypeptide
Gastric inhibitory peptide (GIP) Neuropeptide Y (NPY)
Glucagon Peptide YY (PYY)
Glucagon-like peptide-1 (GLP-1)
Opioid Peptide Family
Others Met- and Leu-enkephalines
Somatostatin Neuropeptide Y (NPY)
Calcitonin gene-related peptide (CGRP) Beta-endorphin
Note: Members of a family share structural homology either at C-terminal, N-terminal or throughout the amino acid sequence,
and thus have overlapping function, i.e. Structural-Activity (Function) Relationship (SAR)
Comparison of carboxy-terminal sequences of
Gastrin and CCK peptides
C-terminal amidation
N-terminal acetylation
Gastrin (G34, G17, G14)
bind to CCB
AA Ala Tyr Gly Trp Met Asp Phe NH2
end with amide CONH2 group
make the chain more stable
bind to CCA
CCK (CCK33, CCK8)
AA Asp Tyr Met Gly Trp Met Asp Phe NH2
HSO3 Biologically active region
• Gastrin & CCK share 4 AA identity at their carboxy terminal that is the biological active domain of both molecules
• Each peptide binds to the receptor, i.e. CCKA for CCK & CCKB for gastrin, and thus both exhibit similarities in physiological properties
Physiological functions of Gastrin and CCK
Gastrin:
1. To stimulate acid secretion by the gastric parietal cells
2. To stimulate the growth of gastric mucosa, i.e. trophic action
trophic action
3. To stimulate gastric motility
CCK:
1. To stimulate digestive enzyme secretion by the pancreatic
acinar cells
alpha amino, protease, lipase
2. To stimulate gallbladder contraction
3. To inhibit gastric emptying
must be in moderate speed
affect the rate of digesiton
Note: Hyper-function or Hypo-function of these peptides causes GI disease, e.g. overproduction of gastrin in a clinical case of gastrinoma
Sequence comparison of the Secretin family
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Secretin His Ser Asp Gly Thr Phe Thr Ser Glu Leu Ser Arg Leu Arg Asp
VIP Ala Val Asp Asn Try Thr Lys
GIP Tyr Ala Glu Ile Asp Tyr Ise Ala Met
Glucagon Gly Asp Try Lys Tyr Leu
16 17 18 19 20 21 22 23 24 25 26 27 28 29
Secretin Ser Ala Arg Leu Gln Arg Leu Leu Gln Gly Leu Val NH2
VIP Gly Met Ala Val Lys Lys Tyr Asn Ser Ile Leu Asn NH2
GIP Lys Ile Gln Asp Phe Val Asn Trp Leu Ala Gln +14 AA
Glucagon Arg Ala Asp Phe Val Trp Met Asp Thr
Indicates identical amino acid to secretin
• This family members share less structural homology throughout the amino acid sequence that is critical for the biological activity
• These peptides, not surprisingly, have diverse and independent actions
Physiological functions of Secretin family members
Secretin: secret bicarbonate in the form of sodium bicarbonate
1. To stimulate bicarbonate secretion by the pancreatic ductal cells
2. To stimulate the growth of exocrine pancreas, i.e. trophic action
3. To inhibit gastric emptying
VIP: excessive secretion of VIP: VIP oma
hyperfucntion of GI movement
1. To stimulate intestinal fluid & electrolyte secretion
2. To increase blood flow (vasodilatation)
3. To relax GI sphincters and circular smooth muscle
GIP:
1. To stimulate insulin release
2. To inhibit acid secretion
3. To inhibit gastric emptying
Note: Hyper-function or overproduction of these peptides also causes GI disease, e.g. overproduction of VIP in VIPoma (see Case Study)
Types of non-peptides acting as gut
neuro-hormonal regulators
Acetylcholine (Ach)
Epinephrine (Adrenaline)
Norepinephrine (Noradrenaline)
Purinergic Agonist (adenosine, ATP)
Serotonin
Nitric Oxide
Dopamine
Histamine
Note: Underlined are amino acid derivatives
Summary of some major regulatory peptides/non-peptides
for the integration of GI functions
Regulator Release Site Major Mode Peptide/
All the GI hormones
are peptides of Action Non-Peptide
Gastrin Gastric G-cells duodenum Endocrine P
CCK Intestinal I-cells Endocrine P
Secretin Intestinal S-cells Endocrine P
GIP Intestinal K-cells Endocrine P
VIP Enteric neurons Neurocrine P
Somatostatin Gastric D-cells Paracrine P
released from the nerve ending of neural cells (esp ENS neurons)
ACh Enteric neurons Neurocrine N
Adrenaline/ Enteric neurons Neurocrine N
Noradrenaline
Histamine Gastric endocrine cells Paracrine N
ATP Enteric neurons Neurocrine N
NO Enteric neurons Neurocrine N
Note: Each regulator can act as either endocrine, paracrine and/or neurocrine, e.g. VIP, for the integration of GI functions
Cellular sites of action of gut regulatory agents
Lamina Epithelia Lumen
propria epical side
Hydrophobic Agents:
They cross cell membrane & have intracellular
sites of actions
Steroids cAMP
Nitric Oxide cGMP
Membrane Ca2+
Hydrophilic Agents: receptors
They do not cross cell membranes & often
stimulate specific membrane receptors
Peptide Hormones Ca2+
Neurotransmitters
G-protein coupled receptors (GPCR):
The major membrane receptor-mediated GI functions
GPCRs have 7 membrane spanning domains and a cytoplasmic binding site for G proteins
N
Extracellular
Ligand
Plasma Membrane-
1 2 3 4 5 6 7 Spanning
Membrane
Domains
Cytosol G-Protein
C
Regulation of adenylate cyclase by
membrane receptors and G-proteins
Membrane Activating ligand Inhibiting ligand
Receptor
G protein receptor
Plasma
Membrane
g
g as +
Adenylate
- ai b
b Cyclase
similar acrion on Adenylate cyclase
Pertussis Toxin-stimulated
GDP GTP cAMP ATP ADP-ribosylation irreversably
inhibits ai
Cholera Toxin-stimulated
A-Kinase Protein Phosphorylation
ADP-ribosylation irreversably
activates as, thus causing
secretory diarrhea Altered Cell Functions
Pathways for neuro-hormonal
regulation of gut functions
A. Endocrine Pathway*
Mucosal Target tissue
Endocrine (e.g. smooth muscle cells)
Cell Stimulus
Intestinal
Epithelial
Cell
Released
Blood circulation
Hormones
* Hormones carried by blood circulation that affect distal targets
Pathways of intestinal regulation
B. Paracrine C. Autocrine
Mucosal endocrine cell
Enterocytes
D. Juxtacrine E. Neurocrine
Enterocytes
Capillary Enteric Enteric
Nerve Nerve
Mast Cell
Summary of neural-hormonal pathways in
regulating GI functions
compare the difference and
1. Endocrine pathway: similarity of the pathways
It is the traditional concept that regulatory hormones (gut peptides) which are released from intestinal
endocrine cells into the blood stream in response to food stimulus, and delivered to distant targets; thus
multiple tissues and cells can be regulated simultaneously.
both 1 and 2 are released from the gut endocrine cell
difference: can be peptide or non-peptide
2. Paracrine pathway:
It is the pathway that gut regulatory agents (peptides/non-peptides) which are released from intestinal
endocrine cells in response to food stimulus, and activate receptors located on cells immediately
adjacent to the paracrine cell, thus altering their behavior and function.
3. Autocrine pathway:
It is similar to the paracrine pathway except the stimulated release of the regulatory agents auto-regulates
the cell’s behavior and function.
4. Juxtacrine pathway:
It describes the actions of released regulatory agents that affect many types of cells that are in close
proximity; for example, mast cells in the lamina propria can secrete histamine, which affects gut mucosal
functions, blood flow, and smooth muscle function.
5. Neurocrine pathway:
It is utilized by enteric neurons that release regulatory agents (peptides/non-peptides) that traverse a narrow
synaptic space to activate specific receptors of target tissues; numerous gut functions can therefore be regulated
in a specific and integrated fashion.
Organization of the enteric nervous system
Secretion Motor Neurons Integrative Circuits
Sensory
Neurons
Program Circuits
Enteric Nervous
System
Gut endocrine cells (Gut Endocrine System)
are found throughout the intestinal epithelium
Characteristics:
• Pyramidal shaped, intercalated
among epithelial cells
• Polarized morphology
• Secretory granules at basal pole
• Ability to sense luminal changes
of food stimuli (pH, temperature,
chemical composition)
quality and quantity of food
facilitate secretion
Distribution of gut endocrine cells
The distribution of most gut endocrine cells is not random; they have region-specific expression and
are physiologically relevant to their primary functions
CCK Neurotensin
Secretin Peptide YY
GIP Enteroglucagon
Gastrin
G-cell in response Jejunum Guanylin Rectum
to peptides
Stomach Duodenum Ileum Colon
Role of gut peptide hormones in
digestion of a meal
Gastric chyme stimulates
release of CCK, Secretin,
Food Bolus GIP from duodenal S- and K- cellsRelease of hepatic bile and
Enters Stomach endocrine cells as well as pancreatic secretions (i.e.
negative feedback on gastric Enzyme & HCO -)
3
secretion and motility
Gastric acid and
pepsin secretion (+)
and increased (-)
gastric motility
Gastrin
Stomach
Duodenum Jejunum
Blood
Capillary
Regulation and integration of GI functions
Case Study
n 48-year-old Caucasian female with watery diarrhea
x 6 years & occasional flushing. No response to
antibiotics. Admitted for dehydration and
metabolic disturbances (Low K+, Cl-)
n Stool neg for pathogens, fat, blood, and WBCs
n Endoscopy negative
n CAT scan – pancreatic mass and hepatic metastases
n Special blood tests ordered
• Explain this patient’s symptoms and metabolic problems
• How can this patient be managed medically?
Histologic appearance of a pancreatic
endocrine tumor (VIPoma)
secretin family
It is a functional endocrine tumor in the pancreas that abnormally produces large amounts of the plasma gut peptide, called VIP
Flushing (as a symptom)
Answers to Questions:
1. Explain this patient’s symptoms and metabolic problems
- VIPoma or pancreatic cholera
- Function of VIP
1. To stimulate intestinal fluid and electrolyte secretion
2. To enhance blood flow (vasodilation)
- Watery diarrhea & dehydration; hypotension
+ -
- Low plasma K (hypokalemia) & low Cl (hypochlorhydria)
+ +
Why is there usually normal plasma Na but not low Na (hyponatremia)?
- Flushing
Mechanism of VIP-induced diarrhea & flushing
Apical Basolateral
membrane membrane
Enterocyte
VIP receptor
Active
Secretion Gs
(CFTR channel) cAMP
Cystic Fibrosis
Transmembrane Protein cAMP
Regulator A.C.
Phosph.
A-kinase ATP
Active NaCl
Absorption
VIP
VIPoma
Diarrhea
Blood capillary
Answers to Questions:
2. How can this patient be managed medically?
- Octreotide, an analogue of somatostatin
Function of somatostatin
- Surgical intervention (?)
It is not feasible as this tumour has already spread
(see Case Presentation: hepatic metastases)
Effects of Somatostatin on the GI tract
n Inhibitory actions of the following
digestive functions:
n Gastric secretion
n GI motility
n Gallbladder contraction
n Splanchnic blood flow
n Intestinal water and electrolyte secretion
e.g. Inhibition of VIP-mediated pathways
• VIP release or synthesis
• Activation of adenylate cyclase-mediated cAMP
Structural analogs of native somatostatin
are more potent and stable
Native somatostatin Octreotide
Phe Phe
S Trp S Trp
S Tyr S Tyr
Thr Thr
• Retains active site (red)
• Blocked C- and N-terminal ends
(decreased degradation, longer
half-life
• ~70 fold greater potency
Octreotide inhibits hormone-mediated
diarrhea by decreasing plasma secretagogue
concentration
8 8
Octreotide Octreotide
Plasma VIP Concentration
6 6
VIP
(ng/ml)
Stool
Output 4 4
(km/D)
2 2
0
0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12
Day
Clinical evidence of somatostatin’s
efficacy
water diareahea
Thank you and See You Again
in GI Physiology
of Human Function 1
