How the gut protects itself…. practising safe digestion’.pcbjcampbl/Lecture 12 - Y1 MBChB...

School of Medicine @UoLmedicine

bjcampbl@liv.ac.uk

http://pcwww.liv.ac.uk/~bjcampbl/Indigestion%202.htm

Cellular & Molecular Physiology, Institute of Translational Medicine

Prof. Barry Campbell

How the gut protects itself…. ‘practising safe digestion’.

Year 1 MBChB –

Gastrointestinal system

Learning Outcomes:

➢ Describe the defensive role of the mucosal barrier in response to attack/digestion and the consequences for the gut when protection fails

➢ Describe the mucus-bicarbonate barrier

➢ Explain the role of prostaglandins in the GI tract

➢ Define how the gastrointestinal epithelium responds when insult leads to injury

➢ Explain the processes restitution and cell migration in response to gut injury

➢ Describe how immune competent tissue monitors intestinal bacteria populations and prevents growth of pathogenic bacteria in the intestine

➢ Define the mechanisms to sense and remove damaged cells (e.g. apoptosis (programmed cell death) and epithelial shedding )

➢ Define the vomiting reflex

Attack and defence in the gut

Acid and pepsin

Ingested drugs (alcohol, aspirin)

Refluxed bile

Smoking

Micro-organisms (e.g. H.pylori)

Ischemia (oxidative stress)

Food allergens

Mucus-HCO3

Cell membrane

Cell migration and renewal

Mucosal blood flow

Prostaglandins

Immune system

Acid inhibition

Programmed cell death

Damaging Protective

Attack and defence in the stomach

HCO3-

Tight junctions

between cells

slow H+

diffusion

Blood supply

carries H+ away, helps

antioxidant function

Mucus-HCO3-

barrier slows H+

diffusion

Acid & pepsin

MUCUS

Mucosal blood flow

Mucosal prostaglandins

Cell migration

and regeneration

pH 2

pH 7

H+

Cell surface

phospholipids

EXOCRINE

PANCREAS

stomach

chyme

VAGUS NERVE

SECRETIN

CCK

Ach

VIP

+

+

HCO3-

Enzymes

The exocrine pancreas produces bicarbonate to

neutralise acidic stomach chyme

DUODENUM

Stretch

receptor

acid Fats &

protein

Duct

cells acinar

cells

Sir William Maddock

Bayliss

Starling introduced the term

'hormone' in the Croonian

Lectures to the Royal College of

Physicians, 20-29th June 1905.

Ernest Henry

Starling

MUCUS

MUCOSA

H+

CGRP/NO releasing

efferent fibres

Afferent nerve fibre

HYPERAEMIA

Arteriole

Increased blood flow in response to

penetrating acid

Restitution - rapid repair mechanisms

Approx. 30 min

Damage

loss

Cell

migration =

restitution

Epithelium

thinner,

but

restored

Key players in repair: Gastrin Regenerating protein (Reg)

Prostaglandins Growth factors Trefoil peptides

Noble PJ et al., Am J Physiol Gastrointest Liver Physiol. 2003; 284(1):G75-84.

Gastrin stimulates migration

1h post addition of gastrin

The gut immune system: Peyer’s patches

FAE VE

LF

Microfold (M cells)

The gut immune system: Peyer’s patches

Immunoglobulin A

(IgA)

innervation

M cell

Cytokinescirculation

IEL

B cellT cell

Antibody

production

macrophageT cell

mast

cell

Antigens of

infectious agents

apical

basolateral

transported

intact

6-10

crypts/villus

CRYPT

250 cells

VILLUS

3500 cells

300 cells/crypt/day

1400 cells/villus/day

150 proliferative cells

32 clonogenic cells

<16 stem cellspaneth cells

Control Irradiated

Life and death of an enterocyte

Damaged cells undergo programmed cell death (apoptosis)

x40 objective.

Duckworth & Watson 2011

Methods Mol. Biol. 2011; 763, 105-114 Carrie Duckworth © 2011

• Cells take ~10 min to shed

Maintenance of tight junctions during cell shedding

The vomiting reflex

Efferent fibres:phrenic & vagus

nerve

Afferent fibres:pain, bloating,

inflammation,

irritants, toxins....

Vomit

Contraction of

duodenum,

pylorus and

antrum

Vomiting centremedulla oblongata

Diaphragm fixed

for inspiration

LOS, UOS &

pharynx relaxed

Intercostal muscles

contracted…

High abdominal

muscular pressure