Download The Gut, our largest sensory organ: the 1st immune

The Gut, our largest sensory organ:
the 1st immune organ
Pr. John B. Furness, ● September 2014
The Gut, our largest sensory
The Gut, our largest sensory organ:
the 1st immune organ
Breizh Algae Tour - Sept. 15th, 2014
87
The gut as a sensory organ
The small intestine presents a surface membrane area of about 60 m2,
making it the largest vulnerable surface of the body.
The total surface of the gastrointestinal tract that faces the external
environment is 100 m2, compared to 2 m2 of skin.
The external milieu (the luminal content of the gut) is continually modified by
ingestion of food, drink and contaminants they may bring with them, by
microorganisms, by microbial products, by enzymatic and chemical breakdown of
complex molecules and by pharmaceuticals.
The intestine has no advance knowledge of the materials that arrive at this surface –
it requires sophisticated sensory and tissue defence systems.
Breizh Algae Tour - Sept. 15th, 2014
88
Gut contents signal via hormones, neurons,
immune responses and receptors
for innate defence
Breizh Algae Tour - Sept. 15th, 2014
Furness et al 2013
91
How extensive is the system?
•12 major types of entero-endocrine cells. The gut is the largest endocrine
organ in the body
•The largest peripheral nervous system, about 500,000,000 neurons
(human). About 50,000 vagal afferents, 6,000 spinal afferents, 2,000
pelvic afferents
•Millions of immune cells
•Innate Anti-microbial and Detoxifying defence throughout the gut
•Fifty or more luminal receptors
Breizh Algae Tour - Sept. 15th, 2014
92
Luminal Receptors
• The taste receptors: Sweet: T1R2–T1R3; amino acids, the umami (savoury) receptor,
T1R1–T1R3; the undimerised T1R3 receptor
• The bitter receptor family, T2Rs
• The sour (acid) receptor, PKD2L1
• Receptors for protein breakdown product receptors: CaSR, LPAR5
(also known as GPR92/ GPR93), GPRC6A, T1R1–T1R3
• Free fatty acid receptors: FFAR 1–3, GPR119, GPR120
• Phytochemical Receptors, including TRPV1, TRPV2, TRPV5, TRPV6, TRPA1,
TRPP2 (PKD2L1); the bitter receptor (T2R)
• Olfactory receptors
• Mechanosensitive channels of nerve endings and enteroendocrine cells
• Receptors for physicochemical attributes, including Temp, osmolarity, pH
• Bile acid receptors, TGR5
• Pattern recognition receptors: Toll-like receptors 1–9, NOD1, NOD2
• T-cell receptors: peptides, lipopolysaccharides, vitamin B metabolites, cytokines
• Receptors for emetogenic toxins
• Receptors for advanced glycation end products (RAGE receptors)
Breizh Algae Tour - Sept. 15th, 2014
Furness et al 2013
93
Enteroendocrine Cells: The primary source of feed-back
signalling for physiological regulation
Nerve
fibres
GLP-1 cell
PYY cell
Breizh Algae Tour - Sept. 15th, 2014
94
Signaling by the Major
Gastrointestinal Hormones
Ghrelin, A cell
Promotes appetite, growth hormone release
Gastrin, G cell
Stimulates acid secretion
Somatostatin, D cell
Inhibits acid secretion
Secretin, S Cell
Stimulates HCO3 production
CCK, I cell
Stimulates gallbladder and pancreas, inhibits appetite
GIP, K cell
Promotes insulin secretion (incretin)
GLP-1, L cell
Increases insulin secretion (incretin), reduces appetite, slows gastric emptying
GLP-2, L cell
Stimulates mucosal growth, enhances nutrient absorption
Peptide YY, L cell
Slows small intestine transit , reduces appetite
Motilin, M cell
Triggers migrating complexes (differs between species)
5-HT (serotonin) , EC cell Low release: stimulates contractile activity and water and electrolyte secretion.
High release: toxin expulsion (nausea, vomiting, diarrhea) (vomiting/ pica differs
between species)
Breizh Algae Tour - Sept. 15th, 2014
Furness et al 2013
95
Luminal sensors:
modification of feeding
Bitter taste stimulation in stomach
In Wild-type, a-gustucin KO and ghrelin receptor KO
Food Intake
g/hr/mouse
Intra-gastric gavage with bitter mix
Plasma Ghrelin
pg/mL
Breizh Algae Tour - Sept. 15th, 2014
Janssen 2011
96
Luminal sensors:
modification of nutrient handling
 Sweet receptor stimulant, sucralose, induces SGLT1 and glucose uptake
SGLT1 protein
SGLT1
mRNA
Different
sweeteners
SGLT1 function
Other sweeteners, aspartame, acesulfame, saccharine
Breizh Algae Tour - Sept. 15th, 2014
Margolskee, Shirazi-Beechey 2007
97
Luminal sensors - hormone release - neural
activation - transporter induction
Breizh Algae Tour - Sept. 15th, 2014
Shirazi-Beechey 2011
98
The Enteric Nervous System:
Notre cerveau originel
(as explained by Michel Neunlist)
There are two ganglionated plexuses: Myenteric, primarily motility control,
Submucosal, primarily secretion/ blood flow control/ immune modulation
Breizh Algae Tour - Sept. 15th, 2014
Furness, 2012
99
Enteric sensory neurons
Enteric sensory
neurons:
modification of
motility secretion,
blood flow, digestion,
appetite etc.
Breizh Algae Tour - Sept. 15th, 2014
100
The complexity of integration of enteric
sensory information:
Exemplified by the L cell
Inputs: Luminal
nutrients
Outputs: regulation
of transit, secretion,
blood flow, mucosal
growth, gut defence,
insulin secretion,
immune function,
appetite
Breizh Algae Tour - Sept. 15th, 2014
Furness et al 2013
101
Gut Defences - overview
he mucosa: large, highly permeable, especially in the small intestine, vulnerable,
but nevertheless a barrier
Mucus layer
Toxin elimination: vomiting, pica, diarrhea
Detoxification: In rumen (cattle etc); small intestine and liver enzymes
Destruction: defensins etc
Innate immunity: macrophages, neutrophils, T cell cytokines
Adaptive immunity: B cell reservoir, CD4-CD8 T cells, NK T cells, MAIT cells, entry of
antibodies into the lumen: Always vigilant, always active
Two way modification:
BacteriaImmune cell-
Breizh Algae Tour - Sept. 15th, 2014
-Immune cell;
-Bacteria
102
The mucosal barrier
Breizh Algae Tour - Sept. 15th, 2014
Hooper et al, 2010
103
Compromised Gut Barrier Function:
heat stress
Thermo Neutral
Heat Stress
P- value
Ileum TER
(Ω × cm2)
182 ± 17
88 ± 18
<0.01
Colon TER
(Ω × cm2)
133 ± 7
102 ± 8
<0.01
Ileum FITC Dextran
(μg/mL/min/cm2)
3.6 ± 0.9
7.9 ± 1.1
<0.01
Colon FITC Dextran
(μg/mL/min/cm2)
2.7 ± 3.6
15.7 ± 3.6
<0.01
Thermoneutral: 21°C; 35–50% humidity (n= 8) for 24 h
Heat Stress: 35°C; 24–43% humidity (n = 8) for 24 h
Breizh Algae Tour - Sept. 15th, 2014
104
Protecting the Gut Barrier
against heat stress
Heat Stress: 40°C; 21% humidity for 1.5 h
Thermoneutral: 21°C; 21% humidity
Breizh Algae Tour - Sept. 15th, 2014
Maseko et al, 2014
105
Innate Immunity: The mucosal barrier and
Pattern Recognition Receptors
Breizh Algae Tour - Sept. 15th, 2014
Mills, 2011
106
Paneth Cells and PRRS
A major source of anti-microbial peptides
The major PRR – Toll Like Receptors
MAMP, PAMP – microbe associated
molecular patterns, pathogen
associated molecular patterns
Breizh Algae Tour - Sept. 15th, 2014
Bevins & Salzman 2011
107
Modulation of adaptive immune responses in the
gut by the Microbiota: Barrier protection and
tolerance
Breizh Algae Tour - Sept. 15th, 2014
Cerf-Bensussan 2010
108
Antigen sensing: follicular, mesenteric and
lamina propria T cells
Breizh Algae Tour - Sept. 15th, 2014
Mowat et al., 2003
109
Chemical selectivity of T cells in gut
CD4+ and CD8+ T
cells - peptide
Breizh Algae Tour - Sept. 15th, 2014
CD1d NKT cells – lipid
Chua et al., 2012
MAIT cells – B vitamins
110
Symbionts and Pathobionts
Breizh Algae Tour - Sept. 15th, 2014
Cerf-Bensussan et al., 2011
111
Anti-inflammatory effect of an L. Delbrueckii strain
in a human epithelial cell line
Breizh Algae Tour - Sept. 15th, 2014
Santos Rocha, Blottière et al., 2012
112
Microbial – immune homeostasis
he gastrointestinal tract is constantly exposed to variable luminal contents, and is
thus always in a state of mild inflammation: the gut immune system is primed
The gut immune system and gut bacteria have co-evolved. Thus in a healthy gut
they are in equilibrium, and bacterial symbionts keep pathogenic bacteria under
control
Dysbiosis occurs when dysequilibrium occurs, and pathobionts mediate mucosal
barrier disruption, tissue damage and systemic disease
Enhancing gut health for animal production
Utilising macro- and micro-nutrients that promote effective nutrient assimilation,
maximise growth, production (milk, eggs) and carcass weight
Utilising additives that are protective (e.g. anti-oxidants) or digestive enhancers
(e.g. some phyochemicals)
Application of probiotics
We need research that provides a stronger evidence base
Breizh Algae Tour - Sept. 15th, 2014
113
A Challenge: Understanding how the different
sensors and their effectors work in harmony
Breizh Algae Tour - Sept. 15th, 2014
Furness et al 2013
114
Merci - Thank you!
All the nutritional benefits of regular worms,
without the torture of having to be awake early
Breizh Algae Tour - Sept. 15th, 2014
115
Thanks for your
attention!