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The Enteric Nervous System:
The Brain in the gut
Gary M. Mawe, PhD
Department of Neurological Sciences
The University of Vermont
Major Topics
• Organization of the Autonomic Nervous System
• Parasympathetic and Sympathetic innervation of
the gut
• Long reflexes of the upper GI tract
• Local reflexes of the intestines (the brain in the gut)
• The Big Brain can override the Little Brain
• Hot topics in enteric neurobiology:
• The vagal anti-inflammatory pathway
• The microbiome-gut-brain axis
Divisions of the Nervous System
CNS
Brain
Spinal
cord
PNS
Somatic
Sympathetic
Autonomic
Parasympathetic
Autonomic vs. Somatic Reflexes
Sensory
ganglion
CNS
Somatic
Skeletal Muscle
Sensory
ganglion
CNS
Autonomic
Parasympathetic
ganglion
Cardiac Muscle
Smooth Muscle
Glands
Dual Innervation of Organs
Inhibitory
ACh
ACh
Parasympathetic
ganglion
Excitatory
ACh
NE
Sympathetic
ganglion
Innervation of the Gut
Fig. 1. From Furness JB. Nat.
Rev. Gastroenterol. Hepatol. 9:
286–294, 2012.
Available at
nature.com/nrgastro/journal/v9/n
5/full/nrgastro.2012.32.html
Parasympathetic preganglionic
Parasympathetic postganglionic
Sympathetic preganglionic
Sympathetic postganglionic
Parasympathetic Preganglionic Innervation of the Gut
Vagus Nerve
Sacral Preganglionic Nerves
Vagal Efferent Innervation Density
Drops Off in the Intestines
Fundus
Jejunum
Ileum
Colon
Submucosal ganglia do not receive vagal efferent input
Fig. 1, C, E, G, I, and 2. From Berthoud et al. Am J Physiol 260: R200-R207, 1991.
Reprinted with permission.
Freely available at ajpregu.physiology.org/content/ajpregu/260/1/R200.full.pdf
Blood Supply of the Gut
Celiac Trunk
Superior Mesenteric Artery
Inferior Mesenteric Artery
Sympathetic Postganglionic Innervation of the Gut
Celiac Ganglion
Superior Mesenteric Ganglion
Inferior Mesenteric Ganglion
Targets of sympathetic innervation in
the gut wall
Vasoconstrictor
Motility (-)
Secretion (-)
Immune tissues
Direct innervation
of smooth muscle
and glands is sparse
Intestino-fugal
projections
Fig. 3.3. From Chapter 3 in Furness et al. Adv Exp Med Biol 817: 39-71, 2014.
Available at http://link.springer.com/chapter/10.1007/978-1-4939-0897-4_3
Enteric Reflex Diagram?
CNS
Parasympathetic
Excitatory
Parasympathetic
preganglionic
Inhibitory
Sympathetic
Prevertebral
ganglion
Most intestinal enteric neurons do not receive direct input from
parasympathetic preganglionic neurons
The major targets of sympathetic postganglionic projections are
myenteric ganglia, submucosal ganglia, and blood vessels.
Enteric neurons provide significant input to prevertebral
ganglia.
The Law of the Intestine
"Local stimulation of the gut produces
excitation above and inhibition below the
excited spot. These effects are dependent on
the activity of the local nervous mechanism."
Bayliss and Starling. The movements and innervation of the small intestine. J Physiol 24:
99-143, 1899.
Freely available at onlinelibrary.wiley.com/doi/10.1113/jphysiol.1899.sp000752/pdf
The Autonomic Nervous System
as originally described by Langley in 1921
Innervation of the gastrointestinal tract
Upper GI tract Long (Vagal) Reflexes
Enteroendocrine cells release signaling molecules
that can have paracrine and/or hormonal actions
Transmission electron micrograph of an enterochromaffin cell.
From Mescher AL. Junqueira’s Basic Histology: Text and Atlas
(12th ed.). 2009, McGraw-Hill Medical. Available at
http://histonano.com/books/Junqueira's%20Basic%20Histology%2
0PDF%20WHOLE%20BOOK/15.%20Digestive%20Tract.htm
(Enteroendocrine cell)
Human rectal biopsy
Chromogranin A
Serotonin
Yoyo, a nucleic acid stain
Enteroendocrine cells may form synapse-like
connections with nerve fibers
Fig. 3D. From Bohórquez DV, Liddle RA.
J Clin Invest 125: 782–786, 2015.
Available at
http://www.jci.org/articles/view/81121
Signals that activate
vagal afferents
GHS-R ⬅ Ghrelin
ObRb ⬅ Leptin
Vagus Nerve
Gastric
ASIC3 ⬅
Proximal
small intestine
Stretch
CCK1R ⬅
CCK
5-HT3R ⬅
5-HT
GIPR ⬅
Distal
small intestine
GLP1R ⬅
Y2R ⬅
GIP
GLP-1
PYY
Mechanisms of
weight loss
following
Bariatric Surgery
Abbreviations:
GLP-1, glucagon like peptide-1;
PYY, peptide YY; OXY, oxyntomodulin
Fig. 2. From Miras AD, le Roux
CW. Nature Rev Gastroenterol
Hepatol 10: 575–584, 2013.
Available at
nature.com/nrgastro/journal/v10/n1
0/full/nrgastro.2013.119.html
Examples of long reflexes affecting
motility in the Upper GI Tract
TLESRs
Accommodation
(receptive, adaptive and
feedback relaxation)
Increased antral
pump activity
Vagus
(Ach)
Vagus
(Ach)
Vagus
(Ach)
Air
NO
NO
(-)
Adapted from Plate 270. In: Netter FH. Atlas of Human Anatomy (6th ed). 2014. Saunders.
Ach
Video
Gastric Sieving, video number 24.
From GI Motility shown by
Videofluoroscopy Part 1
at
http://humanbiology.wzw.tum.de/inde
x.php?id=40&L=1
Parietal Cell (Acid) Secretion
(Cephalic, oral and gastric phases)
Vagal
preganglionic
Gastric Neuron
Parietal Cell
Acetylcholine
Histamine
ECL Cell
Gastrin
Gastrin
G Cell (-) Circulation
(-)
Somatostatin
(inhibitory)
Somatostatin
(inhibitory)
D Cell
Chief Cell Secretion
(Cephalic, oral and gastric phases)
Chief Cell
3
Lipase
Vagal input
Enteric
Nervous
System
2
Pepsinogen
Pepsin
4
1
H+ in Lumen
1. H+ in lumen stimulates a neural reflex
2. Enteric neurons activate Chief cells
3. Release of pepsinogen and lipase
4. H+ converts pesinogen to pepsin
Vagal Reflexes
Upper GI tract motor activity
Decreased gastric emptying and increased biliary motility
1. Fats and protein cause
CCK release from I cells
(-)
(+)
(+)
(-)
I Cell Protein
CCK
Circulation,
ENS reflexes
Vagal reflexes
FAT
(-)
2. CCK enters the circulation,
reaches the gallbladder and
acts hormonally to increase
gallbladder tone
3. CCK activates local neural circuits
(local reflex) between the duodenum and
the sphincter of Oddi that decrease
sphincter of Oddi tone
4. CCK and distension activate vagal
afferent fibers that initiate so-called long (or
vagal-vagal reflexes) to increase gallbladder
tone, decrease fundic tone, and decrease
antral contractile activity
The net result is decreased gastric emptying and increased bile flow
Vagal Reflexes
Pancreatic Exocrine Secretion
CCK
Pancreatic
Enzyme
Secretion
Vagal afferents
and circulation
protein
Fat
CCK
I Cell
Secretin
H+
S Cell
Circulation
Secretin
Innervation of the gastrointestinal tract
Upper GI tract Long (Vagal) Reflexes
Intestines Local (Intrinsic) Reflexes
The Enteric Nervous System
Background: Fig. 3.4. From Furness et al. Adv Exp Med Biol 817: 3971, 2014.
Available at link.springer.com/chapter/10.1007/978-1-4939-0897-4_3
Or at scholarpedia.org/article/Enteric_nervous_system
There are a lot of neurons in the ENS
There are more neurons in the gut (>100 million) than
there are in the entire spinal cord.
Guinea pig myenteric plexus; 2x3 mm region; PGP 9.5
The ultrastructure of the ENS is similar to that of the CNS
Electron micrograph figure from Gershon et al. In: Physiology of the Gastrointestinal Tract (5th ed), Johnson LR (ed). 1994. Raven.
There is extensive neuronal diversity
in the ENS
Morphological properties
Electrical and synaptic properties
Chemical coding patterns
Projection patterns
Guinea pig myenteric plexus
Orphanin FQ, ENK and Calretinin
Neuron types in the ENS
Fig. 3.5. From Furness et al. Adv Exp Med Biol 817: 39-71, 2014.
Available at link.springer.com/chapter/10.1007/978-1-4939-0897-4_3
Almost every known neurotransmitter
can be found in the ENS
Biogenic amines
Acetylcholine
Norepinephrine
Serotonin (5-HT)
Amino Acids
-Aminobutyric Acid
Glutamine
Purines
Adenosine Triphosphate
b-NAD
Adenosine
Neuroactive peptides
Calcitonin gene-related peptide (CGRP)
Cocaine and Amphetamine Regulated Transcript (CART)
Cholecystokinin (CCK)
Dynorphin
Endorphins
Endothelin
Enkephalins
Galanin
Gastrin releasing peptide
Neuropeptide Y (NPY)
Neurotensin
Nociceptin (Orphanin FQ)
Peptide YY
Pituitary adenylyl cyclase activating peptide (PACAP)
Somatostatin
Gasses
Tachykinins (Substance P)
Nitric oxide
Carbon monoxide
Hydrogen sulfide
Vasoactive intestinal polypeptide (VIP)
Thyrotropin-releasing hormone
Key excitatory transmitters
Key inhibitory transmitters
Most receptors that are associated
with neuroactive compounds are
found in the ENS
The ENS is a
pharmacologist’s playground
Fig. 3. From Mawe GM, Hoffman JM.
Nature Rev Gastroenterol Hepatol
10: 473-486, 2013.
Available at
nature.com/nrgastro/journal/v10/n8/full/
nrgastro.2013.105.html
Enteric glial cells are similar to
astrocytes in the C NS
Enteric glia express GFAP, a major component of the
intermediate filaments in astrocytes.
Ablation of enteric glia leads to widespread enteritis.
S100 in the guinea pig myenteric plexus
Image courtesy of Stellie Spear
Enteric Glia Serve Multiple Functions
Fig. 2. From Gulbransen BD, Sharkey KA. Nature Rev Gastroenterol
Hepatol 9: 625-632, 2012.
Available at
nature.com/nrgastro/journal/v9/n11/full/nrgastro.2012.138.html.
Intrinsic reflex circuits exist in the gut
Oral
Aboral
Longitudinal muscle
Myenteric plexus
VideoCircular
of contraction
and relaxation reflex circuts in the gut
muscle
Available at catamountresearch.com/products/gimmSubmucosal plexus
preclin.htm.
Mucosa
Intrinsic reflex circuitry in action
Physiological Saline
Tetrodotoxin in the bath
Guinea pig distal colon
Interstitial cells serve as pacemakers and
mediators of neuromuscular transmission
Fig. 3B. From Sanders et al. Physiol Rev 94: 859–907, 2014.
Reprinted with permission.
Freely available at physrev.physiology.org/content/94/3/859.
Guinea pig myenteric plexus
Kit, PGP 9.5
Other intrinsic reflexes in the gut
Secretion
Longitudinal muscle
Myenteric plexus
Circular muscle
Submucosal plexus
Mucosa
Vasodilation
Enteric neurons even project to
accessory organs of the GI tract
• Decrease gastric emptying
• Increase Bile Flow
• Increase pancreatic secretion
• Regulate sphincter of Oddi tone
Adapted from Plate 272 in Netter FH. Atlas of Human Anatomy (6th ed). 2014. Saunders.
Stress-induced changes in gut function
From Almy TP. Gastroenterology 8: 616-626, 1947.
Stress-induced changes in gut functions
Fig. 4. From Almy TP. Am J Med 10: 60-67, 1951.
Available at
sciencedirect.com/science/article/pii/0002934351902197
Gut disorders involving the ENS
Motility Disorders
• Achalasia
• Gastric Stasis and outlet obstruction
• Intestinal pseudoobstruction
• Megacolon
• Generalized disorders of motility (hypoganglionosis; hyperganglionosis)
Diarrhea due to noninvasive secretagogues
• Ethanol, bile salts, heat-stable toxins of E. coli, and cholera toxin
activate intestinal secretomotor reflexes.
Inflammatory and immunologically mediated
bowel diseases
• Clostridium difficil toxin A induces a neurogenic inflammatory
response by activating extrinsic afferent fibers.
• Inflammatory bowel disease (IBD)?
IBS?
Intrinsic and extrinsic primary afferent
neurons initiate gut reflexes
Vagal afferents
Spinal afferents
Homeostatic
and digestion
reflexes
Nodose
ganglion
Dorsal root
ganglion
Intrinsic afferents
Submucosal
Longitudinal muscle
Myenteric plexus
Circular muscle
Submucosal plexus
Mucosa
Myenteric
Pain and
discomfort
reflexes
Vagus nerve stimulation
Tracey KJ. Scientific
American cover from
March 2015.
Available at
scientificamerican.com/
magazine/sa/2015/03-01/
• Rheumatoid arthritis
• Inflammatory bowel disease
• Asthma
• Diabetes
• Obesity
• Migraines
• Seizures
• Depression
Vagal anti-inflammatory reflexes
Fig. 1. From Matteoli G, Boeckxstaens GE. Gut 62: 1214-1222, 2013.
Freely available at http://gut.bmj.com/content/62/8/1214.full.pdf+html
Interactions Between the
Microbiome
and the Brain-Gut Axis
Mouse behaviors are influenced by changes
in the microbiome
Exploratory behavior is
increased by dysbiosis in
BALB/c mice
Fig. 3. From Bercik et al. Neurogastroenterol Motility 24: 405-413,
2012.
Freely available at onlinelibrary.wiley.com/doi/10.1111/j.13652982.2012.01906.x/full
Fecal transplants in germ
free mice lead to transfer
of strain-specific
behaviors
SPF– Specific pathogen flora
ATM – non-absorbable anti-microbial
Los ratones libres de gérmenes son menos
ansiosos
(Germ Free mice are less anxious)
Fig. 2. From Foster JA, McVey Neufeld K-A. Trends Neurosci 36: 305-312, 2013.
Available at sciencedirect.com/science/article/pii/S0166223613000088
The microbial signals to the vagus nerve are mediated by
enteric neurons
Fig. 1A. From Perez-Burgos et al. FASEB J 28:
3064-3074, 2014.
Freely available at
fasebj.org/content/28/7/3064.full?sid=7d96c
7c8-5217-451b-9a9a-6bfdbf166e6c
Summary
• The ENS is a distinct division of the ANS that
exhibits unique neuronal circuitry
• Long reflexes regulate upper GI tract functions
• Local reflexes regulate intestinal functions
• The Big Brain can override the Little Brain
• Advances in our understanding of the ENS could
improve treatments for many disorders,
including IBD and IBS