THE DIGESTIVE SYSTEM

Homeostasis
The digestive system contributes to homeostasis, in part, by transferring nutrients, H2O, and electrolytes from the external environment to the internal environment.

Geometrical shape = torus

Mouth

Mouth

Anus

Anus

Salivary glands

Mouth Pharynx Esophagus

Liver Gallbladder

Stomach
Pancreas

Large Intestine: Cecum Ascending colon Transverse colon Descending colon Sigmoid colon Rectum Anus

Small Intestine: Duodenum Jejunum Ileum

FUNCTIONS OF THE GI TRACT: Protection

Non-immunological defenses Immunological defenses

Nutrition
Transfer nutrients, H2O, and electrolytes from external to internal environment

Motility Secretion Digestion Absorption

Excretion
Bile entering the gi tract contains organic anions and cations, including drugs and drug metabolites that are either poorly absorbed or not absorbed at all from the gi tract.

Control of GI Functions
Non-immunological Defenses Immunological Defenses Motility Secretion Digestion Absorption Excretion

The functions of the gi tract are controlled by a dynamic interplay between different cell types that interact directly, or through a large number of signaling molecules to form reflex arcs.

Reflex Arc
Presence of Stimulus Detected Afferent Input

Response

Efferent Secreto-Motor Output

Types of reflex arcs controlling GI Functions Processing 1) Nervous and 2) Endocrine Integration 3) Paracrine 4) Immune

Gastrointestinal Motility
Contractions of muscles in the wall of the gastrointestinal tract mix contents of the lumen with digestive secretions and propel contents along the length of the gi tract. 1. Mixing contractions Mechanical disruption of ingested food Mix luminal contents with digestive secretions Facilitate absorption of digestion products 2. Propulsive contractions Propel luminal contents, usually in a caudal direction 3. Tonic contractions Maintain constant tone and intraluminal pressure Contraction of sphincters restricts movement of luminal contents

Gastrointestinal Secretion
1) During digestion of dietary components, a variety of substances are secreted into the gastrointestinal lumen. Surface epithelium Mucus Exocrine glands (i.e., glands with ducts that empty into the lumen) Salivary glands: saliva containing digestive enzymes and mucus Gastric glands: HCl, digestive enzymes, and mucus Intestinal glands: H2O, electrolytes, and mucus Pancreas: pancreatic juice containing digestive enzymes, electrolytes, and mucus Liver and gallbladder: bile containing bile salts 2) The presence of food within the gastrointestinal tract also induces the secretion of hormones and paracrine substances. Enteroendocrine cells (i.e., secrete hormones and paracrine substances) Gastric G cells: release gastrin Gastric D cells: release somatostatin (SS) Intestinal S cells: release secretin Intestinal I cells: release cholecystokinin (CCK)

Gastrointestinal Digestion
The proteins, carbohydrates and fats contained in the diet consist of large macromolecules that cannot be absorbed across the gastrointestinal epithelium.

Digestive enzymes break these macromolecules down (hydrolysis) into absorbable subunits.
For example:

Proteins are broken down to single amino acids

Carbohydrates are broken down to simple one-sugar molecules (i.e., monosaccharides: glucose, galactose, and fructose)

Triglycerides are broken down into free fatty acids and monoacylglycerides

Gastrointestinal Absorption
The gastrointestinal epithelium separates outside (lumen) from inside the body. 1)

epithelium

Absorption of digestion products (along with H2O, vitamins, and electrolytes) enter the body by being absorbed across the epithelial cell layer. Most of the absorption of nutrients, vitamins, H2O, and electrolytes occurs from the small intestine.

2) Absorbed nutrients leave the gastrointestinal tract in blood or lymph. Hepatic Portal Vein Monosaccharides, amino acids, water-soluble vitamins, etc. exit via hepatic portal vein en route to the liver. Lymphatics Lipid digestion products and fat-soluble vitamins are packaged within chylomicrons (a type of lipoproteins) and cannot enter capillaries, but exit via the lymph vessels.

The digestive tract wall consists of four layers:

1) Mucosa
Lines the luminal surface (divided into three layers).

2) Submucosa
Layer of connective tissue, containing larger blood and lymph vessels.

3) Muscularis Externa
Smooth muscle coat (longitudinal and circular muscle layers)

4) Serosa
Outer connective tissue covering

The Mucosa: Consists of three layers

1) Mucous membrane Inner surface epithelial cell layer, separating outside from inside the body.. 2) Muscularis Mucosae Thin layer of smooth muscle adjacent to the submucosa. 3) Lamina Propria Middle layer of connective tissue

The Submucosa: Area under the mucosa between the muscularis mucosae and the circular smooth muscle layer

Contains:
Connective tissue Large blood vessels Large lymph vessels

The Muscularis Externa: Consists of two relatively thick layers of smooth muscle
1) Circular muscle layer Innermost layer whose contraction narrows the lumen.

2) Longitudinal muscle layer Outermost layer whose contraction shortens and stiffens the wall.

Mesentery

The Serosa: Connective tissue covering. Continuous with the mesentery suspending the digestive organs from the inner wall of the abdominal cavity.

The Intrinsic Nerve Plexuses:

Two connected networks of neuronal ganglia and nerve fibers. Submucosal plexus Myenteric plexus

Enteric Nervous System (ENS)

Secretion

Motility

The Enteric Nervous System (ENS), the brain of the gut

The ENS is extremely large (~100 million neurons) and its ultrastructural organization and neuronal diversity are more like brain than peripheral nerve. The ENS is a center of integrative neuronal activity that is able to control the behavior of the gut by neural reflexes, even in the absence of CNS. Acts as a microcomputer with its ENS Reflex Arc own independent software. Presence of Afferent Organized for programmed Stimulus Input IPANs reflexive operations using neural detected elements contained within the Processing ENS and wall of the gi tract itself. interneurons Integration 1. Intrinsic primary afferent ENS efferent neurons (IPANs) respond to Efferent changes in luminal contents Response neurons Secreto-Motor Output and distention of the gut wall and convey information to ENS interneurons. 2. ENS interneurons integrate information and formulate programmed commands
3. ENS efferent motor and secretomotor neurons, etc. act to change behavior of target cells.

CNS
Also organized for programmed reflexive operations that can modulate the ENS programs.
1. Extrinsic primary afferent neurons (EPANs) respond to changes in luminal contents and distention of the gut wall and convey information to the CNS. CNS interneurons and centers integrate information about events in the gi tract with other sensory information and formulate efferent commands. CNS Reflex Arc
Presence of Stimulus detected Afferent Input EPANs Spinal cord Processing Medulla and Higher centers Integration CNS efferent neurons Response Efferent Secreto-Motor Output

CNS efferent neurons convey commands to the gi tract Somatic motor neurons to areas containing skeletal muscle, and Autonomic neurons (sympathetic and parasympathetic) to areas that contain the ENS

ENS Reflex Arc

Presence of Stimulus detected Afferent Input IPANs Processing ENS and interneurons Integration ENS efferent neurons Response Efferent Secreto-Motor Output

CNS Reflex Arc

Presence of Stimulus detected Afferent Input EPANs Spinal cord Processing Medulla and Higher centers Integration CNS efferent neurons Response Efferent Secreto-Motor Output

An understanding of neural reflexive pathways within the ENS and those that involve the CNS is essential to understanding the behavior of the gi tract.

Central Nervous System

Extrinic Primary Afferent Neurons (sensory)

Interneurons Integrative Circuitry

THE BRAIN-GUT AXIS

Short-Loop (ENS) and Long-Loop (CNS) Neural Reflexive Pathways

Motor Programs

Autonomic Nervous System

EPAN Receptor Parasym pathetic Neurons Sympathetic Neurons

Short-Loop Neuronal Reflex Pathway

Utilizes only neural elements within the ENS
EFFECTORS Interstitial Cells of Cajal Smooth muscle Epithelial cells Vasculature Enteroendocrine cells Immune cells

Enteroendocrine cells Chemical signal

Enteric Nervous System Interneurons Integrative Circuitry Intrinsic Primary Afferent Neurons (sensory IPANs)

IPAN Receptor

Secretomotor Motor Vasomotor Neurons Excitatory

Motor Programs

Inhibitory

ENS or enteric neurons:

1. ENS intrinsic primary afferent neurons (IPANs) Convey information about lumenal contents to ENS interneurons 2. ENS Interneurons (ascending and descending) Process and integrate sensory information Control behavior of efferent neurons 3. ENS efferent neurons a. muscle motor neurons Excitatory and inhibitory innervation of smooth muscle b. ENS secretomotor neurons Innervate the mucosa Control secretion c. ENS vasomotor neurons Control blood flow d. ENS intestinofugal neurons Neuronal cell bodies within the ENS, but send axonal projections to sympathetic prevertebral ganglia.

Intrinsic Primary Afferent Neurons (IPANs)

Called IPANs, rather than sensory afferent neurons, because they do not convey sensation from the intestine to the CNS.

Rather, IPANs are ENS afferent neurons that convey information about lumenal contents to ENS interneurons to initiate short-loop neural reflexes.
No IPAN nerve endings reach the lumen of the gut. How do IPANs detect the presence and composition of lumenal contents? 1. Presence of contents within the lumen IPANs within the wall of the gut respond directly to being stretched when the wall is distended due to contents within the lumen. 2. Composition of the lumenal contents IPANs may respond indirectly to intralumenal stimuli IPAN nerve endings possess receptors for chemical messengers (hormones, paracrine substances) released from entero-endocrine cells in the mucosal epithelium into the lamina propria.

Entero-endocrine cells in the mucosal epithelium

1. When stimulated, release chemical messengers (hormones, paracrine substances) into the lamina propria a) These messengers bind to receptors on IPAN (and EPAN (see later)) nerve endings. 2. Taste and feel the presence of luminal contents
a) Taste the chemical constituents of the luminal contents. Receptors (taste buds like on the tongue) on the apical membrane sensitive to: Changes in pH Protein digestion products Fat digestion products D-glucose Chemical irritants Changes in solute concentration b) Feel the mechanical distortion of the mucosa by shear force, pressure, volume, etc. caused by the presence of luminal contents.

Distention and stretch of the gut wall Intraluminal chemical or mechanical stimulus
Enteroendocrine cell

Intrinsic Primary Afferent Neuron (IPAN)

Short loop neural reflex

All neural elements involved in the reflex are contained within the wall of the GI tract.

Altered secretion

ENS neuronal network

Altered motility

The ENS and Entero-Endocrine Cells

Specific intraluminal stimuli lumen first activate enteroendocrine cells are strategically positioned in the mucosa to taste and feel luminal contents and release mediators that activate IPANs. Entero-endocrine cells in the stomach G-cells secrete gastrin D-cells secrete somatostatin etc. Entero-endocrine cells in the small intestine S-cells secrete secretin I-cells secrete cholecystokinin Enterochromaffin cells (EC) secrete serotonin (5HT) etc.

An example of an entero-endocrine cell: Enterochromaffin cell (EC)

Synthesize and store serotonin (5-hydroxytryptamine or 5HT) Taste luminal contents

Nutients Hyperosmolality Change in pH Luminal irritants Invading enteropathogenic microorganisms

Feel luminal contents Mechanical forces on the exerted on the mucosal surface In response to the detection of luminal stimuli, EC release 5HT into the lamina propria. 5HT binds to receptors on IPANs in the lamina propria to initiate a short-loop neural reflex within the ENS that result in changes in secretion and motility.

Intraluminal stimuli may initiate short-loop reflexes that alter secretion by epithelial cells.
Serosa Longitudinal Muscle

Myenteric plexus
Circular Muscle

Submucous plexus

Interneurons
Lamina propria

IPANs

Secretomotor Neurons ACh

Mucosa Lumen

5HT

EC cell

Cl-

Chemical or Mechanical Stimulation

Intraluminal stimuli may initiate short-loop reflexes that alter contractions in the muscularis externa.
Serosa Longitudinal Muscle

Excitatory motor neuron

Myenteric plexus
Circular Muscle

Interneurons

Inhibitory motor neuron

Submucous plexus

IPANs
Lamina propria

Mucosa Lumen

5HT

EC cell

Chemical or Mechanical Stimulation

Entero-Endocrine Cells Example: enterochromaffin cells (EC)

Removal of 5HT from the lamina propria 5HT is a base At physiological pH, 5HT is positively charged and cannot freely enter cells to be metabolized by intracellular enzymes (e.g., monoamine oxidase or MAO) Inactivation of 5HT occurs mainly by transporter-mediated uptake into enterocytes. The serotonin reuptake transporter (SERT or HTT) is the primary molecule responsible for inactivating 5HT in the gut. NOTE: Transcription of SERT is decreased in patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). This contributes to Increased water in stools Increased colonic motility Alternating patterns of diarrhea and constipation

Central Nervous System

Extrinic Primary Afferent Neurons (sensory)

Interneurons Integrative Circuitry

Motor Programs

Autonomic Nervous System

EPAN Receptor Parasym pathetic Neurons

BRAIN OF THE GUT

Sympathetic Neurons

Short-Loop Neuronal Reflex Pathway

Utilizes only neural elements within the ENS
EFFECTORS Interstitial Cells of Cajal Smooth muscle Epithelial cells Vasculature Enteroendocrine cells Immune cells

Enteroendocrine cells Chemical signal

Enteric Nervous System Interneurons Integrative Circuitry Intrinsic Primary Afferent Neurons (sensory IPANs)

IPAN Receptor

Secretomotor Motor Vasomotor Neurons Excitatory

Motor Programs

Inhibitory

Central Nervous System

Extrinic Primary Afferent Neurons (sensory)

Interneurons Integrative Circuitry

Long-Loop Neuronal Reflex Pathway

Utilizes neural elements within both the CNS and the ENS

Motor Programs

Autonomic Nervous System

EPAN Receptor Parasym pathetic Neurons Sympathetic Neurons

Enteroendocrine cells Chemical signal

Enteric Nervous System Interneurons Integrative Circuitry Intrinsic Primary Afferent Neurons (sensory IPANs)

EFFECTORS Interstitial Cells of Cajal Smooth muscle Epithelial cells Vasculature Enteroendocrine cells Immune cells

IPAN Receptor

Secretomotor Motor Vasomotor Neurons Excitatory

Motor Programs

Inhibitory

CNS
Extrinsic primary afferent neuron
Longitudinal Muscle

Pain and Nausea

Myenteric plexus
Circular Muscle

Submucous plexus

Lamina propria

Mucosa Lumen

5HT

Chemical or Mechanical Stimulation

Nerves Extrinsic to the Gut Wall: Connections to the CNS 1. CNS sensory extrinsic primary afferent neurons (EPANs) carry information from the GI tract to the CNS. 2. CNS efferent autonomic nerves from the CNS innervate the ENS. Sympathetic nerves Parasympathetic nerves
Autonomic nervous system input from the CNS modifies the ongoing activity of the ENS.

Distention and stretch of the gut wall Intraluminal chemical or mechanical stimulus
Enteroendocrine cell

CNS Extrinsic Primary Afferent Neuron (EPAN)

Long loop neural reflex

CNS neural elements in the brain and spinal cord are involved in long-loop neural reflexes and alter parasympathetic and sympathetic neural input to the ENS.

CNS neuronal network (brain and spinal cord)

Autonomic Nervous Output

Sympathetic Nervous System Parasympathetic Nervous System

Altered secretion
ENS neuronal network Altered motility

EPANs that convey information from the gastrointestinal tract to the CNS consist of the following three types:
1) Vagal afferent neurons
EPANs within the vagus nerves (X) that convey information to the medulla Neuronal cell bodies within vagal ganglia outside of the medulla.

2) Spinal visceral afferent neurons

EPANs within the splanchnic nerves (i.e., spinal nerves levels that convey information from the viscera to the spinal cord segments T1 to L2 . Neuronal cell bodies within dorsal root ganglia outside of the spinal cord at these levels

3) Pelvic afferent neurons

EPANs within the pelvic nerves (i.e., spinal nerves at spinal cord levels S2 to S4) that convey information to spinal cord levels Neuronal cell bodies contained in dorsal root ganglia outside of the spinal cord at these levels

Vagal ganglion Vagal Primary Afferent Neurons (EPANs)

Medulla
Parasympathetic preganglionic neuron

Vagus Nerve
Longitudinal muscle Myenteric plexus Circular muscle Submucous plexus

Spinal cord (S2-S4)

Dorsal root ganglion

Parasympathetic preganglionic neuron

Pelvic Primary Afferent Neurons (EPANs)

Pelvic Nerve
Longitudinal muscle Myenteric plexus Circular muscle Submucous plexus

Spinal cord (T1-L2)

Sympathetic pre-ganglionic neuron

Dorsal root ganglion Sympathetic paravertebral ganglion

Splanchnic Nerves
Sympathetic post-ganglionic neuron

Sympathetic prevertebral ganglion

Spinal Visceral Afferent Neurons (EPANs)
Longitudinal muscle Myenteric plexus Circular muscle Submucous plexus

ENS intestinofugal neuron

CNS Efferent Secreto-Motor Output to the GI Tract:

1. Somatic efferents (motor neurons) to striated muscle Cranial nerves from the brainstem (medulla and pons) Spinal nerves from sacral spinal cord (pudendal nerves) 2. Visceral efferents (autonomic nervous system (ANS))
Cranio-Sacral Division: Parasympathetic preganglionic neurons Cranial nerves Spinal nerves from segments S2- S4 forming the pelvic nerves Thoraco-Lumbar Division: Sympathetic preganglionic neurons from spinal cord segments T1 to L2 Splanchnic nerves

CNS Efferent Secreto-Motor Output to the GI Tract:

1. Somatic efferents (motor neurons) to striated muscle

Somatic motor neurons innervating striated muscle within the gastrointestinal tract are found in:

1. Cranial nerves (VII, IX, X, and XII), originating from the brainstem, innervating striated muscle of the jaws, tongue, oral cavity, pharynx, and upper esophagus.
2. Pudendal nerves, originating from the sacral spinal cord, innervating the striated muscle of the external anal sphincter.

CNS Efferent Secreto-Motor Output to the GI Tract:

2. Visceral efferents (autonomic nervous system (ANS))

Autonomic Nervous System

CNS Efferent Secreto-Motor Output to the GI Tract:

2. Visceral efferents (autonomic nervous system (ANS))
a. Cranio-Sacral Division: Parasympathetic preganglionic neurons 1) Cranial nerves from the brainstem Axons from parasympathetic preganglionic neurons within the brainstem exit and synapse on postganglionic parasympathetic neurons within parasympathetic ganglia close to, or within, the target organ (long preganglionic fiber; short postganglionic fiber). For example, parasympathetic postganglionic neurons that innervate the salivary glands are located within the submandibular and otic ganglia close to the salivary glands. Where there is ENS, the postganglionic parasympathetic neurons are located within the ENS (except for the distal colon). 2) Pelvic nerves from the sacral spinal cord Synapse on postganglionic parasympathetic neurons postganglionic neurons within the ENS in the distal colon.

CNS Efferent Secreto-Motor Output to the GI Tract:

2. Visceral efferents (autonomic nervous system (ANS))
b) Thoraco-Lumbar Division: Sympathetic preganglionic neurons from spinal cord segments T1 to L2 1) Axons from sympathetic preganglionic neurons exit the spinal cord and enter the sympathetic paravertebral ganglia at the same level. 2) The synapse with the sympathetic postganglionic neuron may occur at different locations (a) Within the sympathetic paravertebral ganglion (at the same level or at another level) In this case, the sympathetic postganglionic fiber exits the paravertebral ganglion chain to innervate the distant target (short preganglionic fiber; long postganglionic fiber). (b) Within a sympathetic prevertebral ganglion, close to the wall of the gi tract, after passing through the paravertebral ganglion (long preganglionic fiber; short postganglionic Splanchnic fiber). nerves In this case, the sympathetic postganglionic fiber exits the prevertebral ganglion to innervate the target (the ENS).

Parotid gland

Sympathetic
Salivary glands

Parasympathetic

Autonomic Nervous System:

Cranial nerves

Stomach Liver Splanchnic nerves

Spleen Pancreas Spinal Nerves (pelvic nerve) Colon Rectum

The cranio-sacral efferent autonomic neurons comprise the parasympathetic division of the autonomic nervous system. The thoraco-lumbar efferent autonomic neurons comprise the sympathetic division of the autonomic nervous system.

Gall bladder

Small intestine

Parasympathetic preganglionic fiber

Salivary Glands

Parasympathetic postganglionic fiber

Parasympathetic Nervous System: Salivary Glands

Submandibular and Otic Ganglia

Salivary glands Preganglionic parasympathetic neurons Neuronal cell bodies in superior and inferior salivary nuclei of the medulla Preganglionic nerve fibers in cranial nerves (VII, and IX) project to submandibular and otic ganglia near salivary glands. Postganglionic parasympathetic neurons Neuronal cell bodies in submandibular and otic ganglia Postganglionic nerve fibers project to and innervate the salivary glands

Parasympathetic Nervous System:

Esophagus through Transverse Colon, Liver, Gallbladder, and Pancreas Preganglionic parasympathetic neurons Preganglionic neuronal cell bodies in dorsal motor nucleus and nucleus ambiguus of the medulla Preganglionic nerve fibers in cranial nerve X (vagus nerves) project to postganglionic neurons within the ganglia within target organs Postganglionic parasympathetic neurons Parasympathetic postganglionic neuronal cell bodies in ganglia within target organs (e.g., intrapancreatic ganglia, ENS, etc.) Parasympathetic postganglionic nerve fibers project to target tissues (e.g., pancreatic acinar cells, ENS interneurons, etc.) Alter secretion, motility, absorption, etc.

Parasympathetic Nervous System:

Descending Colon to Anus
Preganglionic parasympathetic neurons Neuronal cell bodies in intermediolateral cell column of spinal cord segments S2 to S4

Preganglionic nerve fibers contained in spinal nerves form the pelvic nerves which project to postganglionic neurons in the ENS of the distal colon
Postganglionic parasympathetic neurons Postganglionic nerve fibers project to ENS interneurons Alter activity within the ENS
Spinal nerves

Alter secretion, motility, and absorption

Pelvic nerve

Parotid gland Sympathetic

Sympathetic Nervous System:

the thoraco-lumbar division of the autonomic nervous system.

Salivary glands

Paravertebral sympathetic ganglia (chain ganglia) Spinal nerves Splancnic nerves Gall bladder Spleen Pancreas Liver Stomach

Prevertebral sympathetic ganglia (e.g., superior mesenteric ganglia, inferior mesenteric ganglia, celiac ganglia, etc. close to the wall of the gi tract)

Sympathetic preganglionic fiber Sympathetic postganglionic fiber

Small intestine

Colon Rectum

 Sympathetic preganglionic fibers leave the spinal cord through spinal nerves (T1 to L2) These axons enter the nearest sympathetic paravertebral ganglion and have one of three fates: 1. Synapse on a postganglionic neuron within the paravertebral ganglion at the same level 2. Travel up or down a few segments to synapse on a postganglionic neuron within a paravertebral ganglion In the above cases, the postganglionic sympathetic neuron exits the paravertebral chain ganglia to innervate a target tissue. 3. Pass thru the paravertebral ganglion to synapse on a postganglionic neuron within a prevertebral ganglion; The postganglionic neuron exits to innervate an ENS neuron.

Salivary glands Preganglionic sympathetic neurons Preganglionic neuronal cell bodies in spinal cord intermediolateral cell column (T1-L2) Preganglionic nerve fibers enter paravertebral (i.e., beside the vertebra) sympathetic chain ganglia to synapse on postganglionic neurons Postganglionic sympathetic neurons Postganglionic neuronal cell bodies within paravertebral sympathetic chain ganglia

Superior cervical ganglion Postganglionic fibers ascend the paravertebral sympathetic chain ganglia to the superior cervical ganglia and exit to innervate the salivary glands Alter salivary gland secretion and blood flow

1
Paravertebral ganglia

Paravertebral ganglia

Prevertebral ganglia

Esophagus through Entire Colon, Liver, Gallbladder, and Pancreas Preganglionic sympathetic neurons Neuronal cell bodies in spinal cord intermediolateral cell column (T1-L2) Preganglionic nerve fibers pass through paravertebral sympathetic chain ganglia without synapsing and project to prevertebral sympathetic ganglia near the GI tract where they synapse on postganglionic neuronal cell bodies. Postganglionic sympathetic neurons 3 Neuronal cell bodies in outlying prevertebral sympathetic ganglia (e.g., superior mesenteric, inferior mesenteric, and celiac ganglia) Postganglionic sympathetic fibers project to ENS interneurons Alter neuronal activity within the ENS Alter secretion, motility, and absorption, etc.

Spinal cord (T1-L2)

Sympathetic pre-ganglionic neuron

Dorsal root ganglion

Sympathetic paravertebral ganglion

Sympathetic post-ganglionic neuron

Sympathetic prevertebral ganglion Spinal Visceral Afferent Neurons (EPANs) Neural input to the sympathetic postganglionic neuron within the prevertebral sympathetic ganglia: a) Sympathetic preganglionic fiber from the spinal cord

ENS intestinofugal neuron

b) Collateral fiber from spinal visceral afferent neuron c) Collateral fiber from ENS intestinofugal neuron

Neural reflexes possible at three levels:

1) 2) Short-loop (Intrinsic) reflex All elements within the ENS. Long-loop (Extrinsic) reflex Afferent: spinal visceral, vagal, and pelvic nerves Convergence of sensory input, processing, integration: spinal cord, brainstem, midbrain, hypothalamus Efferent: sympathetic or parasympathetic Intermediate loop (prevertebral ganglionic) reflex Collateral sensory fibers from sensory ENS intestinofugal neurons and spinal visceral afferents to prevertebral ganglia modify efferent sympathetic neural traffic.

3)

*There is redundancy!!

Central Nervous System

Extrinic Primary Afferent Neurons (sensory)

Interneurons Integrative Circuitry

THE BRAIN-GUT AXIS

Short-Loop (ENS) and Long-Loop (CNS) Neural Reflexive Pathways

Motor Programs

Autonomic Nervous System

EPAN Receptor Parasym pathetic Neurons Sympathetic Neurons

Enteroendocrine cells Chemical signal

Enteric Nervous System Interneurons Integrative Circuitry Intrinsic Primary Afferent Neurons (sensory IPANs)

EFFECTORS Interstitial Cells of Cajal Smooth muscle Epithelial cells Vasculature Enteroendocrine cells Immune cells

IPAN Receptor

Secretomotor Motor Vasomotor Neurons Excitatory

Motor Programs

Inhibitory

Gastrointestinal Paracrine Substances and Hormones:

When stimulated appropriately, enteroendocrine cells in the mucosa release paracrine substances into the lamina propria and hormones into the blood. GI paracrine substances and hormones influence

Secretion
Motility

Endocrine/Paracrine Regulation of Gastrointestinal Function

GI tract is the largest endocrine organ
Mucosal endocrine cells Mucosal paracrine cells ENS neurons Immune cells -- peptide hormones -- paracrine peptides -- neurocrine peptides

GI tract is the largest immune organ

-- paracrine peptides -- histamine -- prostaglandins -- etc.

Endocrine/paracrine regulators of gi function operate in concert with neural regulation.

Endocrine/Paracrine Regulation of Gastrointestinal Function

GI tract as a paracrine organ
GI paracrine cells are similar to endocrine cells
Paracrine substances are secreted into interstitial space in response to appropriate stimuli. Paracrine substances diffuse to local target cells IPANs and EPANs Absorptive cells Other endocrine cells ENS cells Secretory cells Paracrine cells Immune cells Etc.

Example: Gastric D cells release somatostatin (SS), a paracrine peptide, that inhibits acid secretion by nearby gastric parietal cells.

Endocrine/Paracrine Regulation of Gastrointestinal Function

GI tract as an endocrine organ
GI endocrine cells
GI hormones are secreted into blood in response to an appropriate stimulus. GI hormones act at distant target cells Absorptive cells Other endocrine cells IPANs and EPANs ENS cells Secretory cells Paracrine cells Immune cells Etc.

Example: Secretin, a hormone released into the blood by the small intestine, stimulates gastric D cells to release SS that inhibits acid secretion by gastric parietal cells.

Endocrine/Paracrine Regulation of Gastrointestinal Function

GI tract as an immune organ
GI immune cells
Release paracrine substances into interstitial space in response to appropriate stimuli. bacterial antigenic proteins cytokines histamine peptides prostaglandins Paracrine substances released from immune cells diffuse to local target cells Absorptive cells Endocrine cells IPANs and EPANs ENS cells Secretory cells Paracrine cells Other immune cells Etc.

Control of GI Functions
Non-immunological Defenses Immunological Defenses Digestion Secretion Absorption Motility Excretion

The functions of the gi tract are controlled by a dynamic interplay between different cell types that interact directly, or through a large number of signaling molecules to form reflex arcs.

Reflex Arc
Presence of stimulus Afferent Input

Processing and Integration

Response Efferent Secreto-Motor Output

Types of reflex arcs controlling GI Functions 1) Nervous 2) Endocrine 3) Paracrine 4) Immune