The Integrated Gut from mouth to anus

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The Integrated Gut(from mouth to anus)

• Jim Pierce
• Bi 145b
• Lecture 10, 2008-9

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Gut Function

• Organisms gastrulate to make a gut
• The gut exists
• To take in nutrients
• To excrete wastes
• We understand the locoregional function
• Lets talk about global function

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Gut Function

• The brain is nothing more than
• An overgrown ganglion
• Near the Mouth
• That decides what gets swallowed
• The decision making process for eatingis beyond
  the scope of this class
• We will talk about nutrition and neurohormonal
  nutritional axes during integration lectures

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Gut Function

• Once food is available
• The somatic nervous system allows us to
  consciously control the act of eating.
• From the planning of eating on, the gut must
• Feedforward (in the segments of gut ahead)
• Feedback (in the segments of gut behind)

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Gut Function

• Mechanisms of Feedforward
• Cell to Cell (Single Unit Smooth Muscle)
• Enteric Nervous System
• Parasympathetic input (Vagus Nerve)
• Sympathetic input (Splanchnic Nerves)
• GI and Neuro Hormones

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Gut Function

• Mechanisms of Feedforward
• Locoregional
• Cell to Cell (Single Unit Smooth Muscle)
• Enteric Nervous System
• Global
• Parasympathetic input (Vagus Nerve)
• Sympathetic input (Splanchnic Nerves)
• GI and Neuro Hormones

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Gut Function

• Mechanisms of Feedback
• Enteric Nervous System
• Parasympathetic (Vagus Nerve)
• 90 sensory / afferent fibers
• 10 effector / efferent fibers
• GI and Neuro Hormones

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Gut Function

• Mechanisms of Feedback
• Locoregional
• Enteric Nervous System
• Global
• Parasympathetic input (Vagus Nerve)
• GI and Neuro Hormones

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Enteric Nervous System

• Parasympathetic Input
• Primarily Cholinergic Neurons
• Sympathetic Input
• Primarily Adrenergic Neurons
• Underlying ENS
• Primarily NANC (non-adrenergic non cholinergic)
  neurons
• Exitatory Substance P
• Inhibitory Vasoactive Intestinal Peptide

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Substance P

• Substance P is an 11 amino acid polypeptide
• CNS Effects include pain modulation
• Gut Effects of administration include Nausea and
  Pain
• Inhibitor Substance P antagonist (SPA) (aka
  aprepitant) is available in the market in the
  treatment of chemotherapy-induced nausea /
  emesis.

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Substance P
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Vasoactive Intestinal Polypeptide

• Source Made by many different cells throughout
  gut, pancreas, and peripheral nerves
• Main Role Rest and Digest
• Effects
• Vasodilation
• Smooth muscle relaxation
• Increase water and electrolyte secretion by gut
• Stimulated by intragastric fat and vagus nerve

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Vasoactive Intestinal Peptide
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Gut Hormones

• Gut Hormones
• Provide autocrine, paracrine, endocrine signals
  for feedforward and feedback regulation and
  control.
• Provide a level of computation to modulate gut
  function.
• Allow integration with body neurohormonal state.

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Hormones involved in Gut Function
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Eating

• Eating consists of
• The Cephalic Phase(Brain prepares gutvia Vagus
  Nerve)
• Transitioning gutfrom SOMATICto
  AUTONOMICcontrol

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Feed Forward from the Mouth
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Swallowing

• Transitioning from somatic to autonomicinvolves
  the pharynx swallowing reflex.
• Proximal Pharynx is Skeletal Muscle
• Distal Pharynx is Smooth Muscle
• Middle Pharynx is a transition from Skeletal to
  Smooth

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Swallowing

• A midlevel somatic signalstimulates tongue,
  mouth, and pharynx contraction to pushthe food
  bolus into the pharynx.
• This signal also relaxesthe upper and
  loweresophageal sphincters
• This signal also initiatespharyngeal and
  esophagealperistalsis

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Swallowing

• Neural Feedback from the pharynx and esophagus
  initiate swallows to clear leftovers
• Neural Feedback from the Larynx and
  Tracheainitiate cough to clearthe airway
• Locoregional Feedback (reflexes) in the
  esophagusensure esophageal stripping

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Stomach Function

• Stomach indicates to the CNSFullness via Vagus
  nerve
• Gut indicates to the CNSFullness via GI
  Hormones
• Body indicates to the CNSMetabolic State via
  Hormonal Axes
• Well talk more about these decisionsduring
  endocrine system

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Stomach Function

• The whole purpose of the stomach reservoir is to
  convert BOLUS feedingsinto CONTINUOUS feedings.
• To understand all the feedback that goes on,
  lets introduce the GI Hormones

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Hormones involved in Gut Function
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Proximal Stomach

• Proximal Stomach Hormones
• Several Neurotransmitters (especially Seritonin)
• Ghrelin Hot New Hormone
• Likely to be more

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Ghrelin

• Source produced in proximal stomach
• Main Role initially identified as a Growth
  hormone releasing hormone
• Integrates proximal stomach stateinto total body
  metabolic phenotype.
• Not much is known its the new guy

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Ghrelin

• Green is Peptide Backbone

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Leptin

• Source produced by fat cells (not gut)
• Main Role complete the neurohormonal fat axis
  give feedback about fat state to the rest of the
  body
• It circulates at levels proportional to body fat.
  
• It enters the central nervous system (CNS) in
  proportion to its plasma concentration.
• Its receptors are found in brain neurons involved
  in regulating energy intake and expenditure.

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Leptin
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Proximal Stomach

• Goal of Proximal Stomach Hormones
• Integrate the stomach into the bodysmaster
  metabolic plan.

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Distal Stomach

• Distal Stomach (Antrum) is part of thesecond gut
  MVR
• We will find several hormones produced both at
  the distal stomach as well as duodenum and
  pancreas

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Distal Stomach

• Main Distal Stomach GI Hormones
• Gastrin
• Somatostatin

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Gastrin

• Sources Distal Stomach G-cells and Pancreatic
  Islet D-Cells
• Main Role Stimulates proximal stomach secretion
• Growth Role Long term growth hormone for
  intenstinal mucosa
• Functional Roles
• Stimulates parietal cells to secrete acid
• Stimulates chief cells to secrete pepsinogen
• Augments gastric mucosal flow by vascular dilation

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Gastrin

• Gastrin Secretion from G-Cells
• Stimulated by
• Antral Amino Acids oligopeptides
• Antral Calcium or Alchohols
• Antral pH gt 3
• Vagus Nerve
• Inhibited by Antral pH lt 1.5

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Gastrin
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Somatostatin

• Produced in small amounts by Stomach and in
  larger amounts by Pancreatic D cells
• Main Role Globally inhibits GI function
• Keeps the activation by Gut hormones under
  control

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Somatostatin

• Somatostatin Secretion
• Stimulated by All kinds of food
• Inhibited by nothing yet identified
• Clinical Uses Turning down gut secretion and
  controlling gut bleeding (reduces blood flow)
• Disease (too much) Inability to secrete
  wellleads to steatorrhea, gallstones, weight
  loss.

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Somatostatin
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Duodenum

• Duodenal Hormone Secretion
• Secretin
• Cholecystokinin
• Motilin
• Gastric Inhibitory Peptide

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Secretin

• Source Argyrophil S-cells in duodenum
• Major role Increases secretion from pancreas
  (particularly bicarbonate)
• Minor roles
• Increase bile flow
• Decrease stomach acid by decreasing gastrin
  release
• Inhibit gastric emptying

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Secretin

• Secretin Secretion
• Stimulated by
• Acid
• Fats and Lipids in the Duo
• Bile salts
• Inhibited by high pH in the Duo

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Secretin
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Cholecystokinin

• Source I-cells of the duodenum and proximal
  jejunum
• Main Role Aids in fat processing by increasing
  bile secretion
• Growth Role Trophic factor for Pancreas and
  Gallbladder
• Targets Gallbladder, Pancreas, Sphincter of Oddi

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Cholecystokinin

• Functions
• Squeeze Gallbladder
• Relax Sphincter of Oddi
• Increase pancreatic secretion
• Increase intestine motility, decrease gastric
  emptying
• Trophic factor on pancreas and gallbladder mucosa
• Secretion stimulated by
• Duodenal Fat (long chain FA and micelles)
• Duodenal Amino Acids (tryptophan phenylalanine)
• Secretion inhibited by trypsin, chymotrypsin

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Cholecystokinin
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CCK and Secretin

• Compare and Contrast
• Both cause bile and pancreatic juice secretion
• CCK increases Liver gt Pancreas
• Secretin increases Pancreas gt Liver

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Motilin

• Source Cells throughout gut, highest in duodenum
  and proximal jejunum
• Main Role Initiates MMC and increases
  interdigestive gut motility
• Transitions from postprandial to fasting

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Motilin

• Motilin secretion stimulated by
• Duodenal acid and food
• Vagus Nerve
• Gastrin Releasing Peptide
• Inhibited by
• Somatostatin
• Secretin / CCK
• Pancreatic polypeptide
• Duodenal fat

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Motilin
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Gastric Inhibitory Peptide

• AKA Glucose-dependent insulinotropic polypeptide
• Source K-cells of Duodenal glands
• Targets Pancreatic islets, Proximal Stomach
• Main Role Inhibits Gastric Secretion
• Secondary Roles
• Enhances insulin effects
• Trophic Factor for Beta Cells

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Gastric Inhibitory Peptide

• Gastric Inhibitory Peptide secretion
  isstimulated by
• Duodenal Presence of
• Amino Acids
• Glucose
• Long chain Fatty Acids
• Hyperglycemia

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Endocrine Pancreas

• The majority of the pancreasis a secretory
  exocrine gland
• A minority of the pancreas isan secretory
  endocrine gland
• These collections of endocrine cellsare called
  the Islets of Langerhans

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Endocrine Pancreas
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Endocrine Pancreas

• Islets contain
• Alpha Cells - Glucagon (15-20)
• Beta Cells - Insulin (65-80)
• Delta Cells - Somatostatin (3-10)
• PP Cells - Pancreatic Polypeptide (lt 1)
• Epsilon Cells Ghrelin? (lt0.5)

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Alpha Cells - Glucagon
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Beta Cells - Insulin
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Delta Cells - Somatostatin
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Glucagon

• Sources
• Stomach Gastric Glucagon
• Intestines Enteroglucagon
• Primarily from Alpha cells of islets Glucagon
• Main Role Energy Utilization
• Targets Liver and Adipose Tissue, Gut
• (these effects will be covered in endocrine)
• Starts as preprogluagon (180 AA)
• Can become glicentin, glucagon, GLP1,2

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Glucagon

• Functional Liver and Adipose Roles
• Increases hepatic glycogenolysis
• Increases hepatic gluconeogenesis
• Increases hepatic mobilization of glucose
• Increases lipolysis
• Increases ketogenesis
• All produce energy for cellular use

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Glucagon

• Functional Roles in the Gut
• Inhibits gastric acid, pancreatic secretion
• Relaxes stomach and duodenum
• Increases intestinal motility
• Clinical use slows stomach / duodenum / ampulla
  emptying for GI radiology

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Glucagon

• Secretion of Glucagon is stimulated by
• Hypoglycemia
• Elevated serum AA
• Acetyl-choline,
• Gastrin inhibiting peptide
• Gastrin releasing peptide
• It is inhibited by
• Hyperglycemia
• Insulin
• Somatostatin
• Alpha adrenergic stimuli
• GLP-1

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Glucagon
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Insulin

• Well discuss insulin more duringendocrine
  physiology and nutrition
• Source Beta Cells of the Pancreas
• Role 70 Growth Hormone 30 Acute Metabolism

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Pancreatic Polypeptide

• Source PP Islet cells of pancreas
• Main Role Indicates Switch from Gastricto
  Intestinal Phase of Gut Function
• Functional Roles
• Pancreas Decreases Bicarb and Water secretion
• Gallbladder Inhibits contraction
• Intestine Changes from Fasting to Postprandial
  pattern
• Stimulated by Food, Vagus, GI hormones like
  CCK and Secretin

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PP and Motilin

• Compare and Contrast
• Both work proximally to changethe motor pattern
  of intestinal function
• Motilin changes from postprandial to fasting
  patterns
• PP changes from fasting to postprandial patterns

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Peptide YY

• Source Cells in distal ileum, colon, rectum
• Main Role Ileal Brake (For Gastric Emptying)
• Effects
• Inhibits gastric emptying
• Inhibits gastrin stimulated acid secretion
• Inhibits cck-stimulated pancreatic secretion
• Stimulated by intraluminal fat

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Neurotensin

• Source N Cells in distal small intestine
• Main Role Ileal Brake (for Absorption)
• Effects
• Inhibits gastrin mediated gastric acid secretion
• Stimulates pancreatic secretion
• Inhibits intestinal motility
• Triggers mesenteric vasodilation
• Stimulated by luminal fat

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Bombesin

• Source Bombina bombina a european tree frogs
  skin
• Similar structure to gastrin releasing peptide
• Function
• Stimulates release of most GI hormones
• Increases secretion in gut
• Increases motility
• Lick frog get diarrhea

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Bombesin
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Gut Neurohormone Pairs

• ENS
• Adrenergic Neurons, Cholinergic Neurons
• Substance P Neurons, VIP Neurons
• Proximal
• Gastrin, Somatostatin
• GIP, GRF
• CCK, Secretin
• Motilin, Pancreatic Polypeptide
• Distal
• Peptide YY, Neurotensin

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Gut Function

• Weve met the neurohormones.
• Weve eaten some food.
• What happens next?

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Stomach

• Have we secreted and mixed enough?

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Duodenum

• How much secretions do we need?

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Small Intestine

• Which motor pattern do we need?

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Colon

• Have we absorbed enough water?

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Questions?