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  • Check out Soon's notes
  • New slides are different to last year's
  • Today we're talking about gastrointestinal motility, which allows mixing and propulsion of GIT contents, to absorb nutrients and excrete wastes. This is highly regulated.

Summary

  • Optimal time of exposure to various segments of the GI tract is essential for effective digestion and absorption.
  • Motility provides both mixing and propulsion.
  • GIT function is highly regulated by neural, hormonal, local chemical and physical factors.

Swallowing is complex

The anatomy of swallowing
  • Involves voluntary and involuntary phases as well as sharing of the upper airways.
  • Achalasia - difficulty in swallowing
  • Chagas disease - later symptoms include swallowing difficulties
    • Caused by the Trypanosoma cruzi parasite in South Amterica
    • Some destruction of enteric neurons
    • Note the anatomy

Phases of swallowing

  • Voluntary phase ‐ food moved by the tongue pushing upwards and backwards towards pharynx.
  • Involuntary phase
    • Pharyngeal ‐ mechanoreceptors initiate closure of the trachea, relaxation of the UES, and initiation of a primary peristaltic wave. Involves swallowing centre in medulla and several cranial nerves (vagus, trigeminal and glossopharyngeal).
    • Oesophageal ‐ Conduction of food to the stomach is assisted by gravity, primary and secondary peristaltic waves, opening of the LES and receptive relaxation of the stomach. All of this involves local enteric neural reflexes and extrinsic parasympathetic reflexes.

UES/LES: Upper and Lower oesophageal sphincter

  • Upper 1/3 of the oesophagus is skeletal muscle, then there is a transitional area between skeletal and smooth and then the bottom is smooth muscle

Swallowing - step by step

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  • See diagram
  • Gastrooesophageal reflux disease (GORD)
    • Stomach is meant to relax and the pyloric sphincter is meant to open and let the food come in
    • This is controlled by the enteric nervous system - the sphincter is meant to close again properly so that when the stomach contracts, there is no acid reflux
    • Normally: 1-2 times an hour, there is a neuronal firing out of sequence so the acid from the stomach gets into the bottom of the oesophagus (which is a little more hardy than the rest of the oesophagus)
    • In a person with GORD, this may instead occur 5-6 times per hour

Peristalsis

  • Pinch tube at the oral end, dilate at anal end, push this structure, along with the food bolus, downwards

Swallowing as studied by oesophageal manometery

2BGDBPhysiology3.png

Motor functions of the stomach

  • At least 4 events can be identified in the process of gastric filling and emptying:
  1. Accommodation: Receiving and providing temporary storage of food and liquids (without undue increase in pressure).
  2. Mixing of food and liquid with gastric secretory products including pepsin and acid.
  3. Grinding of food to reduce particle size to enhance digestion and permit passage through the pylorus.
  4. Regulating the exit of material from the stomach into the duodenum.

NB:

  • Accommodation occurs via vagal stimulation of the stomach (cutting the vagus nerve stops the stomach expanding -- weight loss)
  • Grinding occurs when you pinch the anal end and dilate the top - keeps squishing up the food
  • Duodenum doesn't like food much, get nauseous very quickly, because the duodenum can't hand a high concentration of nutrients. A surgery for bypassing the stomach will allow people to only eat very small meals. This is a very effective weight-loss strategy.

Neurally-mediated relaxation of (upper) stomach

Neurally-mediated relaxation of (upper) stomach - this response is absence in the case of vagotomy
  • Accommodation: food volume increases without pressure increases
  • Depends on parasympathetic input to enteric nerves
  • Vagotomy was used as a weight loss strategy

If you perform a vagotomy, then the stomach does not expand in volume, so gastric pressure increases rapidly, and you feel full quicker.

Pyloric region of the stomach

Pyloric region of the stomach contributes to the mechanical reduction of particle size and mixing
  • Contributes to the mechanical reduction of particle size and mixing
  • Movements have three stages
  • Altogether this is called the "pyloric pump"
  • When a chunk of food reaches the pylorus, the pyloric sphincter will squeeze shut tight. Then peristaltic contractions will only squeeze against the pyloric sphincter, grinding it up.

Regulation of gastric emptying

2BGDBPhysiology6.png

  • Most things inhibit gastric emptying
    • Almost anything in the duodenum will stop the stomach releasing
  • Things stimulating gastric emptying include gastric volume/pressure
  • Gastrin released by the stomach doesn't have a net effect on emptying (it decreases motility but also makes the gastric contents more liquid)

Content of meal influences rate of gastric emptying

2BGDBPhysiology7.png

The rate is greater if:

  • Liquid>solid
  • Non-nutrient>nutrient
  • CHO>protein>fat
  • Neutral>acid

Motor functions of the small intestine

  • Optimal time of exposure to various segments of the GI tract is essential for effective digestion and absorption.
  • Motility provides both mixing and propulsion.
  • GIT function is highly regulated by neural, hormonal, local chemical and physical factors

Structure of the GIT

2BGDBPhysiology8.png

  • A very nice picture that shows a cross section of the small intestine - important to learn this
  • Modern names of nerve layers = submucosal/myenteric. Old names: Meissner's/Auerbach's

Musculature of the GIT

  • The GI tract is predominately smooth muscle
  • Exceptions are:
    • Upper third of the esophagus
      • including upper esophageal sphincter
    • External anal sphincter
    • These are composed of skeletal muscle

Smooth muscle is electrically active

2BGDBPhysiology9.png

  • Smooth muscle shows continual oscillations in membrane potential called "slow waves".
    • Frequency decreases down the intestine:
      • 3/s in stomach;
      • 12/s in duodenum; 8/s in ileum; 3/s in colon
      • Thus, there is a gradient from the top of the small intestine to the large intestine.
    • Periodically the slow waves give rise to "spike potentials"
      • These are slow Ca++ mediated action potentials (APs).
    • This increases cytoplasmic Ca++ and gives rise to smooth muscle contraction

Smooth muscle in the gut is a little bit electrically active on its own (like cardiac active) - we call these "slow waves". However, this baseline stimulation is virtually irrelevant when neural control is applied. Calcium is still the signal for this contraction (like with skeletal muscle), but there are different molecular mechanisms

Smooth muscle electrical oscillations

  • Where there's a spike there is a contraction
  • You can stimulate it to the point where it no longer does anything
  • Hyperpolarisation --> less likely to contract (due to some hormones)

Generation of slow waves by ICC

  • Interstitial cells of Cajal (ICC)
    • Contained within the smooth muscle layers.
    • Derived from mesenchymal cells.
    • Some ICC act as electrical pacemakers.
  • Contain specialized ion channels that underlie slow wave activity.
    • Others ICC transfer excitability to the smooth muscle cells.
      • Act through gap junctions.
      • Spread the excitation more widely
  • Interstitial cells of Cajal act as both pacemakers and also transfer excitability to nearby smooth muscle cells (so that enteric nervous system can stimulate just one ICC, and it spreads the excitation throughout the smooth muscle

Interstitial cells of Cajal (ICC)

ICCs are unique and distinct cell types in the gut, morphologically intercalated between nerves and smooth muscle cells

  • Two classes of ICC networks:
  1. Intramuscular ICC
    • Spindle shaped. Scattered throughout circular and longitudinal muscle layers.
    • Closely associated with nerve fibers.
    • Spreads excitation from ENS to SMC.
  2. Myenteric plexus ICC
    • Triangular or irregularly shaped, multiple processes forming branching networks between longitudinal and circular muscle layers.
    • Pacemaker generators

Tonic contractions

  • Suited to the function of sphincters
  • Underlying electrical activity can be either:
    • repetitive spike potentials
    • sustained depolarization
    • "latching"
  • May need inhibitory transmission (ATP, NO, VIP) to relax some smooth muscle

If you turn off skeletal muscle (don't activate it), it goes limp. However, smooth muscle can stay constricted even after you stop stimulating it. Therefore the enteric nervous system includes nerves to both excite and relax smooth muscle. But this is handy for sphincters (you can tell them to constrict and they'll stay this way for a long time)

Ileocaecal sphincter controls movement of chyme from small to large intestines

2BGDBPhysiology10.png

  • Large intestine is to the left, SI to the right
  • There is a valve between LI and SI -- we don't want LI bacteria to regurgitate back into the ileum
    • This acts very similarly to the internal anal sphincter or lower oesophageal sphincter
  • Irritation --> causes it to close. Fluidity --> causes it to open

Peristalsis

  • Peristalsis: a wave‐like movement of muscles in the GI tract, characterized by the alternate contraction and relaxation of the muscles that propel the contents downward.
  • Peristalsis is mediated by the local, intrinsic enteric nerves (ENS) as it is not affected by vagotomy or sympathetectomy.
  • Peristalsis moves contents down the GIT
  • Occurs in oesophagus, stomach and all the way through the SI and LI. It is a wave-like movement. It is a complex motor pattern. It is mediated by the vagus and sympathetic nervous system, but it operates without either or both of them.

Peristaltic contractions come in many forms

  • Peristaltic contractions generally only travel small distances
  • Peristaltic bursts can happen over short bursts and go over short or long distances, it's sometimes highly irregular. Can go in all different patterns.

Segmentation contractions

  • Segmentation contraction: a non‐propulsive mixing motility seen especially in the small intestine
  • Segmental rings of contraction chop and mix the ingested materials to enhance digestion.
  • Segmentation mixes contents!
  • This is for mixing. There may be segmentation in an area, then peristalsis to move the contents to the next area, then more segmentation etc

Fasting patterns of motility: MMC

MMCs
  • Migrating motility complex (MMC): a contractile wave periodically moving down the GI tract from the mid‐stomach to ileum.
  • Housekeeper function.
  • Associated with increased levels of the intestinal hormone motilin.
  • Only seen during fasting: Interrupted by feeding
  • After not eating for 6 hours, the GIT performs housekeeping contractions, to clean out epithelium and other debris, and this is associated with the hormone motilin.
  • As soon as you start to eat, this stops almost instantaneously when you start eating

MMCs

  • Can see the contractions moving down the gut when fasting, but then feeding interrupts the MMCs

Functional bowel disorders

  • For example, Irritable Bowel Syndrome (IBS), slow transit constipation, gastroparesis and gastrooesophageal reflux disease (GORD)
  • Characterised by a lack of histological defect, therefore 'functional'
    • So what's the basis?
  • The innervation of the GIT is likely to be the answer ...
  • Diabetic gastroparesis - because high levels of glucose damage the nerves of the stomach (just like peripheral neuropathy) - paralyze gut
  • However, functional bowel disorders, the histology of the nerves looks fine, it's just based on how the nerves are programmed and behave
  • Reflux is probably a problem of the enteric nerves (controlling the peristaltic waves)
  • There is no histological reason for the defect

The enteric nervous system (ENS)

  • Complex network of neurons
    • located in the gut wall from the oesophagus to the anus
  • Two nerve plexuses
    • Myenteric plexus (Auerbach's)
      • motor and integrative functions
    • Submucosal plexus (Meissner's)
      • secretion, vasodilation
  • Controls moment‐to‐moment motility and secretion of the GIT
  • Secretion and dilation occur together - if you want to secrete something, you need vasodilation so there is blood for the secretions to be carried away in

Three divisions of the ANS innervate the GIT

2BGDBPhysiology13.png

  1. Parasympathetic
  2. Sympathetic
  3. Enteric (sticks to itself in the GIT, doesn't affect the body too much)
    • Inhibited by sympathetic
    • Activated by parasympathetic
  • The gut, unlike other organs, has it's own nervous system (intrinsic to itself)

The ENS is part of the autonomic nervous system

  • Third division of the ANS
    • with the sympathetic and parasympathetic
    • as defined by Langley in the early 1900's
  • Has all neurons for a reflex arc
  • As many neurons as spinal cord!
    • 10^9 enteric neurons in humans
    • that's 1,000,000,000
    • a billion (or a 1000‐million)


  • Enteric NS: there are just reflex arcs - sensory neurons --> interneurons --> effector neurons
  • There are about as many neurons as in the spinal cord, but a lot of them are repetitive (because we have to repeat the same activities the whole way down)

Types of GIT innervation

  • Intrinsic to the GIT
    • ENS ‐ Enteric nervous system
    • Contains sensory neurons, interneurons and motor neurons
    • Mostly independent
  • Extrinsic to the GIT
    • Afferent (vagal and DRG)
    • Efferent (sympathetic, parasympathetic)
    • May interface though the ENS
    • Receives information from the ENS


  • Intrinsic
  • Extrinsic
    • Efferent - from CNS to gut
    • Afferent - from gut to CNS (vagal and DRG)
      • E.g. feeling of fullness
      • Colon - don't feel peristaltic waves etc
  • Diabetic neuropathy - the sensory nerves in the area release substance P and other substances to help dilate blood vessels and assist healing (point = afferent nerves can have efferent branches that participate in local reflexes)
  • Enteric nervous system can shortcut sometimes, by sending efferent signals from the end of the gut up through the sympathetic ganglion back to the top of the gut (rather than going through 8-9m of enteric NS).

Enteric nervous system (ENS)

2BGDBPhysiology14.png

Myenteric ganglia form a 2d plexus

2BGDBPhysiology15.png

  • There are ganglia that run in a plane, then have neurons passing between them to share fibres

Three types of enteric neuron

Three types of enteric neuron. SMP-Meissners plexus; MP-Auerbachs plexus
  • Intrinsic sensory neurons
    • Also called IPANs (Intrinsic primary afferent neurons)
    • Found in the MP and SMP
  • Interneurons
    • Descending and ascending the GIT
    • Mainly in the MP
  • Motor neurons
    • Inhibitory and Excitatory (relaxation/contraction)
    • Circular and Longitudinal Muscle (found in the MP)
    • Blood vessels and Enterocytes (found in the SMP)

Intrinsic = within the GIT (not from the CNS)

Enteric sensory neurons

Enteric sensory neuron
  • Sensory neurons receive information from sensory receptors in the mucosa and muscle
    • Sensory receptors in mucosa respond to mechanical, thermal, osmotic and chemical stimuli
    • Sensory receptors in muscle respond to stretch and tension
    • Neurotransmitters:
      • Fast: ACh (nicotinic)
      • Slow: ACh (muscarinic), Tachykinins (e.g. substance P)

Enteric interneurons

Enteric interneuron
  • Interneurons are responsible for integrating information from sensory neurons and providing it to enteric motor neurons - "programming"
    • Types: Ascending (oral) and descending (anal)
    • Neurotransmitters:
      • Fast: ACh, 5-HT, ATP (ionotropic)
      • Slow: Tachykinins, ACh, 5-HT, ATP (metabotropic)

The gut can "learn" to work in the opposite direction: if you cut some out and invert it and put it back in, it will operate in the opposite direction after a few weeks of being "unhappy".

Enteric motor neurons

Enteric motor neuron
  • Motor neurons control motility and secretion by acting directly on effector cells (smooth muscle, secretory cells and endocrine cells)
    • Excitatory motor neurons
      • Contraction/vasoconstriction/secretion
    • Inhibitory motor neurons
      • Relaxation
      • Vasodilation

Neuromuscular transmission in the GIT

  • Excitatory
    • Acetylcholine (ACh) - Muscarinic receptors
    • Substance P (SP) - Neurokinin (NK) receptors
  • Inhibitory
    • ATP
      • Fast action
    • Nitric oxide (NO)
      • Medium action
    • Vasoactive intestinal peptide (VIP)
      • Slow action

Nitric oxide is produced by nitric oxide synthase, and it causes vasodilation and gut dilation

Neuromuscular transmission and the peristaltic reflex

2BGDBPhysiology20.png

  • Distension activates myenteric plexus sensory neurons which activate reflexes causing a wave of relaxation then contraction

Enteric neurons form circuits

2BGDBPhysiology21.png

  • This circuit is repeated every centimetre, so there is a high density of nervous tissue is present per area in the gut
  • Enteric neurons form circuits and nerve circuits underlie enteric reflexes

Objectives

  • Understand the main motility patterns present in the esophagus, stomach, small intestine and large intestine.
  • Understand the sequence of events that allow voluntary and involuntary control of swallowing.
  • Appreciate that gut motility is controlled by the ENS and modulated by sympathetic and parasympathetic nerves.
  • Know the types of neuron in the ENS and the primary neurotransmitters used.
  • Understand that complex motor patterns are made of simpler reflexes which themselves are made of enteric neural circuits