Intercellular communication in the gut-endo, para, neuro

Question 1

Ways to communicate intercellularly in the gut

Answer 1

Neurocrine transmission:
-acetylcholine, nitric oxide, noradrenaline
Paracrine transmission:
-serotonin and histamine
Endocrine:
-Secretin
-Gastrin
-CCK (fat digestion, bile bladder movement)
-Incretins
-GLP-1
-Motilin
-Ghrelin

Question 2

Neurocrine transmission

Define &name the neurotransmitter

Answer 2

Neurocrine transmission is when nerve terminals release a transmitter onto a target cell or into the blood. Neurotransmitters are a type of neurocrine secretion. Many neurocrine transmitters are found in the gut. We have already come across the following:
- Acetylcholine (ACh), released onto muscarinic receptors, excites gut smooth muscle and stimulates secretion of many glands.
- Nitric oxide (NO) and vasoactive intestinal peptide (VIP) typically relax smooth muscle. VIP stimulates secretion.
- Noradrenaline, released by sympathetic neurons rather than neurons of the ENS itself, is typically inhibitory, but promotes contraction of sphincters and vascular smooth muscle. (facilitate in salivary reflex)

Question 3

Paracrine transmission

Answer 3

Paracrine transmission involves a locally-produced substance, diffusing through the extracellular fluid to work on neighbouring cells of a different cell type.
-Doesn’t travel in the blood

Examples?
Serotonin and histamine which do not travelled into the bloodstream

Question 4

Endocrine transmission – gastrointestinal hormones

Answer 4

They are all peptide hormones without binding proteins with a relatively short halflife.
-stimulate the secretion of acid (gastrin) and base (secretin)
-help remove fat (CCK- bile salt secretion from liver)
-help synthesis insulin (GIP and GLP-1)
-initiate migrating myoelectric complex (motilin)
-the only hormone to initiate hunger/appetite(ghrelin)

Endocrine transmitters (hormones) travel via the blood. Gastrointestinal hormones are all peptides, secreted by the enteroendocrine cells which are scattered throughout the gut epithelium. Most types have an apical membrane which is exposed to the gut lumen. Receptors on this membrane detect luminal conditions and stimulate hormone release in response to e.g. certain nutrient substances. It used to be thought that a particular enteroendocrine cell-type released a particular hormone, e.g. secretin from S cells. This classical description, found in the textbooks, is repeated below. However, recent work suggests that there is much more overlap than this: a given enteroendocrine cell may in fact secrete a variety of different hormones.

Question 5

Secretin

where, why

Answer 5

Secretin is secreted by S cells of the duodenum in response to the presence of acid. – It is a negative feedback pathway, it acts several different organs
-Key roles: stimulates pancreatic growth, bicarbonate and water secretion. Also: inhibits gastric acid secretion and motility; promotes constriction of the pyloric sphincter

The discovery of secretin (1902)

• HCl added to duodenum of a dog: pancreatic secretion increases.
• HCl added to denervated loop of jejunum (blood vessels intact): pancreatic secretion increases.
• Extract of mucosa of jejunum injected into jugular vein: pancreatic secretion increases.

Question 6

Gastrin

Answer 6

Gastrin is secreted by G cells of the gastric antrum and duodenum in response to nervous stimulation and the presence of peptides and amino acids. Its most important roles
Gastrin are to stimulate secretion by parietal cells, and to promote growth of the oxyntic mucosa.

Question 7

Help to remove those fat digested production

Answer 7

CCK: Bile-bladder-movement, ball bladder contraction

Question 8

Promote insulin release-Blood-glucose control

Answer 8

The incretins are GIP (glucose-dependent insulinotropic polypeptide) and** GLP-1** (glucagon-like peptide 1). GIP is secreted from K cells in the upper small intestine, GLP-1 from L cells in both small and large intestines.

Released following a meal, the incretins augment insulin release from the pancreas. GLP-1 agonists are used to treat type II diabetes, and are of increasing interest in treating obesity.

Question 9

Initiate the migrating myoelectric complex

Answer 9

Motilin is secreted cyclically during fasting by M cells in the upper small intestine; release is under neural control. Its only known action is to initiate the migrating myoelectric complex.

Question 10

The only hormone that stimulate appetite

Answer 10

Ghrelin is secreted by endocrine cells of the stomach in response to fasting. Although many GI hormones inhibit appetite, ghrelin is unusual in that it works on the hypothalamus to stimulate appetite. It also promotes growth hormone release from the pituitary gland.
Promotes appetite- the only hormone in humans,
While there are many gut hormones suppress appetite.

Question 11

Potentiation

Answer 11

An individual cell may have receptors for more than one type of chemical messenger, or different receptor subtypes for the same messenger. Potentiation is when the response of such a cell to a combination of messengers exceeds the sum of the responses to each messenger delivered individually. This reflects the activation of different intracellular pathways, all contributing to the same end.
To allow more responses making sure both are activated like information processing.

Think about the possible advantages of potentiation.
To get more secretion with the sum of both X and Y
-coincidence detection

Question 12

Saliva and salivation

Answer 12

The sublingual and submandibular glands produce a mixed mucous/serous secretion, the parotid glands only a serous secretion in most species. The major functions of saliva are as follows:
- Lubrication: glycoproteins called mucins are produced by mucus-secreting glands. Solution of food products facilitates taste, speech and swallowing.
TASTE, SPEECH, SWALLOWING
- Defence: lysozyme, lactoferrin and antibodies (IgA) are found in saliva. Proline-rich proteins bind to and neutralize the effects of plant tannins, in humans as well as herbivores.
- Buffering: bicarbonate ions raise the pH of saliva from slightly acidic at basal secretion levels to around 8 during active secretion.
- Digestion: salivary amylase (not present in cats, dogs or horses) breaks down starch to oligosaccharides. Although inhibited by low pH in the stomach, when protected inside a bolus of food activity can continue for up to half an hour, and it has time to digest up to 75% of the starch in a meal.
+ haptocorrin (pronouns similar to lactoferrin), haptocorrin protects the vitamin B12 from the acidity, and is secreted by the salivary gland.

Xerostomia refers to the sensation of oral dryness, which can result from diminished saliva production

What do lysozyme and lactoferrin do?
Immune system to engulf other Gram-positive bacteria and lactoferrin binds to iron in the mouth so bacteria cannot get iron

Question 13

Name the mechanisms that do exocrine secretion

Answer 13

Pancreatic acinar cells
Small intestinal crypts
Sweat glands
Lacrinal glands
Gills

Question 14

How to produce a diagram of a salivary..?

Answer 14

1)Draw a polarised epithelium
The acinus lumen and the ECF side.

2)The Na-K ATPase are usually at the basal side.
And the NKCC1 with the Na+ moving into the cells, which facilitate the transport of Cl- and K+
3) Then the Na+ is pumped out into the ECF while K+ is facilitated diffused out into the ECF on the basal side.
4) This generates a charge difference with a more negatively charged on the left and positively charged on the right.
5) This allows sodium and water to move across the junction to allow water to diffuse into the lumen.
6) We want NaCl in the lumen so that the water will flow.

Question 15

What would be the result of CFTR dysfunction in cystic fibrosis?

Answer 15

Pancreas will clog up with the fluid unable to come out
Constipation in the intestine
Maldigestion

Question 16

What would be the effect of overstimulation of the normal CFTR

Answer 16

Diarrheal
Vibrio cholerae will secret Cholera toxin which activate the chloride channels that will leads to diarrheal of up to 20L of water.

Question 17

Why would we want to exchange Na+ for K+/ Cl- for HCO3-?

Answer 17

Na+ is less abundant than K+
To keep Na+ levels in the mouth low? You can taste sodium better

For the buffering effect of HCO3-
To protect urself from vomiting, acid from the food.
Increased salivation to protect your tenth before vomiting.

Question 18

Vomiting will induce:

Answer 18

Dehydration
Metabolic alkalosis
Hypokalaemia,
Dental erosion
Hypovolemia (limited volume of blood)

Question 19

Salivation mechanism

Answer 19

The acinar cells produce the primary secretion, which is isotonic to plasma and is high in NaCl. The accumulation of NaCl in the acinar lumen draws water into the lumen by osmosis.

Acinar cells also secrete salivary enzymes and other proteins, by the process of exocytosis, and some are specialised to secrete mucus. Contraction of myoepithelial cells helps to empty the saliva into the ducts.

Myoepithelial cells contraction to help release the saliva

The primary secretion is modified by the duct cells; the saliva becomes more hypotonic as it proceeds through the ducts. Aldosterone promotes ion exchange in the salivary ducts, as in the kidney.

Question 20

Control of salivation is mediated almost entirely by the

Answer 20

Control of salivation is mediated almost entirely by the ANS. There is an anticipatory response to the prospect of food in the cephalic phase of digestion, and salivation is further promoted by e.g. chewing or acid in the mouth.
- Parasympathetic fibres secreting ACh and VIP promote vasodilatation and increase blood supply, metabolism and growth. PNS stimulation also causes contraction of the myoepithelial cells and, via ACh, opens more of the acinar cell channels, increasing the volume of saliva secreted.
- -Release muscarinic acetylcholine after nicotinic acetylcholine
- Sympathetic fibres can promote vasoconstriction, but not as part of the salivary reflex when dilatation dominates. SNS fibres promote myoepithelial cell contraction and, via cAMP, exocytosis, increasing protein content.
- -Release NA after nicotinic acetylcholine

There is some crossover between the cAMP (SNS) and Ca2+ (PNS) pathways within the acinar cells. Potentiation in e.g. amylase production has been observed in some experiments.

Question 21

Mastication (chewing)

Answer 21

-Mechanically breaks down food
-Increase surface area
-Swallow unmasticated food in cotton bag: majority of foods are incompletely digested

Question 22

Oesophagus

Answer 22

The interior of oesophagus is folded so opens only when food goes down by stretching.
Inner circular layer and outside longitudinal layer
Supported through skeletal muscle 2/3 ways down the oesophagus- somatic motor neuron used to deliver sequential contraction.
If there is a stroke, the oesophagus is not gonna contract normally.

Bottom 2/3 is smooth muscle meaning overlap in the middle. (dogs skeletal all the way)

Question 23

Swallowing

Answer 23

When a bolus of food is pushed towards the back of the mouth by the tongue, touch receptors in the pharynx initiate the swallowing (deglutition) reflex, coordinated in the swallowing centre in the medulla and lower pons. The respiratory centre of the medulla is directly inhibited by the swallowing centre for the very brief time that it takes to swallow: this is referred to as deglutition apnoea. The process of swallowing is very complicated, involving the fine control of multiple striated muscles in the pharyngeal region, with a view to preventing you from inhaling the food.
The upper oesophageal sphincter (UOS) consists of the striated cricopharyngeus muscle. The muscles of the longitudinal and circular layers of the upper third of the human oesophagus are striated, innervated by the vagus nerve. The middle third contains a mixture of smooth and striated muscle, while the muscle of the lower third is entirely smooth. Striated muscle tends to extend much further down the oesophagus in most domestic species.
-Keeps the oesophagus closed, the pressure drops to allow food goes in.
-As we move down the oesophagus, the food is propelled downwards, the smooth muscle facilitates without somatic motor neuron innervation.
A primary peristaltic wave begins just below the UOS and sweeps the bolus downwards at a rate of 3-5 cm sec-1. If the bolus fails to be moved all the way to the stomach, a secondary peristaltic wave is initiated by the persistent distension of the oesophagus. This is initiated partly by a local reflex and partly through a vagovagal reflex.
The lower oesophageal sphincter (LOS) is a region of specialized circular smooth muscle at the bottom of the oesophagus. It is controlled by ENS fibres, which as usual receive input from the ANS. Normally tonically contracted, the sphincter relaxes even before food has arrived, as part of a feed-forward vagal reflex. NO is believed to be the key ENS transmitter which promotes this relaxation.

-Prevent stomach acid to come up inducing heartburn.
-The oesophageal sphincter allows relaxation before the food comes down as a feedforward effect through vagus nerve using NO
Moving down the food first mediated by the skeletal muscle innervated by the extrinsic nerve, and then smooth muscle taking over, and intrinsically promoting a peristaltic contraction.
But the lower part also uses feedforward which is another type of intrinsic innervation.

Paralysis results in the tightly restricted oesophageal sphincter which results in birds beak in achalasia. The cause is unknown, but one is known with a reduviid bug containing Trypanosoma cruzi, one possible outcome is achalasia.
The LOS and the surrounding crural diaphragm are important in preventing the acid contents of the stomach from entering the oesophagus (gastro-oesophageal reflux leading to heartburn and possibly Barrett’s oesophagus). If the reflex relaxation of the sphincter is somehow compromised, as occurs in achalasia, there may be considerable difficulty in swallowing.
The oesophagus secretes only a small amount of mucus, used to lubricate food during swallowing and (at the lower end) to protect the mucosa against acid reflux.

What is Chagas’ disease?
Leads to beak’s oesophagus where the innervation of the lower oesophagus sphincter cannot be opened

Question 24

Emesis

Answer 24

Stretch to the GI tract with a very large amount of food through stimulation of vagus nerve to the medulla where vomiting centre located. Some drogs can act on the GI tract or chemoreceptor trigger zone where the blood-brain barrier is permeable.
Touching back of throat, dizziness, genitourinary damage also
Emesis (vomiting) is coordinated in the vomiting centre in the medulla oblongata. Receptors on the floor of the fourth ventricle of the brain represent a chemoreceptor trigger zone, stimulation of which leads to vomiting. The chemoreceptor trigger zone lies outside the blood-brain barrier and hence can be stimulated by blood-borne drugs which induce vomiting (emetics). Emetics can also work within the gut, sending stimuli to the brain via the vagus.

Vomiting entails:
- Increased salivation.
- Retroperistalsis, starting from the middle of the small intestine, sweeps the contents up the digestive tract into the stomach through the relaxed pyloric sphincter. Bile can enter the vomit if the vomiting is severe.

(small intestine to stomach only, if small intestine contains toxin, it would help to release the toxin, also the alkaline solution to neutralise the acidic solution is the stomach)

• A lowering of intrathoracic pressure (by inspiration against a closed glottis), coupled with an increase in abdominal pressure as the abdominal muscles contract, propels stomach contents into the oesophagus without the involvement of retroperistalsis; the lower oesophageal sphincter relaxes.
  (Contraction not needed, just lowering of intrathoracic pressure and raising of abdominal pressure, this help the food to be pushed, lower oesophageal sphincter relaxes)
• If the upper oesophageal sphincter remains contracted, the person is said to retch: the contents drain back into the stomach. After a few retches, the sphincter may relax and the stomach contents (vomitus) are expelled.
• If UOS relaxes, emisis occurs
  Rats, mice and rabbits are incapable of vomiting.

Why is the increased salivation beneficial?
Prevent damage to the tenth, because saliva contains bicarbonate

Question 25

The stomach

Answer 25

The antrum has a thick muscle wall for contraction. Fundus can be used to maintain the gas. Electrical activity in the stomach after the meal, the slow waves mediate the lower part of the stomach while fundus not without interstitial cells of Cajal. They will generate slow waves three times per minute, the gastric slow waves come later and later in time downwards, which then action potential occurs with the calcium coming in. The pylorus remain relatively tight. The grinding activity is called the retropulsion, the soft food can be grind down very effectively. It will be pushing food back and forth because the pylorus is not opened. It later relax afterwards to allow material drain out, but each tightens of contraction will close the pylorus again.

Question 26

Control of stomach emptying

Answer 26

Achieving the emptying -Migrating myoelectric complex (motilin) Reducing the rate -Entero(intestine)gastric reflexes, when there is too high a rate of emptying into the small intestine -It kicks in when food enters too quickly to inhibit stomach emptying -Triggered by detection in the duodenum in excess acid, fat digestion products, peptides and amino acids, duodenal stretch and the ileal break. -Could be related to cholecystokinin, these are all negative feedback to reduce the rate.

Question 27

The general functions of the stomach are:

Answer 27

- To act as a reservoir to allow food to be eaten quickly, releasing contents at a controlled rate; (To allow eat more food in a short time-the vagal-vagal reflex as a positive feedback) - To facilitate digestion, including initiating protein digestion; - To destroy some of the ingested microbes, through acidity; - To help regulate appetite through feedback effects on the brain, and to help regulate the activity of later parts of the gut through feed-forward mechanisms.

Question 28

Structure of the stomach

Answer 28

A vagovagal reflex responsive to oesophageal or stomach stretch causes the fundus and body of the stomach (but not the antrum) to relax so that up to 1500 ml of food can be accommodated with little increase in pressure: this is referred to as receptive relaxation. The antrum of the stomach has thicker muscular walls and performs more forceful contractions than does the proximal stomach. The antrum leads into the pylorus, the circular muscle of which forms a functional (if not anatomically discrete) pyloric sphincter. This is usually very narrowly open, limiting the rate of stomach emptying. A small amount of liquid contents drains rapidly into the duodenum at the onset of feeding, whereupon nutrient sampling is followed by a feedback effect on the rate of subsequent stomach emptying.

Question 29

Gastric motility

Answer 29

ICCs in a pacemaker zone in the body of the stomach generate slow waves at a frequency of around 3 min-1. The slow waves propagate down toward the pylorus but stop there, because the pyloric sphincter region lacks ICCs (action potentials can still propagate into this region though). Gastric slow waves have a characteristic spike-and-plateau structure; towards the antrum, action potentials may be superimposed on the plateau. Whether or not the gastric smooth muscle actually contracts depends upon the neural and hormonal background. In the fed state, substances including acetylcholine and gastrin increase the duration and amplitude of the plateau and thus increase the chance of action potentials and contractions occurring. Following a meal, contractions sweep down through body and antrum, becoming increasingly powerful as they progress. As the wave of contraction approaches the pylorus, the pyloric sphincter contracts to prevent passage of ingesta. The stomach contents are forced backwards towards the middle of the stomach in a process called retropulsion (illustrated on the right). The resulting ‘antral mill’ breaks up larger particles surprisingly effectively. Food is mixed with gastric secretions, forming chyme. The pylorus relaxes between contractions, and it is then, under the influence of tonic gastric pressure, that contents are allowed to pass into the duodenum. Liquid passes through easily but solid particles need to be ground down to under around 2 mm diameter in order to pass. The tougher the food and the larger its particles, the longer it tends to remain in the stomach. The graph below is based on the experiments on dogs performed by Hinder & Kelly (1977).

Question 30

Retropulsion

Answer 30

Following a meal, contractions sweep down through body and antrum, becoming increasingly powerful as they progress. As the wave of contraction approaches the pylorus, the pyloric sphincter contracts to prevent passage of ingesta. The stomach contents are forced backwards towards the middle of the stomach in a process called retropulsion (illustrated on the right). The resulting ‘antral mill’ breaks up larger particles surprisingly effectively. Food is mixed with gastric secretions, forming chyme. The pylorus relaxes between contractions, and it is then, under the influence of tonic gastric pressure, that contents are allowed to pass into the duodenum. Liquid passes through easily but solid particles need to be ground down to under around 2 mm diameter in order to pass. The tougher the food and the larger its particles, the longer it tends to remain in the stomach. The graph below is based on the experiments on dogs performed by Hinder & Kelly (1977).

Question 31

Rate of stomach emptying

Answer 31

The glucose solution goes quite rapidly, the time it takes for 50% to be lost which is like half an hour which drains out quickly as fluid. Diced liver is quite soft but still need to be grind down which contains a lag phase when nothing is draining out with two hours. The plastic spheres will never leave the stomach because it is quite big and cannot pass the pylorus. -What happens to them? This relates what happens in between the meal? -The migrating myoelectric complex, measuring slow waves with the spikes. It shows that waves go from stomach antrum to duodenum to jejunum to ileum. The migrating as the housekeeper of the intestine which allows one hours to two hours after the fasting state. This rely on the motilin hormone to induce the slow waves to drain out the object in the stomach between meals.

Question 32

The migrating myoelectric complex

Answer 32

In the fasting state, the stomach generally rests quietly for around 90 minutes, whereupon there are ten minutes of intense activity. Contractions sweep any remaining food towards a relaxed pylorus (N.B. unlike in the fed state!), helping even large particles left behind from the last meal to be pushed through into the duodenum. The wave of contractile activity continues down into the terminal ileum, and is referred to as the migrating myoelectric complex. It is initiated by the hormone motilin.

Question 33

Control of gastric emptying

Answer 33

The level of tone of the pyloric sphincter is carefully controlled by the body. ENS intrinsic control is, as usual, modulated by the ANS and circulating hormones. Relaxation is promoted by inhibitory fibres within the ENS, which release nitric oxide. The migrating myoelectric complex promotes emptying of residual particles from the stomach between meals, but neural and hormonal reflexes are more often involved in slowing the emptying of stomach contents, generally by inhibiting gastric motility and/or tightening the pyloric sphincter. Many reflexes, neural or hormonal, result in a slowing of emptying in response to things appearing in the small intestine at too fast a rate. These are examples of enterogastric reflexes (i.e. signals from intestines to stomach). A slowing of gastric emptying occurs in response to: - Excess acid (duodenal pH dropping below 4); - Fat digestion products in the duodenum; - Peptides and amino acids in the duodenum; - Duodenal stretch; - The ‘ileal brake’, referred to earlier Which is considered to be the most important hormone regulating gastric emptying? Cholecystokinin (CCK) is secreted by I cells in the duodenum and jejunum in response to long-chain free fatty acids and monoglycerides. It stimulates gall-bladder contraction, pancreatic secretion and growth, and inhibits gastric emptying and appetite.- From upper intestine

Question 34

Essay questions (lecture 2) - Why do we have gut hormones? - How is ingesta moved through the oesophagus? - What are the functions of the stomach? How are its activities controlled? (2000)