Essay: PBL WRTE-UP – A Gut Feeling 

PBL WRTE-UP – A Gut Feeling
Introduction
In this scenario a clinical scientist is researching potential oral rehydration treatments that can be used to treat conditions that cause extreme water loss, such as cholera. To understand how these potential treatments work, it is essential to look at how water, ions and solutes are transported within the gut: in both healthy individuals and cholera affected individuals. I will also look at the different sources of fluid in the body, the role of water in the body during digestion and the types and causes of diarrhoea.
Learning Objectives:
1. What is diarrhoea? What are the different types of diarrhoea? 2. Fluid in the body
– Sources of fluid?
– Function of water in digestion 3. Cholera
– Cellular mechanism of Cholera 4. Treatments
– Rehydration therapies
– Acid-base disturbances accompany severe diarrhoea 5. Table of results
1. Whatisdiarrhoea?
Diarrhoea is defined as ‘a condition in which faeces are discharged from the bowels frequently and in liquid form’
According to the World Health Organisation diarrhoea is the second leading cause of death in children and kills 525,000 children under five every year.
Contaminated food and water sources are the most common cause, especially faeces-contaminated water from sewage, septic tanks and animals. (3)
Severe diarrhoea can lead to rapid dehydration, as bodily fluids are lost in stool, vomit and sweat, and due to reduced absorption of water, they cannot be replaced. Electrolytes such as sodium, chloride, potassium and bicarbonate are also lost from the body. (3)
Types of Diarrhoea:
Diarrhoea is the disturbance of normal water and electrolyte absorption and secretion. The intestinal lining is either unable to absorb fluid or actively drives the enterocytes to secrete it.
– Acute diarrhoea: An abrupt onset on of 3 or more stools a day, lasting no longer than 2 weeks usually caused by an infective agent.
– Persistent diarrhoea: Diarrhoea lasting from 2 to 4 weeks, if infection is slower to resolve, or offending agents are continually used.
– Chronic diarrhoea: Diarrhoea lasting over a month as a result of disease, medication or general abnormalities. (4)
(1) or passing stool more often than usual or exceeding 3 times a day. Diarrhoea can
be caused by many different things, for example: bacterial infections, viral infections, food
intolerances, malabsorption or medicine. Symptoms of diarrhoea often include painful abdominal
cramps, bloating and nausea. (2)
There are 4 basic types of diarrhoea: osmotic, secretory, inflammatory and deranged motility: (5)
– Osmotic Diarrhoea: Osmotically active solutes, or excessive amounts of solutes retained
in the lumen of the small intestine prevents normal water absorption. This can be caused by an incomplete breakdown or malabsorption of nutrients. The inability to absorb certain components of foods, sugars and minerals draws water into the lumen. This leads to an electrolyte imbalance and passing of large amounts of fluids in the stool. (6)
– Secretory Diarrhoea: Most commonly caused by toxins produced by pathogenic bacteria in the gut. The normal absorption processes of epithelial cells via ion channels are impaired, and cells are induced into a state of active fluid secretion. Water is secreted into the intestinal lumen. (4) Vibrio cholera, E. coli, hormones secreted by certain types of tumours and certain other metals can all cause secretory diarrhoea. (5)
– Inflammatory and Infectious diarrhoea: Disturbances or breach of the gastrointestinal barrier due to bacterial or viral pathogens such as Salmonella and E. coli can lead to destruction of the gut mucosa. This can result in reduced absorption and exudation of serum and blood into the intestinal lumen. (5) Inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis can also damage the mucosal lining, leading to an inability to absorb fluid. (7)
– Deranged Motility: Different motility of the intestine may also affect water absorption by decreasing contact and exposure between gut contents and absorptive surface area. (7) Nutrients and water need adequate time to be absorbed efficiently. Increasing the rate at which intestinal contents pass, decreases absorption. (5)
2. FluidintheBody
Water is moved passively via osmosis, in relation to osmotic gradients created by the concentration of solutes and ions in the body. Water can move across the tight junctions of epithelial cells paracellularly, or transcellularly via the plasma membrane of epithelial cells.
Water absorption is particularly dependent on sodium which can be absorbed across the apical surface of the intestine, into the epithelium via cotransport with glucose or amino acids. Na+/K- pumps in the basolateral membrane pump sodium until the sodium concentration is higher in the lumen. Sodium then travels down this concentration gradient through sodium-glucose cotransporters. (23)
Sources of Fluid:
A healthy individual ingests 2L of water a day from diet and drinking and 1.5L from saliva. Gastric juices and secretions from the liver, pancreas and intestines make up 5.5L that also enters the digestive system. The small intestine absorbs 8.5L of this fluid, the colon absorbs 400ml and the remaining 100ml is excreted in faeces. (8)
Function of water in digestion:
Water has many functions in the gut, as it aids both digestion and
absorption. It helps dissolve minerals and other nutrients, making
them more accessible to the body. Water is required for hydrolysis
reactions needed to break down ingested materials to be absorbed by the villi in the small intestine. Water is also essential as it liquefies the intestinal contents and facilitates the propulsion of it along
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the digestive system, allowing it to move, and be brought into close proximity with the absorptive epithelium and microvilli, increasing the exposure of the gut to nutrients. Water also combines with mucin granules to form mucus which lubricates and protects the gastrointestinal tract. (10)
3. Cholera
Cholera is an acute diarrhoeal infectious disease caused by the gram-negative Vibrio cholerae bacterium. Cholera is most common in parts of Africa, south Asia and south America and is spread through contaminated water by faeces from an infected person. (9) It is characterised by profuse diarrhoea, which can lead to rapid dehydration and electrolyte loss. In extreme cases and without treatment cholera can be rapidly fatal. 5-10% of people infected with cholera also suffer from metabolic acidosis and circulatory collapse. Cholera is normally treated using oral rehydration treatments. (11)
Cellular mechanism of cholera:
After the ingestion of contaminated water, the cholera toxin is released. Some bacteria are killed by the low acidity of the stomach; however, some reach the lumen of the small intestine, penetrate through the thick mucus and bind to enterocytes – intestinal cells. (12) As the bacteria no longer need to move to reach the intestinal wall, they stop producing flagellin and responds to the change in their chemical surroundings and begin to produce toxic proteins. (13)
The cholera toxin is made up of 6 protein subunits a single A copy and a pentameric B subunit, both joined by a disulphide bond. The B subunit has a GM1 Ganglioside receptor on the enterocyte which induces receptor-mediated endocytosis. Now inside the cell, an A1 fragment of the A subunit activates a G protein – permanently stimulating adenylate cyclase to produce cAMP. The elevated cAMP levels over activate protein kinase A, which phosphorylates and activates the CFTR (cystic fibrosis transmembrane conductance regulator). This leads to an outpour
of Cl- ions into the lumen of the small intestine. (13) Due to the negative charge in the lumen Na+ ions diffuse into the lumen paracellularly, rushing between cells. Moreover, due to lower water potential of the gut contents water also follows via osmosis, and passively moves across the gut mucosa. The constant flow of water into the lumen causes secretory diarrhoea. The high levels of cAMP also inhibit the Na+/Cl- pump in villus absorptive cells, so sodium and chloride can’t renter.
However, the sodium-glucose receptors of absorptive cells are not impaired as they are not affected or controlled by cAMP. This allows rehydration of people affected by cholera, as secondary active transport can counteract the effect of the toxin on the CFTR and Na+/Cl- channels.
The cholera toxin alters the cells it invades irreversibly, so the enterocytes are in a perpetual state of net secretion, as they have decreased ability to absorb sodium and increased chloride secretion. (14) At the base of the Crypts of Lieberkühn of the small intestine, stem cells divide and continually produce daughter cells. This is known as the clonal conveyer belt, as intestinal cells constantly need to regenerate due the harmful environment of the small intestine. As new cells are produced, the old cells are pushed to the top of the villi where they are disposed of. (16) With cholera affected cells, they are locked into a state of permanent secretion, until the altered cell dies. (14)
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Secretory crypt cells primarily ensure water is present in the lumen of the small intestine. Na+, K+ and 2 Cl- ions enter from the interstitial fluid via cotransporter expressed on the basolateral membrane of the intestinal cell. Cl- then moves into the lumen via the CFTR channel on the apical membrane down its concentration gradient. An Na+ gradient that is established by the Na+/K+ ATP channel, this provides the energy required for this. The negative Cl- in the lumen attracts the positively charged sodium ions via paracellular pathways and water also follows via osmosis, down the water potential gradient. (15)
4. Treatments
Normal treatment of diarrhoea:
Usually treatment of the underlying condition that’s causing the diarrhoea helps to relieve the symptoms:
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– For example, removing foods the patient is intolerant to, like gluten in coeliac disease, or removing lactose and dairy if lactose intolerant can help reduce symptoms.
– Stopping medication if that is the underlying cause, or altering diet to reduce fat, caffeine intake and increase fibre and fluid intake can also be beneficial.
Anti-motility medicines can also be used to reduce diarrhoea. Loperamide is known to be very effective as is reduced the muscle movements of the digestive system, increasing the time, and therefore amount of water absorbed from the stools as it passes through the gastrointestinal tract. (18) Diphenoxylate is also often used to treat diarrhoea, as it also slows intestinal contractions, in conjunction with fluid and electrolyte replacement solutions. (19)
Antibiotics may be used if the cause of the diarrhoea is bacterial, for example with cholera, or if the patient has a weakened or compromised immune system. They can shorten the period during which Vibrio cholerae excretes toxins and can reduce the volume of diarrhoea and shorten hospitalisation time. Antibiotics are normally administered for between 3 to 5 days. Single-dose therapy of tetracycline, doxycycline, furazolidone and ciprofloxacin are all very effective in the treatment and reduction of diarrhoea. Again, antimicrobial therapy is given in conjunction with rehydration therapy. (20)
Rehydration therapies:
Cholera treatments concentrate on rehydrating the affected individual and restoring their electrolyte imbalance. This is because of the life-threatening consequences of dehydration.
Oral rehydration therapy is an effective and inexpensive form of treatment and is often sold in a pre-mixed powder. The solution contains equal concentrations of sodium and glucose. As the Na/Glucose symporter on apical surface of intestinal cells is unaffected by the cholera toxin, this is the main target for rehydration
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treatments. The small intestine contains SGLT-1 transporter proteins, and when both sodium and glucose are present the SGLT-1 transports both across the epithelial wall, establishing an osmotic imbalance, as there is now a lower water potential inside the enterocytes. This draws water into the cell, correcting the electrolyte and fluid imbalance. (17) Oral rehydration therapy is effective with secretory diarrhoea. Oral rehydration therapy itself doesn’t cure diarrhoea or the underlying cause of it, but instead treats the severe dehydration which can affect sufferers of cholera.
IV fluids can also be administered to replace fluid and electrolyte loss during severe dehydration. Lactated Ringer solution or an isotonic sodium chloride solution is normally used. (20)
Acid-base disturbances accompany severe diarrhoea:
Metabolic acidosis can often accompany severe diarrhoea as body loses bicarbonate ions in faeces.
Bicarbonate ion is alkaline and plays an important role in the pH buffering system. Bicarbonate ions in the blood transport waste carbon dioxide produced at respiring tissues to the lungs, where it can be exhaled and removed from the body. (21)
Bicarbonate also helps regulate the pH of the small intestine. Sodium bicarbonate is released from pancreas, stimulated by the hormone secretin, and helps to neutralise the acidic chyme that enters from the stomach as it is a weak base. Bicarbonate usually remains in the lumen for some time, then enough is reabsorbed, but due to the diarrhoea the bicarbonate is lost with the watery, frequent stool. This can cause metabolic acidosis. (22)
Conclusion
In this PBL scenario the scientist’s findings are presented here:
This table outlines the effectiveness of different rehydration therapies by comparing values of intracellular sodium concentration and intracellular water volume in a healthy individual to tests where the cholera toxin and different solutes are present. The third, fourth and sixth rows show that glucose is the most essential ingredient causing both the sodium and water concentrations to return to normal. As when glucose is excluded from the treatment, despite what other electrolytes are added, the intracellular concentrations do not improve. This is because of the Na/Glucose symporter which is essential for rehydration.