Diarrhoeal disease

• Describe the gut microbiome and its functions

  Consists of mostly bacteria but also viruses and fungi, which are located within the colon and distal small intestine (100 trillion microorganisms). They assist with digestion, synthesis of vitamins but dysbiosis can occur, where the diversity of the gut microbiome is altered. This results in proliferation of pathogenic microbes that produce toxins and induce damage and inflammation.
• Describe the effects of SCFA production by commensal gut bacteria

  Bacteria can ferment indigestible polysaccharides to produce short chain fatty acids (SCFAs), such as acetate and butyrate, which are absorbed in the colon. SCFAs can protect against gut inflammation, regulate DNA transcription, regulate tight junctions in epithelial cells and regulate mucus secretion. Their production is linked with diabetes, obesity and Alzheimer’s disease.
• Describe the different mechanisms of GI protection

  • High cell turnover: stomach= 2 days, colon and small intestine= 2-4 days. Allows gut to shed attached pathogens.
  • Tightness of junctional complexes: prevents microbes from entering the circulation
  • Barriers: acid destroys bacteria, fluid secretion flushes pathogens and thick mucus layer is almost impenetrable to microbes
  • Immune presence: 70% of immune cells reside in the gut, concentrated within Peyer’s patches, with Paneth cells mediating inflammatory and antimicrobial response
• Describe Diarrhoea

  Diarrhoea occurs when there is a greater osmotic load in the colon, which leads in greater fluid in the faeces. This is usually a result of damage or inflammation to mucosal cells, resulting in incomplete digestion and absorption.
• Describe how the gut mucosa can be damage

  Autoimmune diseases: Coeliac disease and Crohn’s disease

  Infections: poor water and hygiene can lead to infections, which destroy the intestinal walls leading to a reduction in surface area:

  • Bacteria- Shigella and campylobacter
  • Protozoa- entamoeba

  Infections can also cause inflammation of the intestinal wall, such as:

  • Bacteria- salmonella
  • Protozoa- giardia

  Most common cause of diarrhoea in the UK is Norovirus and Rotavirus.
• Describe how pathogens can impact ion secretion in the gut

  Enterotoxin producing E. coli (ETEC) strains can ‘hi-jack’ normal cellular processes and increase secretion of water, by increasing the concentration of chloride ions in the intestinal lumen. Water secretion can increase from 2 litres per day to over 20 litres per day, which creates severe dehydration.
• Describe the Normal secretion of water and ions in the intestine

  The crypt is responsible for secreting ions and water, which is stimulate by hormones, such as secretin, nerve reflexes and inflammatory mediators, such as PGE2.
• Describe how cholera toxin alters chloride secretion

  Cholera toxin causes ADP-ribosylation of alpha subunit on G proteins, which prevents GTP hydrolysis and therefore it is constitutively active. This leads to constant action of adenylate cyclase, which increases intracellular cAMP levels and stimulates CFTR channels. This results in increased secretion of chloride ions.
• Describe how rotavirus increases chloride secretion

  Rotavirus signals via phospholipase C to increase intracellular calcium ion levels. This results in stimulated of the calcium-dependent chloride channel, known as TMEM16A and increases chloride ion secretion.
• Describe the main treatments for diarrhoeal disease

  Oral rehydration- administration of a solution containing sodium ions and glucose. Na+ and glucose transport promote the absorption of water through the sodium glucose cotransporter (SGLT1). This is very effective in cholera cases where there has been no damage to mucosal cells.

  Antibiotics- can be effective in some cases
• Describe the disadvantages of antibiotic treatment for diarrhoeal diseases

  • Problems with delivering the effective dose due to antibiotic resistance
  • It doesn’t work against virus caused disease
  • Eradicates “good” bacteria, which increases risk of opportunistic infections such as clostridium difficile.
• Describe some of the potential treatments for diarrhoeal disease- chloride channel blockers

  Two of the main targets are blocking CFTR and TMEM16A channels, however drugs targeting these channels have been found to be effective in animals but not humans. They lack specificity and efficacy since they induce systemic effects and are often not absorbed due to flushing away from the site of action. Crofelemer is an approved drug used to treat diarrhoea in AIDs patients. It is a potent inhibitor of CFTR and TMEM16A, but does have other actions leading to side effects.
• How do opioids lead to constipation?

  There are endogenous opioids in the gut, such as enkephalins and endorphins, which bind to opioid receptors within the gut such as the enteric NS, muscle and epithelia. Opioid receptor activation leads to:

  • activation of potassium channels, which decreases excitability of neurones and muscle cells
  • inhibits neurotransmitter release
  • inhibits cAMP production

  These effects reduce gut motility.
• Describe opioid anti-diarrhoeals

  μ Receptor agonists:

  • loperamide and diphenoxylate
  • decrease peristalsis, decrease gastric emptying and increase sphincter tone

  Enkephalinase inhibitors

  • enhances effects of endogenous enkephalins
  • racecadotril
  • creates all the effects of μ receptor agonists, alongside anti secretory action