infections, intestines and immodium Flashcards
microbiome
in colon and distal small intestine
- the bacteria Express enzymes on their surface that help to break down many of these different polysaccharides and produce other metabolites that then can be absorbed and some of these actually have a really beneficial effect in the gut and these are collectively referred to as short-chain fatty acids.
these are all really important molecules that have numerous health benefits. They are absorbed across the intestinal epithelial cells via a sodium coupled co-transporter and then they get further metabolized, but they also have numerous other effects within the gut.
effects of these shortchain fatty acids on all organs in the body
- They regulate our protection against inflammation within the gut.
- They can regulate transcription of the DNA on messenger RNA and so they have important roles in proliferation of the epithelial cells.
- They also regulate the tight junctions within the epithelial cells and that can help to protect the barrier function of the epithelial cells
- and they can also regulate mucus secretion within the intestinal wall.
- they also activate a class of receptor a class of g-protein coupled receptor that are part of the orphan receptor group.
balance between good bacteria and bad bacteria
There is the balance between good bacteria that tends to have anti-inflammatory properties within the gut and general health benefits versus bad Bacteria that generally cause inflammation of the gut, reduce the gut barrier function and can lead to systemic infections and poor health.
- And when that balance is tipped in the wrong direction, then that can lead to numerous disease processes. And this is known as dysbiosis of the gut microbiome.
- That’s when the diversity of the different species of bacteria is reduced and the balance is tipped in favor of bad bacteria
GI protection
-cell turnover: stomach (2 days) < colon and small intestine (2-4)
-tightness of junctional complexes: stomach > colon> small intestine
- barriers: acid - mucus and fluid secretion
- immune presence (70% immune cells in GI): peyers patches (ileum), paneth cells (inflammatory mediators, antimicrobrials)
- dietary fibres: increased faecal mass = decreased toxins and increased motility
diarrhoeas
when balance goes wrong
- increased osmotic load in the colon = increased fluid in faeces
- causes: damage/ inflammation to mucosal cells (incomplete digestion/ absorption)
- secretion of ions by gut
damage to mucosa
immune/ autoimmune
- coeliac disease, crohns disease
infections (water and hygiene)
- bacteria (shigella and campylobacter) and protozoa (entamoeba) -> destruction of intestinal wall (decreased surface area) leads to blood in faeces
- bacterial (salmonella) and protozoa (giardia) -> inflammation
secretion of ions by gut
- vibrio cholerae, strains of E.coli
- enterotoxins produced by bacteria which ‘hijack’ normal cellular processes.
- intestinal cells normally secrete water (together with mucus and bicarbonate) - 2 litres per day
- in cholera secretion exceeds 20 litres per day
crypts and villus
at the base of each of these Villi structures. There’s a crypt and the crypt is an even smaller and thinner
tube of epithelial cells and at the bottom of this Crypt, you’ve got very rapidly dividing cells.
You’ve also got some of these paneth cells that are secreting antimicrobial peptides and anti inflammatory mediators that are secreted into this small space As an extra layer of protection
what happens as reapidly dividing cells are moving up to the top of the crypt
as the cells are rapidly dividing, they move like a conveyor belt up to the top of structure and when they reach the top they stop they start dying so that they can be replaced.
But what also happens as they move from the bottom of this Crypt to the top of the
Villi structure not only are they dividing but they are differentiating and they’re changing the expression of the various ion Transporters that are specialized for secretion which
occurs in the Crypt Versus those Transporters that specialize for the absorption of nutrients and also absorption of some of the fluid
regulation of intestinal secretion
secretin increases cyclic amp via adenylyl cyclase, which is activated by G alpha S and this activates a chloride Channel.
But also you’ve got acetyl choline which couples to G Alpha Q G protein which then activates phospholipase C to convert PIP2 into diacylglycerol, which remains in the plane of the membrane,
and IP3 which diffuses through the cytosol activates ip3 receptors on the endoplasmic reticulum. these receptors open You get calcium release from the ER and that increases cytosolic calcium concentration
- and that increasing calcium will then activate a calcium dependent chloride Channel
intestinal secretion in cholera
cholera hijacks this whole process because it produces a sustained increase in
cyclic GMP.
how does cholera hijack intestinal secretion regulation
- The Agonist binds to the receptor, this causes GTP to bind to the G alpha s subunit, this dissociates from the beta gamma complex and binds to and activates adenyl cyclase to produce cyclic AMP.
- Now normally GTP is hydrolyzed - the GTP when it’s bound to the alpha subunit is is hydrolyzed by the alpha subunit. It converts it to GDP and this acts as the off switch for this signaling pathway.
- the cholera toxin causes ADP ribosylation of this Alpha subunit, So this is a covalent modification of the alpha subunit that basically prevents it from hydrolyzing the GTP.
- So this means that this signaling Pathways permanently switched on So consequently the cholera toxin produces Huge amounts of cyclic AMP and it never really goes away until it gets degraded by phosphodiesterase.
treatments - oral rehydration
-oral rehydration involves the administration of a solution containing sodium and glucose
- sodium and glucose transport (SGLT1) promotes the absorption of water
- very effective for cholera where no damage to mucosal cells
treatments - anti-biotics
can be effective in some cases, e/g dysenteries.
disadvantages:
- problem delivering effective dose (increased antibiotic resistance)
- dont work against good viruses
- eradicate good bacteria -> opportunistic infections with very bad bacteria: clostridium difficile = chronic colitis
chloride blockers
targets: CFTR and TMEM16A
- drugs which work in animal models but no success in humans
- lack specificty and/ or efficacy: systemic (side effects), non absorbed (flushed away from site of action
