Gut Immunology lecture Flashcards
LO:
- Immunology of the gut: Outline the role of the gastrointestinal tract immunology and the microbiome in maintaining systemic immune homeostasis
- Cells of the gastrointestinal tract: Describe the cellular arrangement of tissues throughout the gastrointestinal tract and relate to local function
- Immunology of the gut: Outline the role of the gastrointestinal tract immunology and the microbiome in maintaining systemic immune homeostasis
- Intestinal disorders: Describe the clinical features and treatment options of small and large intestine disorders
Session plan
GI Tract Immunology
So the first thing to point out is that the GI tract immune system is that the largest and most complex part of the body’s immune system
We will remember from lectures last year that even though, let’s say, the small bowel and large bowel put together is about eight metres long, the actual surface area, once you take into account villi and microvilli with the GI tract is about 200 metres squared. The size of a tennis court.
Now the gut has to deal with a massive antigen load, and that load consists of resident micro biota. It’s about 10 to the power of 14 bacteria involved. It has to deal with dietary antigens, and it has to deal with exposure to pathogens.
So by the virtue of its responsibility to recognise, respond to, adapt to, countless foreign and self molecules, the immune system becomes central to the processes of both health and disease. So it lives in a permanent state of restrained activation. You’ll see that it has to balance tolerance versus active immune response. So tolerance is to food antigens, commensal bacteria, immune reactivity is to pathogens. So it has to get it all done correctly.
So immune homeostasis of gut and development of healthy immune systems requires the presence of these bacteria microbiota.
Relationship between Microbiota & Immune System
So how do we work out what does what and how is it helpful and so forth?
Well, several important effects of micro biota on the immune system have been determined by studies of what are called Gnotobiology spelt GNO, Gnotobiology, which is essentially, you take germ free animals, they’re not colonised by anything. And then you selectively colonise them with particular bacteria. And then you can work out what’s the difference between your germ free mice when they’ve been exposed to that particular selective colonisation and then compare it with conventionally housed mice, which have normal gut microbiota. This is a busy slide, but he’s just there to show you there are big differences.
(Gnotobiology is the science of study of animals or other organisms raised in environments free of germs or those which contain only specifically known germs. Scientists compare gnotobiotic animals with ordinary animals whose bodies carry many germs, like bacteria, viruses and parasites.)
So, for instance, development of small intestine, we’ll be talking about Peyer’s patches, in germ free mice, these are fewer and less cellular than those with conventional microbiota. Let’s go down a bit further. We’ll find, say, Paneth cells, these are important in the defence against pathogens. In the germ free mice these are reduced. They have reduced expression of angiogenin 4 and reduced expression of REG3 gammer, etc. So you can you can work out what’s going on.
The Gut Microbiota – a “Virtual” Organ
- 10 to the power of 14 gut bacteria and 10 to the power of 13 cells in body - most densely populated “ecosystem” on Earth.
- 4 major phyla of bacteria (Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria) (remember as FAB P), also viruses & fungi.
- Provide traits we have not had to evolve on our own - Genes in gut flora 100 times our own genome.
As I’ve already said, there are 10 to the 14 gut bacteria, and that’s an awful lot when you can compare that with the fact that we have 10 to the 13 cells within our body. So the gut microbiota is actually a virtual organ, it’s the most densely populated ecosystem on Earth. There are four major phyla. Bacteroidetes, Firmicutes, and then actinobacteria, proteobacteria. and then are lots of viruses and fungi. So why are they important?
Well, what they’re doing is they’re providing traits that we’ve not evolved on our own. So for a long time, benefits to the host from gut microbiota have been appreciated. What they do is they can provide essential nutrients that we can’t manufacture. They can metabolise what we find to be indigestible compounds. They can act as a defence against colonisation of opportunistic pathogens and also contribute to the intestinal architecture. Here, I’ve mentioned that genes in the gut flora, the number of genes about 100 times our own genome. It’s worth mentioning at this point, when I say microbiota, what I’m talking about is a mixture or blend of microorganisms that make up a community with a particular anatomical niche or within a particular anatomical niche.
A microbiome, you’ll hear referred to, is the collective genomes of all microbiota, so all the different anatomical niches.
So this diagram on the left is looking at key host related factors that influence the balance between stimulation and inhibition of the gut microbiota. So if we go here, we see certain ingested nutrients or certain secreted nutrients can lead to bacterial growth and then we’ll increase the numbers of our microbiota. So those are stimulatory factors.
We also have inhibitory ones, including chemical digestive factors, which cause bacterial lysis. Peristalsis, contractions and opening your bowels can also have effects by eliminating bacteria from the gut. So they’ll decrease cell numbers. So this diagram here is just looking at how many, what’s the gut microbiota in different regions of the gut? So we see in the stomach we’ve only got 10 to the one. Now, that’s because the stomach is full of HCl, pepsin and gastric lipase. Once we get down to the duodenum things start increasing, you’ve got ten to the three.
What’s stopping things growing? Well, it’s bile acids once we get down to the pancreas we’ve got trypsine, amylase, carboxypeptidase. We’re increasing our numbers to ten to the four. We get to the small intestine, we’re then getting up to ten to the seven and once we get to the colon. Remember, in small intestine, the only thing fighting bacteria there are crossborder enzymes. But the colon, there are no host digestive factors, so we’re getting up to numbers of ten to the 12.
Dysbiosis – Altered Microbiota Composition
Symbiosis is a word that just means living together. It doesn’t imply either partner benefits. So within the bowel, we have symbionts. And they will be organisms that live with the host without any benefits or harm to either one. So they’re just there, no one’s gaining anything.
When you get to commensals, that means ‘share a table’, so that describes a micro-organism which benefits from association with the host, that has no effects on the host. So it’s not helping it, it’s not harming it. It’s there because it’s getting something it wants. Once we get to pathobionts, well then we’re talking about, they’re symbionts, they don’t normally elicit an inflammatory response, but under particular conditions, usually environmental, they then have the potential to cause dysregulated inflammation and disease.
So everything’s balanced in this diagram. We’ve got our commensals, we’ve got our symbionts and our pathobionts. Anything that disturbs that, it’s called dysbiosis, an altered microbiota composition. Something will allow the pathobionts to start producing their pathogens, and then you get your dysbiosis.
Dysbiosis – Causes & Disease Development
So what are the causes?
They are wide and varied. Infection, inflammation, diet. Xenobiotics merely means a small chemical compound that enters the gut unnaturally, so they’ll be things like drugs and pollutants. A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual
Genetics will have a role, etc. And depending on what’s driving this you’ll either get healthy microbiota or dysbiosis. Now dysbiosis has been associated with many different things. It happens when pathobionts start producing bacterial metabolites and toxins which have a negative effect on us.
I’ll go through some of these briefly, but you can look at this at leisure. TMAO is trimethylamine-N-oxide, and what that does, if that’s increased, you get increased deposition of cholesterol in your artery walls. So that’s known to be involved with atherosclerosis, which is essentially furring up of your arteries. If we go to 4-EPS, that’s short for 4- ethylphenylsulfate, that’s been associated with autism. SCFA is short chain fatty acids, if they’re decreased, that can lead to inflammatory bowel disease. If they’re increased, it’s been associated with neuropsychiatric disorders such as stress. And AHR ligands are Aryl Hydrocarbon Receptor ligands. They’ve been associated with multiple sclerosis, rheumatoid arthritis and asthma. Just to let you know that NAFLD, NAFLD, is non-alcoholic fatty liver disease, NASH is non-alcoholic steatohepatitis. Steatohepatitis meaning inflammation from from fat.
Mucosal Defense
Physical barriers
- Anatomical
- Epithelial barrier
- Peristalsis
- Chemical
- Enzymes
- Acidic pH
Commensal bacteria: occupy “ecological niche”
“Immunological”: following invasion
- MALT (Mucosa Associated Lymphoid Tissue)
- GALT (Gut Associated Lymphoid Tissue)
So how does the body defend itself, or the gut defend itself? it has numerous things that help it. We know that there are physical barriers, which could be anatomical. It has an epithelial barrier, that’s there, but also we have a mucus layer which is secreted by goblet cells. We have epithelial monolayer itself, which is held together by tight junctions. That keeps pathogens out. And we’ll see a bit later, but Paneth cells you may remember, are found in the small intestine, particularly the terminal ileum, they are found in the bases of the crypts of Lieberkuhn, and they secrete antimicrobial peptides which are known as defensins, and lysozyme.
And on top of that, we have peristalsis and top of that as you’ve seen on the diagram before, we have various enzymes, acidic pH, etc. We also have commensal bacteria, which we’ve discussed already. And they can act as an ecological niche or an ecological barrier. But we also, if something does manage to breach the mucosal defence, we then have immunological systems that can occur if an invasion has happened. So two particular ones of interest are MALT, which is mucosa associated lymphoid tissue and GALT, which we’ll be discussing in detail, gut associated lymphoid tissue.
Mucosa Associated Lymphoid Tissue (MALT)
So we’ll talk just briefly about the mucosa associated lymphoid tissue, MALT.
So these are found in the submucosa, below the epithelium and is seen as a lymphoid mass. It contains numerous lymphoid follicles. We’ll explain that in a little moment. And those follicles are surrounded by what’s known as HEV, high endothelial venules, and they’re post capillary venules, and they allow easy passage of homing lymphocytes that circulate. And again, we’ll discuss that in a bit more detail later. So in the oral cavity, this is rich in immunological tissue. The important ones being Palatine tonsils and lingual tonsils and these are cross sections. And you’ll see that they are packed full of lymphoid tissue. Similarly, at the back, we have adenoids, the pharyngeal tonsil.
The tonsils are collections of lymphatic tissue located within the pharynx. They collectively form a ringed arrangement, known as:
=Waldeyer’s ring:
Pharyngeal (adenoid) tonsil
Tubal tonsils (x2)
Palatine tonsils (x2)
Lingual tonsil
The tonsils are classified as mucosa-associated lymphoid tissue (MALT), and therefore contain T cells, B cells and macrophages. They have an important role in fighting infection – the first line of defence against pathogens entering through the nasopharynx or oropharynx.
Gut Associated Lymphoid Tissue (GALT
- Responsible for both adaptive & innate immune responses
- Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
So we’ll go on to gut associated lymphoid tissue. The first thing to point out, gut associated lymphoid tissue is the largest mass of lymphoid in the body, it’s massive. It’s responsible for adaptive and innate immune responses. And as you’d expect, it consists of B and T cell lymphocytes, macrophages, antigen presenting cells and particularly dendritic cells. And there are also specific, specific epithelial and intraepithelial lymphocytes.
This lymphoid tissue can either be non-organised, and most important is intraepithelial lymphocytes, they’re sort of solitary, this is a villus. You can see that these intraepithelial lymphocytes make up about a fifth of the intestinal epitheliumand they’ll consist of cells such as T cells and natural killer cells.
You’ll also see non-organised lymphocytes within lamina propria. It’s labelled here. So those are non-organised, they’re spread around.
But there’s also organised gut associated lymphoid tissue. Most important being Peyer’s patches, which occur in the small intestine, in particular in the ileum, and they’re massed together in intestinal walls adjacent to the mesenteric attachments.
So that happens in the small bowel, particularly as you go down the small bowel you get more and more Peyer’s patches. You have things called caecal patches in the large intestine, and throughout the gut you’ll have isolated lymphoid follicles. And importantly, mesenteric lymph nodes, these are nodes within the mesentery and we’ll see some diagrams of that a little later.
Non-organised GALT
So just to quickly go over what we’re seeing in non-organised GALT’s. You will remember, you have stem cells which produce enterocytes, these rapidly start migrating, like an escalator, to the apex. Then you get apoptotic intraepithelial cells. At the base, you’ll also get Goblet cells formed, again they will go north and produce mucus. Stem cells also produce Paneth cells, which produce anti-microbial peptides, which is what your AMP is. And with in the epithelium itself, you’ll have intraepithelial lymphocytes, they’re found lying between epithelial cells.
Within the lamina propria, you’ll have in the central part of the villus, you’ll have the majority of the intestinal immune cells, including T cells, B cells, macrophages in DC is for dendritic cells. This here is just to point out the difference between small bowel and large bowel. Large bowel doesn’t really have villi, it just has crypts, it doesn’t have Paneth cells, it has lots of goblet cells and also has intraepithelial lymphocytes. If look at organised gut associated lymphoid tissue, in particular, the most important is Peyer’s patches.
Peyer’s Patches – “Immune Sensors”
If we look at organised gut associated lymphoid tissue, in particular, the most important is Peyer’s patches. So they’re found in the submucosa of the small intestine and mainly in the distal ileum. And those aggregated lymphoid follicles are covered by a particular epithelium called follicle associated epithelium. And that’s special because there are no goblet cells there, there’s no secretory IgA, and no microvilli.
This diagram shows the follicle associated epithelium, M-cells, but beneath M-cells, you will then have your Peyer’s patch, which consists of a sub-epithelium dome, which is mainly dendritic cells which help transfer antigens from the gut lumen up here via M-cells to the Peyer’s patch. You will have B cell follicles, most of the B cells are within follicles themselves. You’ll also have interfollicular T cells and they’re all lead down, and this a mesenteric lymph node here. So these are organised collections of native T cells and B cells, their development requires exposure to bacteria microbiota. So in the last trimester of the foetus you’ll have approximately 50 Peyer’s patches, by the time you get to your teens, you’ll have 250. They have a specialised cell called M (microfold) cells within the follicle associated epithelium. Now, these M cells express IgA receptors and they facilitate transfer of IgA bacteria complexes into the Peyer’s patches, and we’ll dwell on that a little in a moment.
Particulate Antigen Sampling: Microfold Cells
So this is the scanning electron micrograph of microfold cells. Here we have low magnitude. You see the dome area here of the Peyer’s patch protrudes between all the villi into the lumen. So it looks like a little head. When we go to medium magnitude, it’s like a carpet. These are micro villi, and where there are indentations that’s where your M cells are. And when we go to higher magnitude, these M cells are seen as epithelial cells with surface microfolds instead of micovilli and antigens are taken up preferentially through these M-cells.
Antigen Sampling: Trans-epithelial Dendritic Cells
Now, there is an alternative route for bacterial invasion that’s independent of M-cells. These are dendritic cells and what they can also do is open up tight junctions, and send their dendrites outside the epithelium and directly sample bacteria and then bring it back and transport those lymph nodes.
Why can they do that? They can do that because they express tight junction protein, such as occludin and claudin 1. So they maintain the integrity of that epithelium barrier once they’ve taken they’ve sampled antigens from the lumen of the gut.
B Cell Adaptive Response
So this diagram is really just to point out, to put it all all together. We will just quickly reiterate, we’ve got M-cells, we’ve got antigens. Those antigens will then be joined together with antigen presenting cells, in this case, dendritic cells. And they’ll engulf the antigens and present them with major histocompatability complex II molecules on the cell surface. Those dendritic cells will then migrate to the Peyer’s patch. And once you get to Peyer’s patch, that’s where you have further, you have your antigen presenting cells, you have your T cells, you have your B cells, they’re all aggregated within Peyer’s patches, and that’s why they all become activated. So mature, naive B cells express IgM in Peyer’s patches that on antigen presentation the class switches to IgA. It’s all influenced by cytokine production. Activated B cells further mature and then they become IgA secreting plasma cells. And as we’ve already said, these all populate the lamina propria.
Just to point out, some of these B and T cells enter the lymphatic system.
Formation of Secretory IgA (sIgA)
Just to point out, some of these B and T cells enter the lymphatic system, for example, plasma cells will then migrate back to the enterocytes. They’ll be taken up into epithelial cells, enterocytes, enzymatic cleavage, and then they’ll be secreted as secretory IgA.
And what is their function? Well, that’s to bind luminal antigen. So by binding it, it then prevents its adhesion and subsequent invasion of the enterocyte. So it’s another defence mechanism. And up to 90 percent of gut B cells secrete IgA.
Lymphocyte Homing & Circulation
So. They don’t just stay there, they move. So we’ll just quickly look at lymphocyte homing circulation. Briefly, you get your antigen coming down to Peyer’s patch, you can get your antigen presentation and activation of your T cells and B cells, they then get transferred to mesenteric lymph nodes where you get lymphocyte proliferation. Then they go into circulation via the thoracic duct.
Now the thoracic duct is the main lymphatic vessel for return of all lymph or otherwise known as chyle to the systemic venous system. Chyle=a milky fluid containing fat droplets which drains from the lacteals of the small intestine into the lymphatic system during digestion.
So, for instance, when you absorb fat, it becomes chyle, and that gets into the venous system via the lymphatic system. Once it enters the circulation via the systemic venous system. It can then enter the peripheral immune system, which is completely separate from the GALT. So you can go to skin, it can go to tonsils where we’ve got the MALT and BALT is another one, that’s actually bronchus associated lymphoid tissue?
So on top of entering the peripheral immune system, you can also exit back into the intestinal mucosa, back to the lamina propria. So that’s a sort of homing circulation.
𝝰4β7 Integrin/MAdCAM-1 Adhesion & Gut Homing
And how does it do that?
Well, there are lots of things written about this, but we’ll just keep to one simple slide. We will take these as being, this is a sort of homing cascade that directs circulating lymphoblasts and B cells back to Peyer’s patches. So we take this as being a lymphocyte. We’ve mentioned these a couple times before. These are high endothelial venules. They are specialised and express something called Mucosal Addressin Cell Adhesion Molecule 1, otherwise known as MadCAM-1. So that’s a specialised adhesion molecule. The lymphocytes express something called Alpha4 Beta7 integrin. So essentially lymphocytes roll along the HEVs until they get tethered by the MadCAM, once that happens, you then get activation.
Think alpha 4 (as fave number) but lots of people prefer 7 so beta 7!
They’re rolling arrests and then they migrate back into the lamina propria. And homing, that’s lymphocytes, but B cells they also do the same thing. So basically, they are getting out into circulation and manage to get their way back to Peyer’s patches, etc.
Rapid Turnover of Enterocytes
- Enterocytes & goblet cells of small bowel have a short life span (about 36 hrs)
- Rapid turnover contrasts with lifespan of weeks/months for other epithelial cell types (e.g. lung, blood vessels)
Q. Why?
=because enterocytes are the first line of defence against GI pathogens. So they’re in the line of fire and they’re the first to be affected by toxic substances in the diet for pathogens. Therefore, because they’re turning over so quickly, the effects of those agents which interfere with cell functional or metabolic rate, etc should, in theory, be diminished. And if any lesions occur, then they’re going to be short lived.
Lower GI Infections
Q. How are these images connected to mucosal turnover?
A.CHOLERA
•London physician who proved waterborne transmission in 1849
So the answer is cholera. So John Snow was a London physician and he worked out how cholera was spread. He did that back in 1849. And how did he do that? He worked out where all the water pumps were, and then he worked out where everyone that had cholera was. So, particularly famous is Broad Street pump, he noticed that all these residents that used that water pump, they all had cholera. And you start going further away, these were people using these water pumps were absolutely fine. So what he did was stop people using that, it caused a big fuss, but when he stopped using that, then, of course, the cases of cholera decreased.
Cholera Infection
What’s the mechanism? Well, cholera is an acute bacterial disease. It’s caused by vibrio cholera, those are the serogroups. What happens is that the bacteria reaches the small intestine, when it comes into contact with the epithelium/an enterocyte, it releases a cholera enterotoxin. So then that cholera enterotoxin then gets internalised through retrograde endocytosis into the enterocyte. There it causes activation of adenylate cyclase, which in turn increases cyclic adenosine monophosphate. And then that causes active secretion of salt and fluid through the activation of the cystic fibrosis transmembrane conductance regulator (CFTR). And once that happens, you lose lots of salt, potassium, chloride, bicarbonate, etc. And following that is water.
We now know it’s caused by the faecal oral route because we’ve seen slide before. So it’s contaminated water in that particular case. The main symptoms are severe dehydration, watery diarrhoea. Hence people were too weak to get up to open their bowels, they put them in beds with holes cut in and buckets underneath, and someone would change it for them. There’ll be other symptoms, such as vomiting and nausea and abdominal pain.
You diagnose it by bacterial culture from a stool sample. You do it on a selective agar, that’s a standard way. There are some rapid dipstick tests which are available. Treatment is essentially oral rehydration and doing that
You can actually get up to 80 percent of people through that. Fortunately now there is a vaccine, but you still get many cases within the country, within the world, 1.3 to 4 million. The last actual indigenous case in the UK was back in 1893, so you’ll recall this gentleman was there in 1849. So that was the last indigenous case. 2017 I think there was something like 13 patients diagnosed with cholera, but they people had flown into the country. Other causes of infectious diarrhoea.
Other Causes of Infectious Diarrhoea - Gastroenteritis
Other causes of infectious diarrhoea. We’ll briefly go through some of these, they are many and numerous, so we can’t possibly cover them all. We can cover some of the ones that are common. Viral includes rotavirus, especially in children, and norovirus, also known as winter vomiting bug. We won’t cover protozoal parasitic infections, but you will at some stage come across Giardia. And then entamoeba histolytica, which is amoebic dysentery, not that common in the UK. Bacterial not only have you got cholera, we’ve got campylobacter, E coli, salmonella, shigella, and I’m going to say C. diff for the time being.
Rotaviruses
So rotavirus- these are RNA viruses. They replicate in enterocytes, there are five types, A to E, type A being the most common one in humans. These are the most common causes of diarrhoea, it’s the commonest cause of diarrhoea and infants and young children worldwide. Treatment is actually just oral rehydration therapy. Even so, it still causes up to 200,000 deaths per year around the world.
There is a vaccine, but before that vaccine, most individuals would have recurrent infections by the age of five, and those repeated infections would give them developed immunity. There is now an oral vaccine against Type A, which was introduced in 2013. And this graph shows the number of laboratory reports in 2013 were up at 14,000, so as soon as that oral vaccine was introduced, 2014, 2015 dropped down to about 4000. So extremely effective
Description:
- RNA virus, replicates in enterocytes.
- 5 types A – E, type A most common in human infections.
Epidemiology:
•Most common cause of diarrhoea in infants & young children worldwide.
Treatment:
- Oral rehydration therapy
- Still causes ~ 200,000 deaths/year.
- Before vaccine, most individuals had an infection by age 5, repeated infections develop immunity.
Vaccination:
•Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013.
Norovirus (genus) Norwalk virus (species)
Norovirus, again, is a RNA virus, has an incubation period, about 24 to 48 hours. Again, has a faecal-oral transmission. But remember, patients that have this, they may shed their infectious virus for up to two weeks so they’re still infectious. These are the ones you hear in the news, they occur in closed communities, particularly in cruise ships you see stranded outside some Caribbean islands. That’s due to norovirus. Their symptoms is acute gastroenteritis, and most people recover within one to three days. So treatment is not usually required. It’s all supportive. You diagnose it by a sample PCR. And it’s very common. Causes up to 685 million cases per year. That’s a lot.
Description:
- RNA virus
- Incubation period 24-48 hours (the period between exposure to an infection and the appearance of the first symptoms)
Transmission:
- Faecal-oral transmission.
- Individuals may shed infectious virus for up to 2 weeks
- Outbreaks often occur in closed communities
Symptoms:
•Acute gastroenteritis, recovery 1 – 3 days
Treatment:
•Not usually required
Diagnosis:
•Sample PCR.
Epidemiology:
•Estimated 685 million cases per year.
Campylobacter “curved bacteria”
Those are the two commonest species. Their transmission is via undercooked meat, especially poultry or untreated water and unpasteurised milk. You only need less than 500 bacteria, it’s got a low infective dose that can cause an illness. Again, you usually let it run its course. You keep rehydrated, you don’t normally need to treat them. If you do, Azithromycin is the standard antibiotic and there are problems with resistance to other antibiotics. In the U.K., there’s still an estimated 280,000 cases per year. This is food poisoning, but only 65,000 of those are actually confirmed, and it is the commonest cause of food poisoning in the U.K.
Most common species:
•Campylobacter jejuni, Campylobacter coli
Transmission:
- Undercooked meat (especially poultry), untreated water & unpasteurised milk
- Low infective dose, a few bacteria (<500) can cause illness
Treatment:
- Not usually required
- Azithromycin (macrolide) is standard antibiotic
- Resistance to fluoroquinolones is problematic
Epidemiology:
- Estimated 280,000 cases per year in UK, 65,000 confirmed
- Commonest cause of food poisoning in the UK
Escherichia coli (E. coli)
E. coli, you will come across many people with E. coli gastroenteritis or E. coli diarrhoea. You have to remember that E. Coli is everywhere, it’s a gram negative intestinal bacteria. And most of the time it’s harmless, but there’s six pathotypes associated with diarrhoea. I won’t go through them all, but this is the one that causes a real problem. E.coli 0157 serogroup. It produces Shigatoxin and verotoxin, and that is associated with 5-10% of patients getting haemolytic uraemic syndrome. That’s essentially lose of kidney function. So that’s the one that causes a big problem. Enteroinvasive E.coli is the one that’s usually associated with bloody diarrhoea.
- Diverse group of Gram-negative intestinal bacteria
- Most harmless
- 6 ”pathotypes” associated with diarrhoea (diarrhoeagenic):
Clostridium difficile (C. Diff.)-management
The real way of saying it is actually Clostridium difficile. And the reason that is, is because it’s actually the Latin for difficult, difficile. And it’s called difficult because it’s very difficult to grow in a laboratory.
This is an important one because this is the one that causes a lot of problem in hospitals and it’s usually caused by people having long term antibiotics. So if we look at this diagram on the right under ‘a’. The purple thing is C. diff. You also have, the green ones are disturbance-sensitive commensals and the grey ones are inflammation-tolerant commensals. So the weird thing is that the microbiota and the healthy human can contain C. diff. So why it’s there and what role it plays in the intestinal ecosystem is unclear, but it can exist without causing a problem.
We go to ‘b’ if you get an intermediate dysbiotic state or dysbiosis, usually starts to be caused by an exogenous disturbance such as antibiotics, you then allow C. Diff. to start colonising the enterocytes and you get an outgrowth in the distal gut. But here it’s important they’re not actually producing a toxin at that particular stage. So when it gets the intermediate dysbiotic state, you still have a chance of returning back to the normal state. The difference being, even though they’re colonising, they’re not producing toxins. Unfortunately, if you then get a pathogen induced disturbance, which creates a supportive environment for the C. Diff. to carry on dividing or surviving. It then starts producing a toxin and it’s that state that you get inflammation of the distal gut. And that’s what’s responsible for the C. Diff. mediated disease.
What is the management? Well, immediately isolate that patient, because this mainly happens in hospitals. It’s very contagious. You stop antibiotics. The treatment is metronidazole or vancomycin. The weird thing is, it’ll be one of your exam questions when you start studying for your final exams, after you’ve qualified, for whatever you want to be. Weirdly metronidazole can cause C. diff as well. It can cause the gastroenteritis. So that not only can it cause it, but it can also be used to treat it. If that makes sense. Recurrent rates are about 15-35% after the initial infection, and if it does recur, it becomes increasingly difficult to treat.
What does work, though, is faecal microbiota transplantation, FMT, you get up to 90 and 98 percent cure rate. So that is an important one that exists in hospitals. The other ones are the ones that you will come across.
Management
- Isolate patient (very contagious)
- Stop current antibiotics
- Metronidazole, Vancomycin
- Recurrence rate 15-35% after initial infection, increasingly difficult to treat.
- Faecal Microbiota Transplantation (FMT) – 98% cure rate
Session review
