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Y2 - BRS - GI > Immunology of the Gut > Flashcards

Immunology of the Gut Flashcards

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1
Q

What is the surface area of the gut?

A

200 m^2

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2
Q

How long is the small and large bowel put together?

A

8 metres

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3
Q

What does the gut have to deal with?

A

Massive antigen load:

  • Resident microbiota 10^14 bacteria
  • Dietary antigens
  • Exposure to pathogens

Has a responsibility to recognise, respond to, and adapt to countless foreign and self molecules

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4
Q

In what state is the gut in constantly to deal with the foreign and self molecules?

A

‘Restrained activation’

Has to balance tolerance (food antigens, commensal bacteria) VS active immune response (pathogens)

Dual immunological role

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5
Q

How are the gut microbiota and its role studied?

A

Gnotobiology

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6
Q

What is Gnotobiology?

A

Take germ free animals (e.g. mice)

Selectively colonise them with selective bacteria

Compare and observe differences in these mice to conventionally housed mice (with normal gut microbiota)

e.g. development of peyer’s patches in the small intestine of germ free mice are fewer and less cellular than those with conventional microbiota, paneth cells (important for defence against pathogens) are reduced in germ free mice compared to conventional

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7
Q

How many gut bacteria are there?

A

10^14 gut bacteria and 10^13 cells in body - most densely populated “ecosystem” on Earth

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8
Q

What are the 4 major phyla of bacteria?

A

Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria

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9
Q

Why is the gut microbiota important?

A

Provide traits we have not had to evolve on our own - genes in gut flora 100 times our own genome

Gut flora genes = 100x our own genome

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10
Q

What are their functions?

A

Provide essential nutrients we cannot manufacture

Metabolise what we find indigestible compounds

Act as a defence against colonisation of opportunistic pathogens

Contribute to intestinal structure

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11
Q

What is meant by the term microbiota?

What is meant by the term microbiome?

A

Mixture of microorganisms that make up a community within a particular anatomical niche

Collective genomes of all microbiota (of all anatomical niches)

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12
Q

What can increase numbers of microbiota?

A

Stimulatory factors:

Certain ingested nutrients

Secreted nutrients

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13
Q

What can decrease the numbers of microbiota?

A

Chemical digestive factors leading to bacterial lysis

Peristalsis and defecation

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14
Q

How does the bacterial content and chemical digestive factors produced by the host (humans) change along the digestive tract?

A

Stomach =
10^1
HCL, Pepsin and Gastic Lipase

Duodenum =
10^3
Bile acids from liver

Jejunum =
10^4
Trypsin, amylase, carboxypeptidase from pancreas

Ileum =
10^7
Brush border enzymes

Colon =
10^12
No host digestive factors

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15
Q

What is meant by the terms:

Symbiosis
Symbionts
Commensals
Pathobionts

A

Symbiosis = living together (does NOT imply either partner benefits)

Symbionts = organisms that live within the host without any benefits or harm to one and other

Commensals = micro-organism that benefits from association with the host, but has no effects on the host

Pathobionts = symbionts that do not normally elecit an inflammatory response, but under certain conditions (usually environmental) have the potential to cause dysregulated inflammation and disease

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16
Q

In a normal gut, how are symbionts, commensals and pathobionts balanced?

A

All equally balanced

________
^

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17
Q

What is dysbiosis?

A

Altered microbiota composition due to disturbance of the symbionts / commensals / pathobionts

—….__
^

e.g. something allowing pathobionts to start producing pathogens

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18
Q

What are the causes of dysbiosis?

A

Wide and varied:

Infection and inflammation
Diet
Xenobiotics - molecules that enter the gut unnaturally e.g. drugs and pollutants
Hygiene
Genetics
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19
Q

What is associated with dysbiosis?

A

Pathobionts produce bacterial metabolites and toxins which negatively affect us

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20
Q

What kind of metabolites and toxins can pathobionts produce?

A
  1. TMAO - trimethylamine-N-oxide = if increase leads to increased deposition of cholesterol in artery walls
  2. 4-EPS - 4-ethylphenylsulfate = associated with Autism
  3. SCFA - short chain fatty acids = if decreased can lead to IBD, if increased associated with neuropsychiatric disorders e.g. stress
  4. AHR - aryl hydrocarbon receptor ligands = associated with MS, RA and asthma
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21
Q

What is NAFLD?

A

Non-alcoholic fatty liver disease

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22
Q

What is NASH?

A

Non-alcoholic steatohepatitis

inflammation from fat

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23
Q

What factors help the gut defend itself?

A

Physical barriers
Commensal bacteria - occupy ecological niche
Immunological systems following invasion - MALT and GALT

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24
Q

What are physical barriers composed of?

A

Anatomical =

  • Epithelial barrier
  • Peristalsis

Chemical =

  • Enzymes
  • Acidic pH
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25
What forms the epithelial barrier?
Mucus layer secreted by Goblet cells Epithelial monolayer has tight junctions keeping pathogens out Paneth cells in the small intestine are found in the bases of crypts of Ueberkuhn = secrete antimicrobial peptides )defensins) and lysozyme
26
What are the immunological defences of the gut if pathogens do invade into the gut/body?
MALT = mucosa associated lymphoid tissue GALT = gut associated lymphoid tissue
27
Where is MALT found?
Found in the submucosa below the epithelium, seen as lymphoid mass containing lymphoid follicles Follicles are surrounded by HEV (high endothelial venules) post-capillary venules, allowing easy passage of lymphocytes Oral cavity rich in immunological tissue - esp. palatine and lingual tonsils, and at the back of the mouth pharyngeal tonsils (adenoids)
28
What is GALT comprised of?
Largest mass of lymphoid in the body Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes
29
What is GALT responsible for?
Both: adaptive & innate immune responses
30
In what two ways can the lymphoid tissue exist?
Non-organised OR Organised
31
What are the main features of non-organised GALT?
Intra-epithelial lymphocytes Make up 1/5th of intestinal epithelium, consists of e.g. T-cells, NK cells Also found within lamina propria lymphocytes
32
What are the main features of organised GALT?
Peyer’s patches (small intestine) Caecal patches (large intestine) Isolated lymphoid follicles Mesenteric lymph nodes (encapsulated)
33
Describe the cells present in non-organised GALT e.g. in the ileum:
Stem cells produce enterocytes that rapidly migrate to apex (top of mirovilli) Apoptosis of the intra-epithelial cells = apoptotic intraepithelial cells at the apex Goblet cells formed at the base, they migrate north and produce mucus Stem cells also produce paneth cells, which produce anti-microbial peptides (AMPs) Within the epithelium itself, there are intra-epithelial lymphocytes - found lying between peithelial cells Majority of immunological cells found in lamina propia (central part of villus) - including T cells, B cells, macrophages and DCs
34
How do the small and large bowel differ structurally?
Small bowel has villi, paneth cells Large bowel has crypts, many goblet cells and intraepithelial lymphocytes
35
What is the main type of organised GALT?
Peyer's patches - 'immune sensors'
36
Where are peyer's patches found?
Found in submucosa small intestine – mainly distal ileum
37
What are peyer's patches comprised of?
Aggregated lymphoid follicles covered with follicle associated epithelium (FAE) FAE contains no goblet cells, no secretory IgA, no microvilli
38
How are Peyer's patches organised?
There is the FAE and M cell layer Beneath the M cell is the peyer's patch consisting of the: Sub-epithelial zone - mainly dendritic cells (help transfer antigens from the gut lumen via M cells to the Peyer's patch) B-cell follicles Interfollicular T-cells All move towards mesenteric lymph nodes
39
What does peyer's patches development require?
Development requires exposure to bacterial microbiota e.g. 50 in last trimester foetus, 250 by teens
40
How do peyer's patches work?
M (microfold) cells are found within the FAE Antigen uptake via M cells within FAE M cells express IgA receptors - facilitate the transfer of IgA bacteria complex into the Peyer's patches
41
What is the route for preventing bacterial invasion separate to M cells?
Via dendritic cells Open up tight junctions and send dendrites outside epithelium to retrieve / sample bacteria from lumen of gut Bring back the bacteria and transport them to mesenteric lymph nodes They are able to do this because they express tight junction proteins e.g. occludin, claudin-1 etc. so maintain the tight-junction barrier after taking sampled antigens from lumen of gut
42
Recap the M cell stuff:
M cells are found on the FAE layer There are antigens present in the lumen of the gut Antigens are taken up via the M cells Dendritic cells, a type of antigen presenting cell (APC), engulf the antigen and present it on the MHC II molecules on the cell surface The DCs then migrate to the Peyer's patch, where there is further immunological response (as the Peyer's patch contains T cells, B cells etc.)
43
What is the B-cell adaptive response in peyer's patches?
Mature naïve B-cells express IgM in Peyer’s Patches On antigen presentation class switches to IgA T-cells & epithelial cells influence B cell maturation via cytokine production Activated B cells further mature to become IgA secreting plasma cells These populate lamina propria Some enter lymphatic system
44
What happens to the immune cells that enter the lymphatic system?
Plasma cells migrate back to enterocytes These are taken up into epithelial cells There is enzymatic cleavage And then they secrete IgA
45
What is the function of sIgA (secretory IgA)?
Up to 90% of gut B-cells secrete IgA sIgA binds to luminal antigen preventing its adhesion and consequent invasion
46
Summarise lymphocyte honing and circulation:
Antigen presents in Peyer's patch Activation of T cells and B cells These are transferred to mesenteric lymph node - lymphocyte proliferation They then go into circulation via thoracic duct (main lymphatic duct for return to venous system) Once it enters the venous system, it can enter the peripheral immune system Or it can also exit back into the intestinal mucosa back to the lamina propria
47
What comprises peripheral immune system?
Skin Tonsils MALT and BALT (bronchus associated lymphoid tissue)
48
How do lymphocytes and B cells return to the Peyer's patches?
HEV express MAdCAM1 which is a specialised adhesion molecule Lymphocytes express alpha-4 beta-7 integrin Lymphocytes roll along the HEVs until they get tethered by MAdCAM1 Leads to activation and rolling arrests of lymphocytes = migration back to lamina propria Transports back to Peyer's patches
49
Why do enterocytes and goblet cells have such a short lifespan?
Approx. 36 hrs (rapid turnover compared to other cells that last weeks / months) Enterocytes are first line of defense against GI pathogens & are first to be directly affected by toxic substances in diet / pathoggens Effects of toxic agents which interfere with cell function, metabolic rate etc. will be diminished So any lesions that occur are short-lived
50
What is the mechanism of cholera infection?
Cholera - is an acute bacterial disease caused by Vibrio cholerae serogroups O1 & O139 Bacteria reaches small intestine and when it comes in contact with epithelium, it releases cholera enterotoxin The cholera enterotoxin gets internalised via retrograde endocytosis into the enterocytes, activating adenylate cyclase This increases cAMP That causes active secretion of salt and fluid via the cystic fibrosis transmembrane conductance regulator (CFTR) Leads to loss of salt, potassium, chloride, bicarbonate and water in the faeces
51
How is cholera transmitted?
Transmitted through faecal-oral route Spreads via contaminated water & food
52
What are the symptoms of cholera?
Main symptoms = Severe dehydration Watery diarrhoea Other symptoms = Vomiting Nausea Abdominal pain
53
How is cholera diagnosed?
Bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available
54
How is cholera treated?
Oral-rehydration is the main management - up to 80% of cases can be successfully treated
55
What are the main features of the cholera vaccine?
Dukoral, oral, inactivated
56
What are some other common causes of diarrhoea?
Viral = Rotavirus (children) Norovirus “winter vomiting bug” ``` Bacterial = Campylobacter jejuni Escherichia coli Salmonella Shigella Clostridium difficile ``` Protozoal parasitic = Giardia lamblia Entamoeba histolytica
57
What are rotaviruses? How common are they?
RNA virus, replicates in enterocytes 5 types A – E, type A most common in human infections Most common cause of diarrhoea worldwide in infants and young children
58
How are rotaviruses treated?
Oral rehydration therapy Still causes up to 200,000 deaths/year. Before vaccine, most individuals had recurrent infections by age 5, repeated infections develop immunity
59
What is the vaccine against rotaviruses?
Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013
60
What are noroviruses? How common is it? How is it transmitted?
RNA virus Incubation period 24-48 hours Estimated 685 million cases per year Faecal-oral transmission. Individuals may shed infectious virus for up to 2 weeks Outbreaks often occur in closed communities
61
What are the symptoms of norovirus? How is it treated?
Acute gastroenteritis, recovery 1 – 3 days No specific treatment - just supportive
62
How is norovirus diagnosed?
Sample PCR
63
What are the 2 most common species of curved bacteria? How common is it? How are they transmitted?
Campylobacter jejuni Campylobacter coli Estimated 280,000 cases per year in UK (food poisoning), 65,000 confirmed Commonest cause of food poisoning in the UK ``` Undercooked meat (especially poultry), untreated water & unpasteurised milk Low infective dose, a few bacteria (<500) can cause illness ```
64
What is the treatment for campylobacter?
Not usually required - supportive e.g. rehydration Azithromycin (macrolide) is standard antibiotic Resistance to fluoroquinolones is problematic
65
What are the main features of E. coli?
Diverse group of Gram-negative intestinal bacteria Most of the time it is harmless 6 ”pathotypes” associated with diarrhoea (diarrhoeagenic)
66
What are the 6 E.coli pathotypes associated with diarrhoea?
Enterotoxigenic E. coli (ETEC) - cholera like toxin, watery diarrhoea Enteroinvasice E. coli (EIEC) - shigella like illness, bloody diarrhoea Enterohaemorrhagic or Shiga toxin -producing E. coli (EHEC/STEC) Enteropathogenic E. coli (EPEC) Enteroaggregative E. coli (EAEC) Diffusely adherent E. coli (DAEC)
67
Which of these is the most problematic?
Enterohaemorrhagic or Shiga toxin -producing E. coli (EHEC/STEC) E. coli O157 serogroup, Shigatoxin/verotoxin 5-10% get haemolytic uraemic syndrome: loss of kidney function
68
Why is C diff. called its name (clostridium difficile)? What often causes c. diff infections? What is weird about C. diff?
It is difficult to grow in a lab Long term antibiotics Healthy microbiota can contain C. diff - so role in intestinal mucus is unclear, but can exist without causing harm
69
When does C. diff become a problem?
Intermediate dysbiotic state caused by a exogenous disturbance e.g. antibiotics C. diff starts colonising enterocytes and you get an outgrowth in the distal gut, but still not producing toxins at this stage Pathogen induced disturbance creates supportive environment for C. diff to continue dividing and surviving - C. diff then starts producing toxin Causes inflammation of distal gut
70
At which stage of C. diff becoming an issue is there a chance to return to normal healthy gut microbiota?
Before C. diff begins producing toxins - so even when it has begun colonising enterocytes, if it is not producing toxins - there is a chance of returning back to normal state
71
What is the management in C. diff?
Isolate patient (very contagious) - tends to happen in hopsital Stop current antibiotics Start them on Metronidazole, Vancomycin Recurrence rate 15-35% after initial infection, increasingly difficult to treat Faecal Microbiota Transplantation (FMT) – 98% cure rate
72
What is weird about Metronidazole?
Can cause and treat C. diff
73
How can reccurent C. diff infections be treated?
Faecal microbiota transplantation - 90 to 98% cure rate

Y2 - BRS - GI (14 decks)

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