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

Immunology of the Gut Flashcards

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
Q

What forms the epithelial barrier?

A

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

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26
Q

What are the immunological defences of the gut if pathogens do invade into the gut/body?

A

MALT = mucosa associated lymphoid tissue

GALT = gut associated lymphoid tissue

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27
Q

Where is MALT found?

A

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)

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28
Q

What is GALT comprised of?

A

Largest mass of lymphoid in the body

Consists of B & T lymphocytes, macrophages, APC (dendritic cells), and specific epithelial & intra-epithelial lymphocytes

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29
Q

What is GALT responsible for?

A

Both: adaptive & innate immune responses

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30
Q

In what two ways can the lymphoid tissue exist?

A

Non-organised
OR
Organised

31
Q

What are the main features of non-organised GALT?

A

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
Q

What are the main features of organised GALT?

A

Peyer’s patches (small intestine)
Caecal patches (large intestine)
Isolated lymphoid follicles
Mesenteric lymph nodes (encapsulated)

33
Q

Describe the cells present in non-organised GALT e.g. in the ileum:

A

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
Q

How do the small and large bowel differ structurally?

A

Small bowel has villi, paneth cells

Large bowel has crypts, many goblet cells and intraepithelial lymphocytes

35
Q

What is the main type of organised GALT?

A

Peyer’s patches - ‘immune sensors’

36
Q

Where are peyer’s patches found?

A

Found in submucosa small intestine – mainly distal ileum

37
Q

What are peyer’s patches comprised of?

A

Aggregated lymphoid follicles covered with follicle associated epithelium (FAE)

FAE contains no goblet cells, no secretory IgA, no microvilli

38
Q

How are Peyer’s patches organised?

A

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
Q

What does peyer’s patches development require?

A

Development requires exposure to bacterial microbiota

e.g. 50 in last trimester foetus, 250 by teens

40
Q

How do peyer’s patches work?

A

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
Q

What is the route for preventing bacterial invasion separate to M cells?

A

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
Q

Recap the M cell stuff:

A

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
Q

What is the B-cell adaptive response in peyer’s patches?

A

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
Q

What happens to the immune cells that enter the lymphatic system?

A

Plasma cells migrate back to enterocytes

These are taken up into epithelial cells

There is enzymatic cleavage

And then they secrete IgA

45
Q

What is the function of sIgA (secretory IgA)?

A

Up to 90% of gut B-cells secrete IgA

sIgA binds to luminal antigen preventing its adhesion and consequent invasion

46
Q

Summarise lymphocyte honing and circulation:

A

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
Q

What comprises peripheral immune system?

A

Skin
Tonsils
MALT and BALT (bronchus associated lymphoid tissue)

48
Q

How do lymphocytes and B cells return to the Peyer’s patches?

A

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
Q

Why do enterocytes and goblet cells have such a short lifespan?

A

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
Q

What is the mechanism of cholera infection?

A

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
Q

How is cholera transmitted?

A

Transmitted through faecal-oral route

Spreads via contaminated water & food

52
Q

What are the symptoms of cholera?

A

Main symptoms =
Severe dehydration
Watery diarrhoea

Other symptoms =
Vomiting
Nausea
Abdominal pain

53
Q

How is cholera diagnosed?

A

Bacterial culture from stool sample on selective agar is the gold standard, rapid dipstick tests also available

54
Q

How is cholera treated?

A

Oral-rehydration is the main management - up to 80% of cases can be successfully treated

55
Q

What are the main features of the cholera vaccine?

A

Dukoral, oral, inactivated

56
Q

What are some other common causes of diarrhoea?

A

Viral =
Rotavirus (children)
Norovirus “winter vomiting bug”

Bacterial =
Campylobacter jejuni
Escherichia coli
Salmonella
Shigella
Clostridium difficile

Protozoal parasitic =
Giardia lamblia
Entamoeba histolytica

57
Q

What are rotaviruses?

How common are they?

A

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
Q

How are rotaviruses treated?

A

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
Q

What is the vaccine against rotaviruses?

A

Live attenuated oral vaccine (Rotarix) against type A introduced in UK July 2013

60
Q

What are noroviruses? How common is it?

How is it transmitted?

A

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
Q

What are the symptoms of norovirus?

How is it treated?

A

Acute gastroenteritis, recovery 1 – 3 days

No specific treatment - just supportive

62
Q

How is norovirus diagnosed?

A

Sample PCR

63
Q

What are the 2 most common species of curved bacteria? How common is it?

How are they transmitted?

A

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
Q

What is the treatment for campylobacter?

A

Not usually required - supportive e.g. rehydration
Azithromycin (macrolide) is standard antibiotic
Resistance to fluoroquinolones is problematic

65
Q

What are the main features of E. coli?

A

Diverse group of Gram-negative intestinal bacteria
Most of the time it is harmless
6 ”pathotypes” associated with diarrhoea (diarrhoeagenic)

66
Q

What are the 6 E.coli pathotypes associated with diarrhoea?

A

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
Q

Which of these is the most problematic?

A

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
Q

Why is C diff. called its name (clostridium difficile)?

What often causes c. diff infections?

What is weird about C. diff?

A

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
Q

When does C. diff become a problem?

A

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
Q

At which stage of C. diff becoming an issue is there a chance to return to normal healthy gut microbiota?

A

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
Q

What is the management in C. diff?

A

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
Q

What is weird about Metronidazole?

A

Can cause and treat C. diff

73
Q

How can reccurent C. diff infections be treated?

A

Faecal microbiota transplantation - 90 to 98% cure rate

Y2 - BRS - GI (14 decks)

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