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Microbiota On Mucosal > L4/5 Gut Mucosa > Flashcards

L4/5 Gut Mucosa Flashcards

1
Q

What is mucus composed of

A

95% water
10% mucin glycoproteins
Siga
Proteins/lipids etc from dead cells

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2
Q

Explain the structure of mucin

A

Has a peptide core
On it has globular d domains with d1,2 and 3 on the n terminus before the vntr in the middle

C terminus has d4,b,c and cysteine knot ck on end

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3
Q

Which part is o glycosylated on ser/thr residues

A

Vntr

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4
Q

Why is mucin special

A

Can polymerise to form the gel part of mucus through disulfide bonding

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5
Q

Which mucin genes and what chr are part of the Mucins forming gel

A

11p15.5
Muc2(intestines)
Muc5ac
Muc6
Muc 5b

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6
Q

How is muc6 diff in structure

A

Has no d4,b or c on c terminal just has ck

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7
Q

Which protease can degrade these mucin polymers and into what

A

Pepsin

Into soluble glycoproteins which can’t form a gel

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8
Q

What are these further degraded by for their glycans

A

Gut commensals like b theta

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9
Q

Give a type of o-glycosylation

A

Galnac

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10
Q

What sort of cells line oesophagus

A

Non-keratinised stratified(many layers) Squamous epithelium (like mouth)

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11
Q

Give the 3 layers of these cells in the mucosa of oesophagus

A

Bottom basal layer above basal lamina is mitotic centre of the cells

Then prickle cell layer where cells spaced out with unknown glycoconjugate barrier

Then functional cell layer which can slowly slough/die and cells move to lumen of oesophagus

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12
Q

Is there a continuous layer of mucus in oesophagus and what releases it

A

No, only small amount released by submucosal gland

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13
Q

Why is it not needed

A

Because cells dying don’t need protected

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14
Q

Give a condition where excessive sloughing occurs

A

Sloughing esophagitis where acute or chronic inflam can occur if people get large fragments of squamous cells vomited or coughed up

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15
Q

What protects oesophagus from acid reflux

A

Hco secretion from both saliva and within esophageal cells

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16
Q

What 2 Mucins from saliva protect esophagus through antimicrobial mechanisms

A

Muc7 and muc5b

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17
Q

How is muc5b crucial in streptococcus mutans to prevent it from being antibiotic resistant

A

Muc5b glycosylated chains can prevent quorum signalling mechanisms of which can usually cause genetic transformation of bacteria into resistant

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18
Q

What is Barrett’s oesophagus

A

The change in terminal squamous cells of oe to intestinal like columnar cells with villi or gastric columnar cells both producing mucus usually not seen in oesophagus (intestinal / gastric meta plasia)

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19
Q

Is this precancerous

A

Yes

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20
Q

Which gastric mucosal columnar cells secrete mucus with mucins 5ac or 6

A

Apical (top of gastric pits) foveolar cells (5ac)
Or neck/base mucous secreting gland cells (6)

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21
Q

What else do foveolar secrete

A

Hco to neutralise gastric acid

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22
Q

What cells make gastric juice

A

Parietal cells produce hcl acid
Then pepsinogen released from chief cells then converted to pepsin (both in gastric pits)

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23
Q

What specialised cells release somatostatin to inhibit acid release for control

A

D cells

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24
Q

What do the cells in gastric pits sit above

A

Basal lamina and then below is the lamina propria (all part of gastric mucosa)

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25
Q

Explain the ph gradient on epi cell surface

A

In lumen of stomach ph is 1-2
HCO trapped by mucins near epithelial surface is 6-7 ph for protection

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26
Q

How does hcl and pepsin get out but can’t rediffuse back in through mucus to stop epi damage

A

At ph above 4 viscous fingers form which are channels of disrupted mucus to allow gastric juice to flow out helped by the hydrostatic pressure they cause in gastric glands

But when they reach lumen the low ph blocks reinvagination back = mucus protection

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27
Q

Which layer of mucus also helped block rediffusuon of acid back to epi cells

A

The firm inner layer of mucus which has polymeric mucin not the soluble outer layer because of the viscosity of the inner layer blocked acid flow

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28
Q

Explain gastric epithelial regeneration after ethanol damage as this freely diffuses through mucus (example of regeneration)

A

Dead cells and mucus will form a cohesive barrier with fibrin which is form converted fibrinogen released after damage

Also hco induced by prostaglandin released too which stops further acidic control

This barrier allows for new cells to migrate up gastric pits and sit on basal lamina to form new layer (stem cells from gastric pits)

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29
Q

How long does this reepitheliasation take

A

1 hour

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30
Q

Which type of aggressive pepsin replaces pepsin 3 as most abundant in gastric and duodenal peptic ulcer disease

A

Pepsin 1

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31
Q

What is this able to do

A

2fold greater mucin degradation in ph2 and 6 fold in ph4

Converts polymerised to soluble so reducing gel barrier

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32
Q

Molecular weight analysis in normal, gud or dud showed what % were soluble mucin forms

A

65% for gastric was soluble
35% for normal
50% for duodenal disease

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33
Q

Explain the pathogenicity associated with h pylori infection

A

Can cause gastritis and if chronic can lead to gastric cancer

Also involved in peptic ulceration

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34
Q

What % of cases of gastric cancer from pre-existing infection of hp

A

90%

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35
Q

Where does it get nutrients from

A

The tj disruption it can induce itself or through mild inflammation eg releasing albumin proteins

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36
Q

How does it survive under the mucus layer

A

It needs to be protected from ph2 so before it enters mucus layer it uses it’s urease activity which converts urea to ammonia neutralising acid

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37
Q

Why is more soluble mucin found in h+

A

Urease can degrade mucin through ammonium

38
Q

Which part of stomach does h pylori colonise best and why

A

Antrum because few parietal cells so less acid

39
Q

Which adhesin on hp binds mucin 5ac Lewis b or cell surface Lewis b (muc1)

A

BabA

40
Q

What does this cause

A

Interaction in the mucin but also can induce t4ss to deliver virulent proteins into cell

41
Q

Give example of virulent fsctor injected by t4ss

A

CagA which can disrupt ecadherin and bcatenin complex interactions disrupting tj between cells

42
Q

What else can be injected in via t4ss that can activate nod1 and inflammation

A

Peptidoglycan (dapi) of hp

43
Q

How does hp structure help it enter mucus

A

Has 5/6 polar flagellate which can rotate and enter viscous mucus

44
Q

How is flagella not recognised on hp by tlr5 confusing the immune system

A

The n terminus is different

45
Q

How is lps activation of tlr4 by hp also downregulated

A

Express ‘self’ Lewis x antigen on the lps

46
Q

Whcih enzymes do they have which stops ros killing through detoxifying ros

A

Catalase and sod

47
Q

How does hp aswell as mucus which impedes movement of neutrophils affect neutrophils directly

A

It downregulated neutrophil receptors for chemoattractant il8

48
Q

COLONIC MICOSA L5

A

.

49
Q

Where is protein core / backbone synthesised and then travel to for glycosylation

A

Er then through Golgi network for glycosylation

50
Q

Give example of n glycosylation being important too eg fucosylation or sialic acid addition

A

Muc1 on all epithelial has n-glycans and which help folding

51
Q

Where is the bilayer existing from gastric down the thickest and thinnest

A

Thinnest in small intestine

Thickest in colon

52
Q

What is the first step in mucin polymerisation and packaging in secretory vesicles

A

At ph7.4

D3 trimer forms where 3 d3 domains form disulfide bonds with eachother

At this point the c terminal Ck and n terminal d1/d2 is sticking out

53
Q

What does the ph drop to in Golgi and secretory granules

A

6 then 5.2 respectively

54
Q

What else happens at this stage

A

Ca levels increase

55
Q

What does the lower ph and ca increase help form

A

Non covalent bonds between the d1/d2 domains and new d3 domains so that there is a 6 side ring with 6d3 trimers at each corner

This is how it’s stored

56
Q

What happens to these non covalent bonds when mucin is secreted and why

A

They are disrupted so little rings dissolve with no d1/2 and d3 interactions

Because ca is exchanged for na and ph rises again

57
Q

What happens next

A

Ck domains will start to become hinges (ck diners form) where the d3 trimer at 6 corners are linked with ck domains

Hexagonal Net formation where the corners are d3 trimers and sides are ck dimer links

Causes expansion of mucin and uptake of water forming a gel

58
Q

Expansion by what fold

A

1000-3000

59
Q

How does akkermansia feed off outer layer of mucus in colon

A

Has a o-glycopeptidase A (pfam13402 containing)

Cleaves backbone off mucin and help utilise glycans

60
Q

Give 3 structures that help bacteria bind Mucins when they live on outer layer

A

Fimbriae (ecoli)
Flagella
Adhesins (lactobacillus binds non specific glycans)

61
Q

How is it suggested bacteria can induce this bilayer formation from inner to outer (explains why colon has thickest)

A

Butyrate production and uptake by colonocytes causes their boxidation
The co2 from this converted to HCO from carbonic anhydrase which increases the ph and precipitates calcium

This as we know allows stratification of Mucins as the d1/2 and d3 interaction disrupted = wider net

Explains why low HCO in cf causes aggregation of mucus on surface

62
Q

Which tf does butyrate induce action of on muc2 promoter

A

Ap-1

63
Q

How can tlr stimulation by flagella or lps cause mucin secretion from secretory vesicles of colonic crypt goblet cells

A

Downstream signalling through myd88 adaptor protein on tlr receptor and subsequent ros generation causes nlrp6 inflammasome activation which stimulates muc2 exocytosis

64
Q

Explain the differences in bacteria eg in transcriptomics found by li 2015 in ecoli from colonise mice lumen or colonic mucus

A

Ecoli within the mucosal layer had adapted by increasing exp of enterobactin siderophore for better iron uptake for growth (low iron in mucus)
Also were found to increase proliferation rate from half life of 8 to 3hr to keep up with regeneration of mucus

Also since they can’t utilise mucinnglycans they use non specific carbon sources like phospholipids in the mucus layer

65
Q

What other bacteria also were able to proliferate quicker in mucus layer and uprwgulsted Pul 78 for o-glycans and Pul 72 for n glycans

A

B theta

66
Q

How is tolerance through lps kept in colon

A

Low exp levels of lps in colon

67
Q

What did Shan 2013 hope to study

A

How muc2 in small intestine pp can induce dc to have anti inflammatory properties

68
Q

How could dc from pp interact with glycosylated muc2 in combo with lps

A

Through galactin protein 3 on dc bind side chains

69
Q

What sorts of cytokines were downregulated by this

A

Il8,il12, tnf

70
Q

Which anti inflam cytokines were induced by the interaction

A

Il10 and tgfb = tregs

71
Q

Which tf which blocks nfkb was upregualted by muc2 showing how it can modulate the cytokines

A

B catenin

72
Q

What was the issue with the study

A

Used pig gastric mucin instead of muc2 human

73
Q

Explain the effect wt shigella flexneri had on Mucins structure on surface and how this impacted its invasion ability

A

Wt flexneri was able to produce a lattice mucin layer on top of colonic epi cells which contained muc5ac in high amounts

It accumulated and was not able to spread from surface trapping the Mucins. As well as this wt flexneri was able to induce sulfation of the mucin side chains

Since it was found in vivo could invade cell better these mechanisms could be why

74
Q

Why was this not backed up by expression effects the wt shigella had

A

It didn’t increase mucin exp eg of muc5ac only muc2 slightly. So doesn’t explain the large amounts of tight bound Mucins on surface

75
Q

Where is 5b located (not down gi tract)

A

Airways

76
Q

Where is susceptible to proteolysus by pepsin

A

Where glycosylation is sparse (same with iga) ie the protein cores

77
Q

Explain the link between mucus shaping the Microbiota in uc

A

Loss of complex glycans, increases in sialyl rich rn antigen which increases strains with silaidade activity eg ecoli

78
Q

Give the cross feeding interaction between hifidum and breve due to its exo sialidases

A

Can release sialic acid from mucin sialoglycans so that breve can then use the mucins

79
Q

How often does gastric mucosa turnover occur

A

Every 72-96 hours

80
Q

Why would nsaids cause PUD

A

Inhibition of cox1 so blocks production of protective prostaglandins (which usually if barrier injury will stimulate release of hco and mucus for repair)

81
Q

Although babA binds Lewis B on muc5ac for interaction, how is muc1 a decoy

A

Also has it on cell surface and bc it’s c and n terminus are separated in er production it can be released to stop interactions with cells

82
Q

How is disruption between b catenin and E cadherin also tumorigenic

A

B catenin sustains wnt signalling whcih causes continuous proliferation

83
Q

How does toxin vacA stop an effective adaptive response

A

Downregulated of il2 to stop T cell effector proliferation

84
Q

At what conc do mucins become gel

A

20mg/ml

85
Q

Why are trefoil peptides important in mucus

A

Released can interact or cross link with mucins to help form a gel

In stomach found important for epithelial restitution after injury and mouse models with tff2 show resistance to nsaids damage

86
Q

Why is ca important for mucin packaging in Golgi / secretory granules

A

Positive charge attracts negative mucin together to pack vs when drops in lumen the mucins will repel from eachother

87
Q

Polymorphisms in which mucin are associated with stronger chronic gastritis by h pylori

A

Muc1 (steric hindrance and decoy binding are important )

88
Q

In dss mouse model, which species of bacteria was able to reverse colitis via increased mucus thickness and tj expression

A

L. Reuteri (makes sense because of il22 effect)

89
Q

Which disease has some mucin degrading r gnavus clades been associated with due to sialidases and fucosidases

A

Ibd

90
Q

Which commensal has been shown to change glycosylation through fucosylatuon (fut2 enzyme) for their own nutrient advantage

A

B theta

91
Q

Give a viral and bacterial example of adherence when there is too much fucosylation

A

Norovirus (associated with crohns) and salmonella

92
Q

Which h pylori protein looks like iga proteases, induces inflam response but also blocks t helpers via il2 and DISRUPTS TJ (not adherens)

A

VacA

Microbiota On Mucosal (22 decks)

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