L6/7: Microbiota And Health/disease Flashcards

1
Q

What are the major phyla of the gut

A

Bacteroidetes, firmicutes

Some actino and proteo (eg ecoli)

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2
Q

How is it murualistic

A

We benefit from them and they benefit from us via dietary fibre

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3
Q

Explain their role in biosynthesis

A

Of key nutrients and vitamins like folate associated with ntd and cancer

Vitamin k

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4
Q

How do bacteroides have an effect on iga

A

They induce exp of aid for class switching and b cell maturation

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5
Q

How do bacteria induce th17 (two ways)

A

Tlr 5 flagellin causes il6 and il23 release

Or

Sfb induce serum amyloid a for th17 differentiation

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6
Q

Why is th17 important for iga responses

A

It increases the cell exp of pigr (transfer of dimric iga across cell into siga)

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7
Q

Which cytokines do bacteria cause release of for b cell dev

A

Tslp

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8
Q

Which phyla are more diverse at genus level

A

Firmicutes eg roseburia, faecalibacterium, Ruminococcus

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9
Q

How are bacteria involved in metabolic disorders like t2d, obesity, atherosclerosis

A

They regulate metabolic pathways in host

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10
Q

Which major scfa imporgant in inducing pyy for satiety and glp1 for insulin secretion

A

Butyrate and proprionate(main one)

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11
Q

How do they do this

A

Act on gpcr41 and 43 on L- enteroendocrine cells

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12
Q

Give example of low bacteria in t2d

A

Roseburia butyrate producing and akkermansia

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13
Q

What sort of Microbiota are associated with dysbiotic effects in t2d and give example

A

Clostridium eg and prevotella Copri

Ef involved in increase glucose uptake from gut and branched aa which cause insulin resistance

(They prefer protein utilisation over glycans)

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14
Q

How might acetate be obesogenic

A

Substrate for hepatic and adipocyte lipogenesis , cholesterol synthesis and also causes release of ghrelin hormone iincreasing appetite

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15
Q

What do bacteria do to primary bile acids conjugated cholic and chenodeoxycholic acid

A

Deconjugate them via bile salt hydrolases (beh) and de hydroxylate them via bile acid inducing enzymes (bai)

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16
Q

What are they conjugated by usually

A

Taurine or glycine

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17
Q

How is deconjugation important in reducing cvd risk through reducing ldlc

A

It makes them hydrophobic so are lost in faeces meaning more cholesterol needed to converged to bile acids

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18
Q

Explain how meat diets through gut Microbiota metabolism can cause atherosclerotic risk

A

Choline and carnitine from red meat can be metabolised into tma by Microbiota

Then by hepatic host fmo they will oxidise it into tma-oxide (Tmao)

This upregulates scavenehrr ldl receptors on macrophages and also blocks cholesterol conversion into bile acids = increased ldlc and plaques

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19
Q

What are the secondary bile acids produced by bacteria

A

Lithocholic and deoxycholic acids

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20
Q

Which gut Microbiota metabolite looks like paracetamol and competitively binds to its enzyme to convert it to active form

A

Pcresol

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21
Q

Which enzyme

A

Sulfotransferase sult1a1

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22
Q

Which cardiac drug is inactivated by eggerthella Lenta

A

Digoxin into dihydrodigoxin

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23
Q

How does it stop working

A

Less affinity for na/k ATPase target in heart

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24
Q

Which chemotherapeutic drug can be reactivsted in gut after deconjugation in liver

A

Irinotecan (active chemo compound is called sn-38)

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25
Q

How and why has this led to inhibitors being administered with irinotecan to block toxicity

A

B glucoronidases and because it’s toxic

Screened for inhibitors of these enzymes

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26
Q

Give some examples of complex glycans for fibre used by B,f,a,p

A

Plant wall polysaccharide- xylans
resistant starch
Fructans polysach or FOS

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27
Q

Give an example of cross feeding on xylans

A

B ovatus can use complex xylans and then metabolise them into simple xylans used by bifido adolescentis (can’t grow separately)

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28
Q

What would happen if butyrate wasn’t present for b oxidation

A

Colonocytes needs to get energy from glycolysis which releases a lot of o2 making the gut aerobic which is bad

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29
Q

How is this bad and allows salmonella typhimurium

A

They can use oxygen as a respiratory electron acceptor for growth through their cytochrome bd oxidase they have
(Mutualists don’t)

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30
Q

How does ppary have to do with this

A

Activated by butyrate as it is an activator of b oxidation

Without ppary inos No synthase can be released and conversion into nitrate can be used by salmonella again for nitrate resp = outcompete

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31
Q

Give an example of a butyrate producing bacterium low in these situations

A

Clostridium

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32
Q

How can butyrate have anti cancer effects

A

It is a HDAC inhibitor. Can cause hyperacetylstion of apoptotic pathways = dead cancer cels

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33
Q

Which scfa act as acetyl donors for dn lipogenesis

A

Acetate and butyrate

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34
Q

How does acetate help colonisation resistance

A

Lowers ph

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35
Q

How can acetate be used to produce more butyrate

A

Cross feeding on acetate

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36
Q

How do all 3 cause antiinflammation pathways

A

Proprionate is HDAC 6 and 9 inhibitor which induces fox p3 exp

All 3 binds gpcr43 on tregs fox p3+ surface and activates them and causes secretion if il10

Il10 induces m1 to m2 shift which is antiinflam and also stops antigen presentation

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37
Q

How do they induce exp of amps in paneth cells

A

Downstream activation of stat3 txn activator by gpr43 binding

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38
Q

Which tj protein is upreg through hif1 through induction by anaeorbic butyrate

A

Claudin-1

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39
Q

How do they increase muc2

A

Ap1 txn activator allegedly or hdaci

40
Q

What can bacteria metabolise/ferment instead of fibre in high protein low carb diets

A

Amino acids

41
Q

Give an example of a detrimental metabolite this produces

A

Hydrogen sulfide which breaks down mucus barrier and also can be converted to thiosulfate then tetrathionate used as an aea by enteropathogens

(Also tmao production)

42
Q

Give some other potentially detrimental metabolites which are not beneficial unlike scfa

A

Ammonia, indolic substrates, branched chain fatty acids

43
Q

L2- Microbiota diversity and influences

A

D

44
Q

Name some things affecting gut composition

A

Antibiotics
Diet
Birth mode
Breastfeeding
Disease eg Ibd

45
Q

What is lost through c section from mother transfer in vaginal delivery

A

Bifido and bacteroides

46
Q

What can be transmitted instead from hospital environment

A

Opportunists eg enterobacteraciae like klebsiella or enterobacter (phylum is proteobac)

47
Q

Give some things more likely in C-section babies

A

Immune problems eg hypersensitivity, ibd and metabolic problems like diabetes (low butyrate?)
ASTHMA!!

All associated with proteobac

48
Q

Is the dysbiotic composition known

A

No

49
Q

What can grow on breast milk hmo best

A

Bifido infantis or adolescentis

50
Q

Other than hmo what does formula milk also lack which is bad

A

Antimicrobial lactoferrins
Iga from mother

51
Q

What can usually outgrow in formulae milk

A

Alterations eg increase proteobac like ecoli

52
Q

What are they associated with that bifido is not (negatively associated)

A

Allergies

53
Q

What happens in fermentation of hmo

A

Scfa production

54
Q

What can cross feed from hmo or prebiotic inulin-fructans breakdown by bifido

A

Butyrate producing eg faecalibacterium prausnitzii (firmicutes)

55
Q

Can fmt be done from mother to child after c section to retain normal bacteria

A

Yes but only done on small samples of babies so far

56
Q

From ff fed mice. Does it show that diversity of Microbiota can ever be regenerated

A

No. There is chronic loss

57
Q

Why is this bad

A

Reduced the metabolic potential and immune potential that diverse microbes can have

58
Q

What is a major factor in reducing this diversity

A

Diet change where not enough dietary fibre or not diverse enough for the cross feeding to happen

59
Q

Give example from the 16s metagenomics study on crohns firmicute composition

A

43 otu found in gut of healthy vs significant loss of all firmicutes (13 otu) eg clostridia

60
Q

How does butyrate affect proinflam cytokines through nfkb

A

Blocks degradation of ikb meaning nfkb is txn repressed

61
Q

What other differences between industrialised modern society and traidiotnal has changed Microbiota

A

Sanitation, antiobiotic use

62
Q

Which types of bacteria have increased which is potentially bad in industrialised

A

Verrucomicrobia feeding on mucin
And bacteroidaceae also feed on mucins

63
Q

Give example of lost cazyme diversity through time in society

A

Prevotellaceae (fmricutes) are part of the vanish species

64
Q

Changes in diet etc how does this create a lag phase in host adaptation which causes bad microbe-host interactions eg ifnslmation

A

The body can’t adapt as quick to these changes like Microbiota so end up getting obesity or inflammation etc

65
Q

Rexplain Desai 2016

A

Ff fed mice showed increase mucin degrades akkermansia and caccae
And increased cazymes exp like gh109 for galnac but reduced for plant polysaccharides

Increased susceptibility to citrobacter

66
Q

What did glucose fed mice do similarly in dss induced colitis mice

A

Increased mucin degraders and cazymes because can’t use glucose

Showed this excacerbated dss induced colitis

67
Q

Give an example of fmt success story

A

Used to treat C. difficile infections eg post antibiotics because antibiotics kill it but spores remain in gut

Fmt allows to get rid of spores

68
Q

Give an example of a bacteriocin for this

A

Thurin cd from bacteroides thuringiensis

69
Q

What is probiotics for

A

Usually live microbes llactobacillus and bifido which can help colonise eg bifido causes cross feeding with butyrate producing ones

Also modulate immune responses like lactobacillus gg induces siga in gut response

70
Q

What is currently being added to formula as a prebiotic and what is a challenge to add in

A

Fos and inulin fructan

Challenge is hmo

71
Q

Where can inulin be found

A

Eg Chicory, garlic

72
Q

Give a gut-brain axis example of how brain modulates the gut neuro immunity and microbe composition

A

Cortisol regulation through the Hypothalmic-pituitary-adrenal axis = during chronic stress active

This can cause gut permeability through tj disruption, reduce bacteroides spp and promote immune activation eg il6 increase and McP-1

73
Q

How can scfa modulate behaviour / satiety/a peptide through the brain

A

Through L-enteroendocrine release of glp-1 and pyy which act to stimulate feelings of satiety and reduced appetite

74
Q

What positive effect does butyrate also have on the brain

A

Maintains the bbb integrity

75
Q

How does inflammation in gut through dysbiosis then link to depression

A

Cytokines travel through vagus nerve and chronically activate the HPA axis which is thought to a cause of chronic stress and depression

76
Q

Which nt can lactobacillus and bifido release having neuromodulatorg effects

A

Gaba

77
Q

Which cytokines is said to activate hpa but downregulate the gr for negative feedback = chronic stress and depression from gut dysbiosis

A

Il6

78
Q

Why would as you age show lower diversity overall

A

Different diets for example

79
Q

Does alpha diversity increase over someone’s lifetime

A

Yes (this is where within a. Sample you get more diversity)- eg as a baby you’re first colonised with facultative aerobes then at 120 dol change to obligate such as bifido based on milk

80
Q

How does glp-1 act in the pancreas after release by scfa

A

Reduced b cell apoptosis
Insulin release and glucagon decreases = insulin sensitivity (reduced risk of diabetes)

81
Q

Which one is currently being used for diabetes therapy

A

Glp-1

82
Q

Along with this dysbiosis, which bacteria which could be increased in t2d increases risk and how

A

Prevotella copri through preference of protein digestion which produces bcaa causing insulin resistance

83
Q

Which other 2 bacterial metabolites can help reduce t2d risk/obesity through glp1 and how

A

Secondary bile acid production eg lithocholic acid can bind tgr5 and cause release of glp1

Trp metabolite Indole also promotes glp-1 release

84
Q

What are the effects of ammonia and phenol which are by products of aa degradation

A

Tj disruption and permeability

Ammonia also increase pro inflam cytokines like tnfa

85
Q

How does h2s disrupt the mucosal barrier

A

Disulfide bonds

86
Q

Which aa counteracts the negatives of aa metabolism and how

A

Trp- produces Indole or Indole derivatives like indole3aldehyde known to reverse colitis through binding ahr and il22 release = mucus formation and amp release

87
Q

What compositional change is associated with ageing

A

Over bloom of proteo bacteria over reducing firmicutes
Likely a combination of reduced complex glycans for example or lifestyle leads to this

This then drives feedforwaed loop of inflammation eg through LpS dominant enterobacteriacea which then promotes chronic inflammation = drives expansion of facultative proteobac even more eg via aea nitrate

88
Q

Explain the change of microbes between vaginal and c-section

A

Vaginal obtain lactobacilli from vagina , bifido and bacteroides

C-section are colonised by both skin strep/staph and also NICU opportunists eg enterococcus and klebsiella (associated with nec too)

89
Q

What virulence factor does the likes of klebsiella oxytoca have associated with babies in the infirmary

A

Tilivalline causing intestinal permeability

90
Q

Within 6-12 months what happens to this difference

A

The colonisation becomes similar between the 2 except still reduced bacteroides in c-section

91
Q

What gf is present in human milk which blocks tlr4 so has protective effect

A

Egf

92
Q

Which bifido species are major in hmo breakdown through fucksidases and sialidases

A

Infantis and bifidum

93
Q

What do bifido produce from hmo/inulin prebiotics which promote cross feeding to butyrate producing eg f prausnitzii

A

Acetate produced which can be eaten by them to produce butyrate

94
Q

Which other bacteria used in probiotics can also produce acetate and lactic acid to reduce ph for pathogenic

A

Lactobacilli eg reuteri (also for barrier function through amp and mucus)

95
Q

What are synbiotics

A

The proposed idea of mixing pre with postbiotics for their food

96
Q

What is the problem with the range of prebiotics used now eg fructan inulin, fos

A

Soluble so don’t reach the distal colon for a beneficial effect

Need to expand

97
Q

How are secondary bile acids (shown in inflammatory dysbiosis to be low in production) anti inflammatory / tolerance inducers

A

Bind FXR or tgr5 to induce m2 polarisation

Also block roryt which stops ilc3 polarisation and it’s downstream inflam effects