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Unit 10 > Week 2: Gut Immunity and the microbiome > Flashcards

Week 2: Gut Immunity and the microbiome Flashcards

1
Q

What is the ratio of human to non-human cells in the gut?

A

Significantly more non-human than humans cells

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2
Q

What is the common relationship between the gut microflora and the host?

A

Symbiotic relationship
Commensal most common - one benefits the other sees no harm or benefit
Mutalistic - both benefit

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3
Q

What are some of the facotrs that can negativly affect the gut microbiota in the adult?

A

Proton pump inhibitor
Antibiotic use
Saturated Fatty acid intake
Sugar (fructose intake)
Excessive protein consumption
Altered pH

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4
Q

What are some of the factors that can positively impact the gut microbiota in the adult?

A

Dietary fibre intake
Probiotic intake

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5
Q

What are some of the effects causing disease from an unhealthy gut microbiota?

A

Increased gut permeability
Decreased SCFA production
Increased TMAO production (inflammatory)
Increased LPS production causing endotoxemia
Increased CVD risk
Cognitive decline
Insulin resistance and metabolic syndrome risk increases
Increased risk of diahorrea

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6
Q

What are some of the positive effects of a healthy gut microbiota?

A

Increased SCFA production
Increased antioxidant production
Decreased indoxil sulphate (kidney toxin)
Improved lipid metabolism
Low gut inflammation
Insulin sensitivity
reduced risk of some infections
Decreased gut permeability
Low risk of endotoxemia (LPS in blood)

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7
Q

How does the microbiota develop in a healthy early life?

A

Conception
In utero: exposed to maternal vaginal flora, this is a low diversity, mainly lactobacillus spp in HIC and garnderella spp in LMIC
After birth in neonate: increase in diversity including streptococcus thermophilus and increased microbiota for age score (MAZ score)
Weening/ up to 2 years old: Increased diversity of flora, including clostrodium spp, faecalbacterium and ruminoscoccus

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8
Q

How does the gut microbiota develop in a malnourished early life?

A

Conception
Vaginal flora has a greater diversity, including Prevotella spp and gemella spp
Neonate: increased gammoproteobacteria and decreased MAZ score
Weening/ up to 2 years old: Decreased diversity of flora, with loss of many species and growth of potentially pathological species such as E.coli, S.aureus and clostrodium

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9
Q

What factors in early life are important to the development of a healthy microbiota?

A

In utero: Adequate nutrition, good hygiene and antibiotic use
Neonate: normal vaginal delivery, term delivery, breastfeeding with high maternal antibody
Young child: Adequate nutrition and hygiene

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10
Q

What factors in early life contribute to the development of a diseased microbiota?

A

In utero: vaginal infection, poor hygeiene, maternal undernutrition
Neonate: Low birth weight, diahrrea, not breastfeeding, enterophathogen carriage
Child: poor hygeine/nutrition environmental ehteropathy

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11
Q

At what age is the gut microbiota considered to closely mirror that present during our adult life?

A

2-3 years

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12
Q

What factors influence the composition of the gut microbiota in adults?

A

Genetics (effect immune system etc)
Immune system
BMI
Diet lifestyle
Evolutionary history (gut architecture) - affects what species are most able to colonise (shown similarities in mucosa between closely related species)
Antibiotics
Age

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13
Q

What phylum of bacteria are most commonly found in the gut microbiota?

A

Firmicutes
Bacteriodetes

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14
Q

What phylum of bacteria make up the minority of the gut microbiota?

A

Actinobacteria
Proteobacteria
Archaea

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15
Q

What changes in gut microbiota is associated with IBD?

A

Increase in proteobacteria and actinbocateria,
Mainly at the consequence of bacteriodetes and slightly for firmivutes

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16
Q

What are the changes in gut microbiota associated with necrotising enterocolitis?

A

Large increase in probacteria as the consequence of other phylum (some firmicutes remains)

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17
Q

What are the associated changes in gut microbiota in T2DM?

A

Increased bacterioidetes at the consequence of firmicutes

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18
Q

What is important to consider about the microbiome of the whole human body in regards to distribution?

A

Vary different proportions of microbes found in different locations both inside and outside the human body?

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19
Q

Define microbiota

A

Community of microbes that live in and on an individual, can vary substantially between environmental sites and host niches in health and disease

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20
Q

How do commensal bacteria benefit health?

A
  1. Outcompete pathogenic species
  2. Degrade toxins into harmless substances
  3. Critical for development of GI immune system - enable to establish tolerance by reaching a set point between detecting and forming an effector response against commensals
  4. Produce vitamin e.g VitK
  5. Break down non-digestiable carbohydrates into smaller more soluble molecules
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21
Q

How does gut micorbiota link to physiology?

A

Intermediate of food to physiology, helps break down indigestable material into soluble material that then has a physiological effect.

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22
Q

What dietary intake is associated with a healthy microbiota?

A

Low in fat and protein
High in plant fibres

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23
Q

How does a healthy microbiota process fooods in a healthy diet?

A

Indigestable polysaccharides are produced by host enzymes
These are fermented by gut microbiota to short chain fatty acids

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24
Q

How does an unhealthy microbiota process foods from an unhealthy diet?

A

Host proteases produce large amounts of peptides that are broken down into amino acids
Abberent microbiota reaction with amino acids in a miscellaneous fashion, sulfate reduction, deamination or decarboxylation.
Resulting products can have a physiological affect.

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25
Q

What sort of diet encourages the growth of unhealthy gut microbiota?

A

High in animal fat and protein but low in plant fibres

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26
Q

What is the overall physiological affect of higher levels of short chain fatty acids?

A

Lower risk of obesity and insulin resistance

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27
Q

What are the three different SCFA that are produced by microbiota?

A

Acetate
Propionate
Butyrate

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28
Q

What are the mechanism by which SCFA bring out their physiological affect?

A

Absorbed into cell by transport protein if charged or by passive diffusion
Can enter portal circulation and travel to liver and be incorporated into glucose, cholesterol and fatty acids

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29
Q

What are the uses of acetate in the body?

A

Substrate for synthesis of cholseterol and long chain fatty acids
Modulates the activity of immune cells

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30
Q

What are the uses of propionate in the body?

A

Substrate for gluconeogenesis in the liver
Influences the secretion of appetite regualting hormones

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31
Q

What are the uses of butyrate in the body?

A

Energy source for colonic epithelial cells
Promotes gut barrier integrity.

32
Q

What is the association between gut microbiota and obesity?

A

Obesity - associated with a decreased number of bacteriocides

33
Q

How does dieting affect the microbiota?

A

Low fat or low carbohydrate diet - results in bacterioidetes increasing in abundance in correlation with the reduction in body weight

34
Q

What is dysbiosis?

A

Change in composition in gut microbiota - change in the relative prevalence of species and the species present.

35
Q

What is the difference between pathobionts and symbiotants?

A

Pathobionts - a symbiot that is able to promote pathology in certain environmental conditions
Symbiotant - living in symbiosis with the host, promotes a physiological state

36
Q

How can short chain fatty acids affect the gut lumen?

A

Increased methane production
Decreased luminal pH
Increased mucus secretion
Decreased barrier permeability

37
Q

Describe how SCFA bring about changes in the GIT?

A

Typically produced after a meal
Acetate, propionate and butryrate
Activates GPCR 41/43 to cause L cells in the gut to secrete gut hormones PYY or GLP-1
increased energy expenditure and increased glucose stimulates insulin secretion
Leads to reduced blood glucose.

Butyrate specifically can act as a substrate in beta oxidation in colonic cells

38
Q

What are some of the molecular products produced by aberrant gut microbiota handling amino acids?

A

Hydrogen sulfide
Ammonia/amines
Gas (H2, CO2)
Organic acids
Indole
Increased acetyaldehydes

39
Q

What are the effects of abberant bacteria and poor diet on the gut epithelial layer?

A

Decreased mucus secretion
Increased luminal pH
Increased permeability

40
Q

Describe the structure/relationship of commensals in the small intestine

A

Is absoprtion dominanted
So only has a singular thinner mucus layer and a rapid pass through time
This means produces a larger amount of a-defensins from paneth cells and has peyers patches as a method of protection against pathogen
Therefore has fewer microbiota present that the large intestine

41
Q

Describe the structure/relationship between commensals and the large intestine?

A

Larege intestine has a outer and inner mucus layer - this is thicker than in the small intestine
Inner mucus is relatively sterile and the outer layer contains most of the commensals.
Contains non-digestable carbohydrates produced in the ileum.
Beta defensins may be expressed but has less antimicrobial peptides than the small intestine
Is secretion dominated with a slow pass through time, therefore has a larger amount of commensals.

42
Q

What is the key immune features of the mucus in the GIT?

A

Abundant IgA which binds to commensals
Prevents them from penetrating through the mucosal barrier.

43
Q

What prevents excessive reaction to commensals in the GIT?

A

PRR expressed by gut epithelial cells and immune cells are tightly regulated
Variation in the types of PRS, the proportion/number of PRRs and the coupling of PRR to the intracellular signaling - less likely to activate an immune response

44
Q

What is an example of a tighlty regulated PRR in the gut immune system?

A

TLR5 - only expressed on the basolateral surface of gut epithelial cells
So will not react to flagella on bacteria in the mucus (an the apical side)

45
Q

What is the function of TLR activation in the GIT immune system?

A

Enhances the epithelial barrier and increases antimicrobial peptide and mucus secretion

46
Q

How can dendritic cells in the GIT help prevent an overresponse to commensals

A

Gut regulatory DC cells - express PRR that can be activated by commensals
Results in regulatory cytokine production - often causing naive T cells to develop into inducible T reg cells.

47
Q

What PRRs play a role in preventing an exaggerated response to commensals in the GIT?

A

TLR5
NOD2

48
Q

What is the role of NOD2 in the GIT immunity in reference to commensals?

A

Is an intracellular PRR, responds to peptidoglycan component MDP
Triggers pro-inflammatory responses

49
Q

How can dendritic cells in the GIT come into contact with an antigen?

A

Antigen delivered by M cells
IgA secreted into lumen binds to antigen, this conjugate can then travel by transcytosis through the M cell cytoplasm from apical to basolateral membrane
By uptake of apoptotic cells or pathogens directly.

50
Q

What is the role of T cells in the gut immunity?

A

Peyers Patches - naive T cells to provide protection at mucosal surface
Intraepithelial Lymphocytes -IELs - mainly CD8+, gamma delta or alpha beta, detecting infected and stressed epithelial cells
Th17 generated - aberrant response is linked to immune-mediated inflammatory disease

51
Q

Explain the role of dendritic cells in the condition immune response in the GIT to commensals.

A

Gut epithelium produced retinoic acid, TGF-alpha and TSLP
Causes the development of a CD103+ regulatory DC in the gut.
These suppress Th17 and Th1 (hence suppress pro-inflammatory response).

Produce RA and TGFbeta to encourage a naive T cell to develop into a T regulatory cell

52
Q

What is the role of macrophages in the GIT in creating tolerance to commensals?

A

Skewed to a regulatory phenotype

53
Q

How do Treg cells induce tolerance at the GIT?

A
  1. Produce inhibitory cytokines IL-10 and TGF-beta
  2. CDC25 - sequester IL2 - suppress other T cell phenotypes
  3. CTLA-4 Higher affinity reactions with B7 (CD80) then CD28 - induced energy in other T cell phenotypes
  4. cytotoxic activity through perofin and granzyme release
  5. Convert ATP to adenosine causing inactivation of other T phenotypes
  6. Promotes epithelial repair - produce EGF molecules
54
Q

What is the main antibody function of IgA?

A

Neutralisation

55
Q

What are the two different methods by which class-switching can occur?

A

T dependent
T-independent

56
Q

Describe how class switching in the gut can be activated by the T dependent mechanism?

A

Three activation signals:
Co-stimulation from the T cell in the form of CD40L on T cell binding to CD40 on B cell
Combined with TGF-beta secretion from the T cell, encourages B cell to switch to produce IgA antibody.

57
Q

Describe how class switching to IgA can be activated by the T-independent pathway int he gut?

A

DCs directly product APRIL and BAFF
Interact with B cells by carbohydrate receptors - causes production of IgA antibodies.

58
Q

What is the response to pathogenic bacteria in the GIT?

A
  1. Pathogen attaches to or invades the GIT
  2. TLR/NLR are triggered in epithelial cells - causing chemokine release to attract neutrophils.
  3. Pro-inflammatory dendritic cells (sample antigen from gut - M cell??) trigger an effector T cell response
    Pro-inflammatory M1 also activated and secrete cytokines
  4. T-cell cytokines stimulate epithelial cells to produce antimicrobial peptides, pro-inflammatory cytokines and chemokines
  5. Th17 (enhance neutrophils) or Th1 (activate M1) proinflammatory response often occurs
59
Q

What is the role of Intra-epithelial lymphytes in the GIT response to a pathogen?

A

Kill infected epithelial cells.
By cytokine release and have NK cell receptors on their surface allowing killing by perofin and granzyme release

60
Q

What opportunistic infection is common in the GIT after antibiotic use?

A

Clostridioles difficile

61
Q

Describe the mechanism of C.Diff infection in the colon?

A
  1. Antibiotic use causes dysbiosis of microflora - allows increased C.diff growth which outcompete other microbes
  2. C.Diff Toxin A and Toxin B are produced

Inactivation of RHO family protein and destruction of actin cytoskeleton by some strain producing transferase

  1. Initiates a cascade leading to apoptosis and rounding of colon epithelial cells,
  2. This leads to a substantial loss in barrier integrity
62
Q

What treatment is commonly used for a recurrent C.diff infection?

A

Fecal microbiota transplantation

63
Q

What is a fecal microbiota transplantation?

A

Healthy Donor stool sample is screened for infectious diseases.
Feces turned into a preparation for administration
Infused into recipient through a nasoenteric tube, enema or colonoscopy.
THis replaces the recipients microbiota - helps to outcompete the levels of C.diff and regulate the GIT immune response

64
Q

What is the hypothesis behind the cause of IBD?

A

Excessive immune activation towards the gut bacteria can cause IBD.

65
Q

What features can be shown in the epithelium of the IBD case?

A

U - ulceration of the mucosa
G - granuloma
Zoomed in image shows lymphocytes, macrophages, Giant cells and no necrotic centre
Hence is an immune non-caesating granuloma

66
Q

What is Crohns disease?

A

An IBD - believed to be caused by an abberent response against commensal bacteria
Affects all layers of the bowel
Can affect all parts of the GIT
Most commonly the terminal ileum and start of the colon.

67
Q

What are the sympotms of crohns?

A

Abdominal pain and diarrhoea
Tiredness and fatige
Feverish
Mouth Ulcers
Loss of appetite and weight loss
Perianal symptoms e.g fistulas

68
Q

What is the MOA of vedolizumab in Crohns disease?

A

Inhibits the interaction with alpha 4 beta 7 integrin molecule - this prevents the migration of immune cells to the GIT.
Including the migration of B cells, CD4+ cells and CD8+ cells
This reduces inflammation and promotes a wound healing environment.

69
Q

What genes are associated with Crohns disease?

A

NOD2
IL-23R

70
Q

How is the NOD2 gene related to Crohns disease?

A

1.Loss of function mutation in LRR region - impaired ability to recognise bacterial MDP, leads to impaired Macrophage, paneth and DC responses
2. Loss of barrier function as pathogens invade and expand
3. Imapired ability to kill intracellular bacteria
4. Increase in pro-inflammatory cytokines in response to impaired bacterial clearance

71
Q

How is the IL-23R gene involved in Crohns disease?

A

Upreglated signalling causes increased Th17 cells and increased pro-inflammatory cytokine release.

72
Q

What is coeliac disease?

A

An immune mediated disease directed towards gluten antigens
Characterised by mucosal inflammation in the small intestine - where loss of villi leads to reduced absoprtion

73
Q

What are the symptoms of coeliac disease?

A

Diarrhoea, steatorrhoea, anemia and vitamin deficiencts

74
Q

What mutations are associated with coeliac disease?

A

HLA-DQ2
HLA-DQ8
These better present the gluten antigen

75
Q

What are the histological changes shown in coeliac disease?

A

Immune infiltrate - including large numbers o lymphocytes and plasma cells
Loss of microvilli - leading to reduced surface area/

76
Q

What is the biological process behind coeliac disease?

A
  1. Gliadin (component of gluten) is broken down into peptides then modified by transglutaminase (TGG/TG2)
  2. Th1 cells are activated against these peptides
  3. Produce IFN-y to activate M1 - inflammation
  4. B cells recognise TG2 bound to gliadin peptides, activated by specific T cell - results in plasma cells secreting antibodies against TG2
  5. Damaged epithelial cells secrete IL-15 activating cytotoxicity in IEL
77
Q

Describe what is meant by gut homing of T cells and how this occurs?

A

Gut homing is when the gut origininating dendritic cells (regulatory and pro-inflammatory) cause imprinting of alpha 4 beta 7 in T cells, this allows all T cell types to migrate back to the source of infection in the gut - hence carry out their function in the right area.

Unit 10 (37 decks)

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