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GI 3 > Microbiota and Mucosal Barriers > Flashcards

Microbiota and Mucosal Barriers Flashcards

1
Q

What kind of mucosal barrier is there in the small intestine?

A

villi + crypts = barriers

all from the Crypt stem cell

absorptie enterocytes = main cell type and has goblet for mucus

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2
Q

What type of mucosal barrier is there in the large intestine?

A

just crypts, no villi but lots of goblet cells, some M cells with two mucus layers

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3
Q

What are the extrinisic barrier defenses?

A
  • Mechanical/Involuntary Reflexes – Cough – Gag – Peristalsis
  • Structural– Mucus
  • Chemical– Acid – Enzymes – Antimicrobial peptides and polypeptides
  • Microbiological – Commensal microbiota
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4
Q

Mucus = Viscoelastic gel that defines structure of extrinsic barrier and are secreted by specialized____ cells

A

Goblet

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5
Q

How much mucus do Goblet cells secreate?

A

– Secretion can be constitutive or regulated
– Humans secrete 10 liters of mucus/day

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6
Q

Mucus/Mucins forms selectively permeable mucus blanket
– Variable thickness depending on:
– Comprised of :
– Contains :

A

anatomic site and pathophysiology

a variety of mucins, water, ions, proteins, and lipids

antibodies, antimicrobial peptides, and bacteria

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7
Q

• Mucus-commensal interactions; Mucins play big role in host defence
– Specific binding of some commensals via______
– “grazing” on mucus-cleaving specific sugars from tips of oligosaccharides
– Small subset of commensals digest mucins

A

adhesins

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8
Q

What type of role do mucins play in host defense?

A

Mucus-commensal interactions

Bacterial exclusion

Containment of secreted antibodies and antimicrobials

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9
Q

How do mucins work to exclude bacteria?

A

– Thickness and viscosity contribute to exclude bacteria
– Bacteria and LPS have been shown to induce MUC gene expression
– Pathogens have developed specific mechanisms to evade barrier
(flagella, interference with exocytosis)

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10
Q

Bacteria and LPS have been shown to induce___ gene expression

A

MUC

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11
Q

Containment of secreted antibodies and antimicrobials by Mucins:
– _____ and other secreted antibodies bind mucus through low affinity
bonds, and interact with commensals and pathogens
– _________ may be contained via electrostatic interactions with mucins

A

IgA

Cationic AMP

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12
Q

How does mucous work to propel bacteria away?

A

Once bacteria bind, induces release of granules which increase modulation of apoptotic pathways and increase inflammatory pathways; as well as propel bacteria way from surfce

*The pathogen can attach but gets propelled way d/t steric hindrance

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13
Q

How do bacteria get past mucus?

A

There are things called M cells which allows for passage, usually the tight jnx and mucs prevent entry.

Some bacteria will produce toxins that reduce mucus production and distrurb tight junctions

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14
Q

What are key mucosal chemical defenses?

A

Acidification; pH at 3.5-4 is bacteriostatic

Toxic oxygen derived products like free radicals

Toxic nitrogen oxides; like NO

antimicrobial peptides

enZ; lysozyme

Lactoferrin to compete for Iron

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15
Q

What is the main secreator of AMPs?

A

Paneth Cells

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16
Q

constitutively expressed cationic AMPs, have anti-microbial and chemo-attractant properties, kill target microbes by forming pores in their cell membrane hence disrupting their membrane integrity

A

Alpha Definsins; Paneth cell AMPs

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17
Q

glycosidase, specifically hydrolyzes peptidoglycan which is present in bacterial cell wall

A

Lysozyme C

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18
Q

selectively catalyzes hydrolysis of fatty acids in bacterial cell membrane, bactericidal with preferred activity against Gram-positive bacteria

A

Phospholipase A2

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19
Q

C-type lectin, binds to peptidoglycan, bactericidal against Gram-positive bacteria, inducibly expressed upon Toll-like receptor (TLR) activation by bacteria or microbial products (PAMPs, MAMPs)

A

RegIIIγ

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20
Q

RegIIIγ: C-type lectin, binds to peptidoglycan, bactericidal against
_______ bacteria, inducibly expressed upon _____ activation by bacteria or microbial products_____

A

Gram-positive

Toll-like receptor (TLR)

(PAMPs, MAMPs)

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21
Q

Phospholipase A2: selectively catalyzes hydrolysis of ______ in bacterial cell
membrane,_____ with preferred activity against
______bacteria

A

fatty acids

bactericidal

Gram-positive

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22
Q

α-Defensins: constitutively expressed ______, have anti-microbial
and chemo-attractant properties, kill target microbes by

A

cationic AMPs

forming pores in their cell membrane hence disrupting their membrane integrity

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23
Q

sequencially distinct from conventional cryptdins,
antibacterial activity comparable to cryptdins

A

Cryptdin related sequences (CRS)

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24
Q

What are the pathogen strategies for evasion of AMPs

A
  1. Protease secreation, efflux pupmps, modulate antimicrobial peptide expression, capsule formation, surface charge modification
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25
Q

– Predominant immunoglobulin in mucosal secretions, monomeric & polymeric
– Predominantly produced locally, not from circulation

A

sIgA

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26
Q

sIgA: Secretory component (SC) is part of____, transports IgA into secretions

A

pIgR

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27
Q

– Also associated with SC in mucosal secretions
– May not be transported as well due to MW restrictions in SC dependent transport
– Compensatory increase with IgA deficiency

A

IgM

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28
Q

– Found at same levels as IgM
– Proportion of IgA to IgG varies by site and time of collection (ie: proportion varies
through menstrual cycle)
– Not selectively transported in humans

A

IgG

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29
Q

Found in low concentration, associated with mucosal allergic responses

A

IgE

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30
Q

Found in low concentration in milk and saliva

A

IgD

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31
Q

Serum IgA
– Predominantly_______
– Polymeric IgA-j chain containing polymers and variable but low amount of SIgA.

A

monomeric

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32
Q

Mucosal IgA
– Predominantly

A

polymeric

33
Q

• Structure consists of alpha chain, J chain (only associated
with pIgA), and secretory component
• Synthesized as monomer and forms pIgA prior to secretion
• Approximately ____ of IgA secreted daily
• Metabolized and cleared by____

A

4 grams

liver

34
Q

How do we induce mucosal IgA?

A

DC samples outside, DC present to B cells and T cell in mesenteric lymph node to induce activation of IgA secreating Plasma cell–> joined with J region and transcytosis across epithelium

35
Q

IgA works by : Inhibition of adherence
– Surrounds microbe and repels attachment to mucosal surface
– Agglutination of microbes by _______

A

Fc-Fc interactions

36
Q

Mucus trapping-May associate with mucins, and trap microbes in
mucus blanket

A

one of the mechanisms of IgA

37
Q

How does IgA cause virus neutralization?

A

– Mechanism may depend on antibody specificity, isotype, and concentration
– Inhibition of cellular attachment
– Neutralization within epithelial cells

38
Q

How does IgA function in Enzyme and toxin neutralization

A

– In saliva, inhibition of enzymes from oral bacteria (neuraminidase,
hyaluronidase, chondroitin sulfatase, glucosyltransferase)
– In gut, neutralization of bacterial toxins (cholera toxin, heat-labile
enterotoxin, clostridial enterotoxin A)

39
Q

How does IgA cause inhibition of antigen epentration

A

– IgA deficient subjects show increased absorption of food antigens

40
Q

How do microbes evade IgA utilizing proteases

A

– Cleave one of several prolyl-seryl or prolyl-threonyl peptide bonds in hinge
region. Cleave off intact Fab fragments that retain binding activity
– Exquisitely substrate specific, not inhibited by protease inhibitors
– Cause local IgA deficiency in vivo
– Meningitis association (H. influenzae, N. meningitidis, S. pneumoniae)

41
Q

Why do Glycosidases work well against IgA?

A

– IgA is heavily glycosylated, and subject to damage by bacterial
glycosidases, disrupting conformation, net charge, and resistance to proteolysis

42
Q

IgA binding proteins
– Cell surface proteins that bind IgA non-specifically (ie: Fc)
– Lectin binding of ______ in IgA hinge region

A

O-linked carbohydrate

43
Q

The totality of native microbes, their genetic information and the milieu in which they interact
• Humans have 10X more bacteria in their gut than human cells. The colonizing
bacteria contain 100X more genetic content than the human genome.

A

Microbiome

44
Q

Healthy microbiota contains a balanced composition of three major classes of bacteria-

A

 Symbionts- Share mutual relationship with the
host, have known health promoting functions
 Commensals- Permanent residents of this
ecosystem and provide no benefit or detriment to the host
 Pathobionts- Live as commensals but have the
potential to induce pathology

45
Q

______- Share mutual relationship with the
host, have known health promoting functions
____- Permanent residents of this
ecosystem and provide no benefit or detriment to the host
______- Live as commensals but have the
potential to induce pathology

A

Symbionts

Commensals

Pathobionts

46
Q

Altered microbial composition (dysbiosis)
is associated with diseases-

A

inflammatory
bowel disease (IBD), autoimmunity,
obesity, diabetes, asthma and allergy,
colorectal carcinoma, etc.

47
Q

– The primary role of mucosal surfaces are to allow normal
__________ while protecting the host from infection
– The mucosal immune system protects the host from the microbiota
– The microbiota has a________ role in host protection and host physiology

A

physiological function

symbiotic

48
Q

Which area in the GI has the most diverse bacterial composition?

A

The colon is the most diverse

49
Q

A combination of immune, nutritional and environmental
factors shape microbial composition

A

Non-immune factors: oxygen tension is key in upper GI while the colon is more anaerobic, pH, digestive enZ and bile salts

Immune Factors: defensins and IgA

50
Q

How can oxygen tension regulate microbiota composition?

A

Increaed oxygen will increase amt of facultative anaerobic bacteria but only in mucosal associated bacteria; see inflammation

51
Q

Innate immune factors modulate intestinal colonization

A

Change antimicrobials in gut will change the composition of bactiera

52
Q

What is the composition of human breast milk?

A

mostly lactose, HMO= human milk oligosaccharides, Protein and lipids

HMO are digested by bifodobacterium longum which is good for us thus babies on breast milk have more good bacteria

53
Q

How does long and short term nutrition effect the composition on gut bacteria?

A

IG need long term diet to change them: see bacteriodes in high fat/low fiber diet

see prevotelia in low fat/high fiber diet

54
Q

What are the protective functions of the intestinal microbiota

A

pathogen displacement, nutrient competition, receptor competition and make anti-microbials

55
Q

What is the structial functions of intestinal microbiota?

A

enhances barrier, induction of IgA, enforces tight apical jucntions and helps with immune sytem devo

56
Q

Metabolic functions of the intestinal microbiota

A

help control IEC differentiation, metabolize dietary carcinogens, ferment non-digestible dietary residues, ion absorption and salvage of energy

57
Q

Anaerobic inetstinal microbiota

A

Bifodobacterium

Clostriudium

Bacteroides

Eubacterium

58
Q

Aerobic microbiota

A

Escherchia

Enterococcus

Streptococcus

Kelbsiella

59
Q

In the absence of bacterial colonization
– Mice lack a mature mucosal immune system we see:

A
  • Underdevelopment of lymphatic tissues
  • Delayed B cell migration in response to bacterial antigen
  • Reduced antibody diversity
  • Reduced lymphocyte responsiveness
60
Q

Upon reconstitution of a normal microbiota
– Mice develop normal mucosal immune function

A

• Increased lymphocyte infiltration of gut mucosa
• Germinal center formation in Peyer’s Patches
• Induction of innate antimicrobial effector molecules
• Treatment with bacterial polysaccharide from bacterial symbiont (B.
fragilis) restores many immune functions

61
Q

How do microbiota induce epithelial antimicrobials in the lumen?

A

MAPS on bacteria contact TLR on the lumen–> increase signal of MYD88–> get production of REG3 that kills bacteria and increase anti-microbial expresion

62
Q

Microbiota induction of epithelial antimicrobials: basolateral function

A

bacteria uptake via DCs that sample the environment and interact with innate cell types

get production of IL-22 to induce production of antimicrobials

63
Q

How does the microbiota induce production of IgA?

A

M cell ineract with bacteria in peyers patch OR migrating DC cells do–> induce b and T cell activation in mesenteric LN–> now have IgA+ B cell

IgA+ B cell recirculates–> becomes plasma cell–> secreates IgA

IgA transcytosis through the epithelium

64
Q

Commensal bacteria ferment nondigestible dietary polysaccharides to produce

A

short chain fatty acids (SCFAs)

65
Q

regulate PMNs, dendritic cells, macrophages/monocytes, and intestinal epithelial cells
• induce regulatory T cell differentiation
• regulate expression of virulence factors on bacterial pathogens

A

SCFAs

66
Q

• Animal models
– ______ animals have increased susceptibility to enteric infection
– Disruption of microbiome by____ induces susceptibility to
enteric colonization and infection

A

Germ free

antibiotics

67
Q

Commensal microbiota prevent pathogen colonization via:

A
  • Bacteriocin production
  • SCFA production
  • Consumption of oxygen
  • Competition for nutrients
  • Competition for attachment sites
  • Induction of epithelial antimicrobials
  • Induction of mucus production and secretion
68
Q

How does C.Diff become a disease state?

A

antibiotics kill off commenals–> C.Diff gets through epithelium and makes toxins causing mucosal injury–> PMNs and RBC leak into gut

69
Q

Role of commensals in digestion

A

:

  • mediation bile acid synthesis
  • lipid absorption
  • amino acid metabolism
  • vitamin synthesis
  • SCFA production
70
Q

Commensal role in immune system

A

Byproducts of commensal fermentation
(metabolites) regulate the immune system

71
Q

Abnormal immune response to colonizing bacteria in a genetically susceptible
host

A
72
Q

Obesity and obesity related diseases, including diabetes and nonalcoholic
fatty liver disease and the role of commensal bacteria:

A

– Efficiency of bacterial fermentation and production of metabolic byproducts
can contribute to obesity and its complications

73
Q

Role of commensals in cancer

A

– Byproducts of bacterial metabolism can promote cell growth and act as carcinogens

74
Q

Role of commensals and microbiota in allergies/asthma

A

– The “Hygiene Hypothesis” (decreased early infections lead to immune dysregulation)
– The “Microflora Hypothesis” (dysbiosis leads to immune dysregulation)
– The “Vanishing Microbiota Hypothesis” (Interactions with certain microbes are wired
into our immunoregulatory networks based on their constant presence in our
environment resulting in tolerance. Loss of these co-evolved microbes can result in
allergic hyper-responsiveness.)

75
Q

In IBD; see abnormal bacterial colonization and immune fuction:

The characteristic shift in microbial colonization moves from______
anaerobic bacteria to____ anaerobic species, predominantly
proteobacteria, most likely associated with increased oxygen tension
caused by inflammation

A

obligate

facultative

76
Q

Benefits of probiotics

A

– Improve intestinal barrier function
– Stimulation of mucin secretion
– Stimulation of antimicrobial peptide expression
– Inhibition of adherence and invasion of pathogens
– Enhance IgA production
– In epithelial cell culture, some probiotics have anti-inflammatory activity
(attenuate IL-8 and TNF-a secretion, inhibit NF-kB pathway, prevent apoptosis).
– Metabolic and neurologic effects are currently being examined.

77
Q

How are probiotics used to treat immune disorders

A

• Restoration of a “healthy” biota
• Restoration of barrier function (prevent excess antigen transfer
across skin and gut barriers)
• Skew T cell immune responses to Th1 type.

78
Q

“a viable microbial food supplement which beneficially
influences the health of the host”

A

probiotic

GI 3 (15 decks)

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