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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
– Predominant immunoglobulin in mucosal secretions, monomeric & polymeric – Predominantly produced locally, not from circulation
sIgA
26
sIgA: Secretory component (SC) is part of\_\_\_\_, transports IgA into secretions
pIgR
27
– 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
IgM
28
– 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
IgG
29
Found in low concentration, associated with mucosal allergic responses
IgE
30
Found in low concentration in milk and saliva
IgD
31
Serum IgA – Predominantly\_\_\_\_\_\_\_ – Polymeric IgA-j chain containing polymers and variable but low amount of SIgA.
monomeric
32
Mucosal IgA – Predominantly
polymeric
33
• 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\_\_\_\_
4 grams liver
34
How do we induce mucosal IgA?
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
IgA works by : Inhibition of adherence – Surrounds microbe and repels attachment to mucosal surface – Agglutination of microbes by \_\_\_\_\_\_\_
Fc-Fc interactions
36
Mucus trapping-May associate with mucins, and trap microbes in mucus blanket
one of the mechanisms of IgA
37
How does IgA cause virus neutralization?
– Mechanism may depend on antibody specificity, isotype, and concentration – Inhibition of cellular attachment – Neutralization within epithelial cells
38
How does IgA function in Enzyme and toxin neutralization
– 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
How does IgA cause inhibition of antigen epentration
– IgA deficient subjects show increased absorption of food antigens
40
How do microbes evade IgA utilizing proteases
– 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
Why do Glycosidases work well against IgA?
– IgA is heavily glycosylated, and subject to damage by bacterial glycosidases, disrupting conformation, net charge, and resistance to proteolysis
42
IgA binding proteins – Cell surface proteins that bind IgA non-specifically (ie: Fc) – Lectin binding of ______ in IgA hinge region
O-linked carbohydrate
43
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.
Microbiome
44
Healthy microbiota contains a balanced composition of three major classes of bacteria-
 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
\_\_\_\_\_\_- 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
Symbionts Commensals Pathobionts
46
Altered microbial composition (dysbiosis) is associated with diseases-
inflammatory bowel disease (IBD), autoimmunity, obesity, diabetes, asthma and allergy, colorectal carcinoma, etc.
47
– 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
physiological function symbiotic
48
Which area in the GI has the most diverse bacterial composition?
The colon is the most diverse
49
A combination of immune, nutritional and environmental factors shape microbial composition
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
How can oxygen tension regulate microbiota composition?
Increaed oxygen will increase amt of facultative anaerobic bacteria but only in mucosal associated bacteria; see inflammation
51
Innate immune factors modulate intestinal colonization
Change antimicrobials in gut will change the composition of bactiera
52
What is the composition of human breast milk?
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
How does long and short term nutrition effect the composition on gut bacteria?
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
What are the protective functions of the intestinal microbiota
pathogen displacement, nutrient competition, receptor competition and make anti-microbials
55
What is the structial functions of intestinal microbiota?
enhances barrier, induction of IgA, enforces tight apical jucntions and helps with immune sytem devo
56
Metabolic functions of the intestinal microbiota
help control IEC differentiation, metabolize dietary carcinogens, ferment non-digestible dietary residues, ion absorption and salvage of energy
57
Anaerobic inetstinal microbiota
Bifodobacterium Clostriudium Bacteroides Eubacterium
58
Aerobic microbiota
Escherchia Enterococcus Streptococcus Kelbsiella
59
In the absence of bacterial colonization – Mice lack a mature mucosal immune system we see:
* Underdevelopment of lymphatic tissues * Delayed B cell migration in response to bacterial antigen * Reduced antibody diversity * Reduced lymphocyte responsiveness
60
Upon reconstitution of a normal microbiota – Mice develop normal mucosal immune function
• 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
How do microbiota induce epithelial antimicrobials in the lumen?
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
Microbiota induction of epithelial antimicrobials: basolateral function
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
How does the microbiota induce production of IgA?
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
Commensal bacteria ferment nondigestible dietary polysaccharides to produce
short chain fatty acids (SCFAs)
65
regulate PMNs, dendritic cells, macrophages/monocytes, and intestinal epithelial cells • induce regulatory T cell differentiation • regulate expression of virulence factors on bacterial pathogens
SCFAs
66
• Animal models – ______ animals have increased susceptibility to enteric infection – Disruption of microbiome by\_\_\_\_ induces susceptibility to enteric colonization and infection
Germ free antibiotics
67
Commensal microbiota prevent pathogen colonization via:
* 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
How does C.Diff become a disease state?
antibiotics kill off commenals--\> C.Diff gets through epithelium and makes toxins causing mucosal injury--\> PMNs and RBC leak into gut
69
Role of commensals in digestion
: - mediation bile acid synthesis - lipid absorption - amino acid metabolism - vitamin synthesis - SCFA production
70
Commensal role in immune system
Byproducts of commensal fermentation (metabolites) regulate the immune system
71
Abnormal immune response to colonizing bacteria in a genetically susceptible host
72
Obesity and obesity related diseases, including diabetes and nonalcoholic fatty liver disease and the role of commensal bacteria:
– Efficiency of bacterial fermentation and production of metabolic byproducts can contribute to obesity and its complications
73
Role of commensals in cancer
– Byproducts of bacterial metabolism can promote cell growth and act as carcinogens
74
Role of commensals and microbiota in allergies/asthma
– 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
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
obligate facultative
76
Benefits of probiotics
– 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
How are probiotics used to treat immune disorders
• 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
“a viable microbial food supplement which beneficially influences the health of the host"
probiotic

GI 3 (15 decks)

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