20. Mucosal barrier and microbiota Flashcards
What are the 4 types of extrinsic defenses of the GI?
- Mechanical/involuntary: cough, gag, peristalsis
- Structural: mucus
- Chemical: acid, enzymes, antimicrobial peptides/polypeptides
- Microbiological: commensal bacteria
What is the viscoelastic gel that defines the structure of the extrinsic barrier?
Mucus
What is mucin/mucus secreted by?
Goblet cells–10 liters a day
What is the composition of mucus?
Mucins Water Ions Proteins Lipids Antibodies/antimicrobial peptides/bacteria
What are the three main roles of mucins in host defense?
- Mucus-commensal interactions
- Bacterial exclusion
- Containment of secreted antibodies and antimicrobials
What are the mucus commensal interactions?
Mucus binds commensals with adhesins
Graze on mucus
Some digest mucus to prevent clogging
How is mucus involved with bacterial exclusion?
- Thickness/viscosity physically exclude bacteria
- Bacteria and LPS incude mucus gene expression
How does mucus act to contain secreted antibodies/antimicrobials?
- IgA and other antibodies bind mucus with low affinity
- Cationic AMP (antimicrobial peptides) contrained via electrostatic interactions with the mucus
What are lung surfactant proteins that act as reg proteins in the GI?
Lectins
What are some enzymes and inhibitors that are involving in GI chemical defences?
Lysozyme
Peroxidases
SLPI
sPLA2
What are the two cationic anti-microbial peptides that directly kill bacteria by forming pores in the microbial cell walls
Defensins (alpha, beta, theta)
Cathelicidins
What are two antimicrobial peptides that are involved in iron sequestration to prevent bacteria from using the iron?
Lactoferrin
Lipocalin
What makes antimicrobial peptides?
WBCs
Epithelial cells lining mucosal surfaces
What is a group of cationic antimicrobial peptides char by invariant 6-cysteine array involved in intramolecular disulfide bonding?
Defensins (alpha, beta, theta)
What type of defensins are produced by the mucosal epithelium and can be constitutive or inducible?
Beta
What type of defensins are synthesized by PMNs and paneth cells constitutively?
Alpha-defensins
Paneth cell granule contents
alpha defensins (HD5 and HD6) CRS peptides Lysozyme sPLA2 RegIII gamma Angiogenin-4 alpha-1-antitrypsin TNF-alpha IL17a MMP7 IgA
What is the predominant immunoglobulin in mucosal secretions, can be monomeric and polymeric?
sIgA
What shows a compensatory increase with IgA deficiency?
IgM
What ig is found at the same levels as IgA, with the proportion varying by site and time of collection?
IgG
What Ig is found at low concentrations in the GI and is associated with mucosal allergic rxns
IgE
What Ig is found at a low conc in the milk and saliva?
IgD
Serum IgA is mostly ___meric, while mucosal IgA is ___meric
Monomeric
Polymeric
What does the structure of IgA consist of?
Alpha chain
J chain (polymeric IgA)
Secretory component
How much IgA is secreted daily?
4 grams
What are the two ways that DCs can be exposed to bacteria in the gut lumen?
- DC can sent protrusions though the epithelial layer
2. Bacteria can pass through M cells of the peyers patches
What are the biological activities of IgA?
- Inhibition of adherence to epith: surrounds microbe, agglutinate microbe by Fc-Fc interactions
- Mucus trapping: associate with mucins, trap microbes in mucus blanket
- Virus neutralization: inhib. attachement
- Enzyme and toxin neutralization
- Inhibition of antigen penetration
What are the main ways that microbes evade IgA?
- IgA proteases: cleave prolyl-seryl or prolyl-threonyl bonds
- Wide-spectrum proteases
- Glycosidases: damages glycosylation on IgA, disrupting conformation, charge, etc
- IgA binding proteins that bind IgA non-specifically (Fc) or lectin binding of O-linked carbohydrate in IgA hinge region
What is the microbiome?
Totality of native microbes, their genetic info, and the mileu in which they interact
Healthy microbiota contains a balances of the three major classes of bacteria:
- Symbionts
- Commensals
- Pathobionts
What are symbionts?
Mutual relationship with the host–health promoting
What are commensals?
No benefit or detriment to the host
What are pathobionts?
Live as commensals but have the potential to induce pathology
What is dysbiosis?
Altered microbial composition, associated with diseases like IBD, AI diseases, obesity, asthma, allergy, colorectal carcinoma
What are three organisms that are found in the duodenum?
Streptococcus
Staphlococcus
Lactococcus
What are four organisms found in the jejumum
Streptococcus *
Lactobacillus *
Enterococcus *
Yeast
What are four organisms that are found in the ileum?
Bacteroides *
Clostridium *
Enterobacteriaceae
Segemented filamenous bacteria
What are organisms that are found in the colon?
Bacterioides Clostridium Proteobacteria Actinobacteria Lachnospiraceae Prevotellaceae TM7 Fusobacteria Verrucomicrobium
What are the non-immune factors that sculpt the microbiota?
Oxygen
pH
Enzymes and bile salts
Mucus
What are the immune factors that sculpt the microbiota?
Defensins
IgA
What is the bacteria that is one of the first colonizers of a baby’s GI?
Bifidobacterium longum infantis
What component of breast milk selects for bifidobacterium longum infantus?
HMO (human milk oligosaccharides)
What are the protective functions of the intestinal microbiota?
- Pathogen displacement
- Nutrient competition
- Receptor competition
- Antimicrobial factors like bacteriocins and lactic acids
What are the structural functions of intestinal microbiota?
- Barrier fortification
- Induction of IgA
- APical tightening of junctions
- Immune system development
What are the metabolic functions of intestinal microbiota?
- Control intestinal epi cell differentation
- Met dietary carcinogens
- Synthesized vitamin K, biotin, folate
- Ferment non-digestible residue
- Ion absorption
What was the result of mice lacking a bacterial colonization?
Underdevo of lymphatic tissues
Delayed B cell migration in response to bacterial antigen
Reduced antibody diversity
Reduced lymphocyte responsiveness
What is a new tx for C diff colitis due to antibiotic clearance of normal flora?
Fecal transplantation
What are several ways that commensal bacteria prevent pathogen colonization?
Bacteriocin production SCFA production Oxygen consumption Competition for nutrients and attachement sites Induction of epithelial antimicrobials Induction of mucus production/secretion
What is an important energy product of SCFA metabolism by gut bacteria?
What is the effect of SCFA metabolism on the gut pH?
Butyrate
Acidic pH
How are bacteria involved in IBD?
Abnormal immune response to colonizing bacteria in a genetically susceptible host
How are bacteria involved in obesity and obesity-related disease , like diabetes and fatty liver disease?
Efficiency of bacterial fermentation and production of metabolic byproducts can contribute to obesity and complications
How are bacteria involved with cancer?
Byproducts of bacterial metabolism can promote cell growth and act as carcinogens
How are bacteria involved with allergy?
- Hygene hypothesis–decreased early inf leads to immune dysreg
- Microflora hypothesis–dysbiosis leads to immune dysreg
- Vanishing microbiota hypothesis–loss of co-evolved microbes can result in allergic hyper-responsiveness
What kind of transition of bacterial species occurs in IBD?
From obligate anaerobic bacteria to facultative anaerobic species, predominantly proteobacteria
Associated with increased oxygen tension from inflammation
What is a probiotic?
Viable microbial food suppliment with benefits health of host
What are the criteria for probiotic selection?
- Origin
- Stability in GI
- Viability
- Adherence to human intestinal mucus
- Antimicrobial activity against pathogens
What are the three ways that probiotics may treat immune disorders
Restore healthy biota
Restore barrier function
Skey T cell immune response to Th1 type
