107 - Gut Microbiota II Flashcards
Activation of mucosal lymphocytes 1 2 3 4
1) Lymphocytes in PP or MLN activated, enter blood circulation.
2) Acquire homing receptors (a4b7 integrin, MAdCAM-1 ligand) and chemokine receptors for lamina propria chemokines.
3) Migrate to lamina propria through high endothelial venules (have a4b7 integrins on endothelium)
4) Activated B cells produce sIgA
Predominant T cell subtype in steady state gut mucosa
Treg
Proportion of intraepithelial lymphocytes that are gamma/delta
~10%
Pattern recognition receptors on enterocytes
1
2
3
1) TLR2 and 4 high at birth, downregulated afterwards
2 )TLR3, 7, 9 in endosomes
3) TLR5 expressed on basolateral surface
Effects of mucus layer on gut epithelium
1
2
1) Direct - Block binding sites, produce bacteriocins, etc.
2) Indirect - Interact with PRR
Indirect effects of microbiota on mucus, gut epithelium
1
2
3
1) PAMPS/butyrate leads to increased mucin production
2) SCFA inhibit production of production, secretion of inflammatory cytokines (NF-kB)
3) IL-22 produced after PAMP interaction with intraepithelial lymphocytes, NK-22 leads to increased epithelial integrity
What does PAMP signalling stimulate in the gut?
1
2
3
1) Proliferation of crypt enterocytes and Paneth cells
2) Release of antimicrobial peptides from these cells
3) Induction of regulatory cytokines (TGFβ, IL-10, etc)
MALT structures that develop pre-natally
Peyer’s patches, mesenteric lymph nodes
MALT structure that develops post-natally
Isolated lymphoid follicles
Example of a severe form of undernutrition
Kwashiokor
Kwashiokor study 1 2 3 4 5 6 7
1) Studied effects of gut microbiota on Malawian twin children (particularly deficient in protein)
2) Hypothesised that gut microbiota provided genes for healthy growth and development
3) Prospective longitudinal study, analysis of faecal samples from twins discordant for Kwashiokor
4) Treat both with therapeutic food, compare outcomes.
5) Transplanted faecal microbiota from children into germ-free mice
6) Feed mice normal diet, examine.
7) Treat mice with therapeutic food, examine
Outcomes of Kwashiokor study
Twin with Kwashiokor couldn’t maintain changes in gene content of gut microbiome when changed from poor diet to therapeutic diet.
Mice fed with Kwashiokor microbiome lost weight, microbiome changed composition
Effect of Kwashiokor diet on metabolism
Inhibition of tri-carboxylic acid cycle (TCA cycle). –> inhibition of cellular energy production
What is obesity associated with?
Low-grade inflammation.
Low-grade inflammation associated with obesity
1
2
3
• Induction of inflammatory cytokines (TNFα, IL-1β, IL-6,
IL-17)
• Increase in mast cells, T cells and macrophages
• Increase in Tregs in lean subjects
Effect of low-grade inflammation on obesity
1
2
3
• The associated pro-inflammatory signalling desensitises
insulin receptor and leptin receptor signalling
• High-fat diet fed mice have elevated gut and plasma LPS
and increased intestinal permeability
• Inflammation in obese mice modified by an increase in
Bifidobacteria (reduce intestinal permeability)
Commensal flora that can spread to extra-intestinal areas, cause disease 1 2 3 4 5
Escherichia coli (esp UTI, wounds) Klebsiella sp (wounds, LRTI) Other Enterobacteriaciae Enterococci (VRE) Bacteroides sp (wounds)
What can increase the rick of developing pseudomembranous colitis?
Appendectomy (4x more likely)
Proportion of healthy people carrying C difficile
~3%
How can C difficile cause disease?
Adheres to mucosal epithelium, toxin production
Treatment for C difficile overgrowth
Metronidazole +/- vancomycin
Aspect of gut microbiome that characterises patients with recurrent C difficile infections
Reduced diversity of bacterial species
Success rate of C difficile treatment with faecal transplantation
91-98%
Recent alternative to faecal transplant
Pure culture of 33 bacteria shown to be successful
Prebiotics
Dietary supplements that promote beneficial
bacteria
Probiotics
Live organism that when ingested in adequate
amounts, exerts a health benefit to the host, typically
lactobacilli, bifidobacteria, non pathogenic yeasts