EXAM Lecture 20 Flashcards
sulfate reducing bacteria (SRB)
obtain their energy by oxodizing organic compounds or hydrogen while reducing sulfate to form hydrogen sulfide (H2S) which is damaging
abundance of SRB increases in colonic microbiota of IBD patients - they degrade mucus barrier
5-aminosalicyclic acid inhibits SRB growth AND decreases sulfide production (2 for 1)
Outer mucus layer integrity and IBD
MUC2 C terminal dimerization and MUC2 N terminal trimerization form tight mucin network
disulfide bonds connect these MUC2s together to form the network
- in IBD, reduction of these disulfide bonds results in less viscous mucus layer and greater bacteria penetration
- sulfide producing bacteria can then enter and help make H2S (bad)
(in IBD, proteloytic cleavage of C terminal amino acid residues allows opening in the MUC2 network and penetration by bacteria)
IBD patients have compromised mucus barrier exhibted by :
- reduced mucus barrier thickness
- higher discontinuity of mucus layer
- greater bacteria penetration in mucus
- 3-4 fold higher fecal H2S levels
- loss of mucus associated bacteria (decreased abundance and diversity)
Inflammatory cytokines and epithelial barrier permeability
inflammatory cytokines including IFNy, TNFa, IL-1B, IL-17A increase epithelial barrier permeability by altering expression of tight junction proteins (occludins, JAMS, claudins)
- anti infammatory cytokines (il-10 and TGFb) reduce permeability
Mucosal tregs important in maintaining anti inflammatory tone of epithelial barrier
- commensal bacteria such as clostridium promote accumulation of Tregs within lamina propria
- NOD2 promotes Treg survival
Microbial products and IBD
hydrogen sulife (H2S) impacts host function:
- inhibits cytochrome C oxidase and decreased ATP which
- induces production of inflammatory cytokines (TNFa) and functions as a reactive oxygen species to cause tissue damage
- increased H2S also kills microbes like SCFA that produce butyrate
Butyrate and colonic homeostasis
butyrate production is low in IBD
- decreases pH of colon and inhibits growth of pathogenic bacteria
- improves gut barrier function by stimulating mucin and anti microbial peptides/tight junctions
- anti inflammatory effects: inhibit NFkB and cytokines, reduces ROS formation and increases glutathione
SCFA enemas are colitis treatment
- butyrate enemas
Protein fermentation
high protein diets = undigested protein fermented by microbiota
- fermented protein produces small amount of SCFA (good)
- but many products promote colon cancer
branched chain fatty acids are produced
- correlated with decreased firmicutes and increases bacteroidetes
ammonia produced
- decreases butyrate transporters, DNA damage
p cresol and phenol (tyrosine metabolites) and indole and skatole (tryptophan metabolites)
- p cresol inhibited by carb fermentation
- indole can be beneficial (not ALL protein fermentation products are harmful)
- fiber will move food through faster therefore less time to cause harmful effects
Protein fermentation products: amine and polyamines
bacteria utilize amines and polyamines for
- RNA synthesis
- protection against ROS
- structural components of cell membrane
amount of amines produces can result in changes in bacterial pathogenicity
obesity and chrons
increased disease activity, decreased remission
creeping fat around colon
- more creeping fat in obese IBD vs lean CD
- more inflammatory compared to lean CD
more visceral adipose tissue (acts like creeping fat)
IBD inflammation
decreased Treg, increased Th17
Th17 secretes IL17A
- IL17A secretes CCL20 which recruits more Th17 cells (vicious cycle)
- IL17A also secretes more chemokines to attract more immune cells
- IL17A activates MMP1,3,16 which destroy lamina propria
combined obesity and IBD:
- obesity isnt driving colon damage but Th17 activating IL-17 instead
