The Human Microbiome (Disease) Flashcards
Lecture 3
ILO’s
- Evidence of microbiome causality of disease
- Potential of synthetic microbiomes in medicine
- Potential of metabolic approaches to microbiome manipulations and therapies
Evidence of microbiome in disease
Some diseases are considered to be caused by a single pathogen
Intestinal microbiota is distinct in irritable bowel syndrome - host genetics play a part
- association with microbiota and obesity in mice and humans
Unintentional alteration of the microbiota disrupts normal balance and skew towards metabolic syndrome and obesity (antibiotics)
Helicobacter pylori
Contains a uresase (sp?) enzyme that converts urea to ammonia which is alkaline, so neutralise some of the stomach acid around it
H. pylori is the first formally recognised bacterial carcinogen
Gastric cancer - 4th cause of cancer related death globally
Microaerophilic, spiral shaped, gram negative bacteria
Approx 50% human population is infected
Induces gastritis, peptic ulcers, gastric cancer and mucosa-associated lymphoid tissue lymphoma
Susceptibility is multifactorial (environment, genes, immune status, other microbiology)
Difficult to eradicate
Gut microbiome and IBD
CD and UC - no known cause
see related reading
Microbiome - host internaly in IBD
Adhesive and invasive form of ecoli (AIEC) in CD patients
Intracellular invasion by AIEC is associated with active CD and intestinal pathology
The receptor that facilitates AIEC binding in epithelial cells is unregulated in CD
Host genetics - Defects in innate immunity (eg. mucosal barrier, autophagy, phagocytosis) - Microscopically (loss of barrier, inflammatory cytokines, lesions and fibrotic scarring) - Microbiota (AIEC, dysbiosis, carcinogenic microbiota) - Symptoms
Obesity related shift in microbiota
A shift in the relative abundance of bacteriodetes and firmicutes has been observed in obese humans
Abundance of bacteriodetes increased when dieting - change in abundance correlated with weight lost
Microbiota mediated transmission of obesity in mice: significant association between bloom of Firmicutes
Obesity associated microbiome has more capacity for energy harvest in mammalian cells
HMP and therapeutic interventions
Anti inflammatory gut organisms such as Faecalibacterium might be an effective probiotic for CD
Eradication therapy targeted against ‘harmful’ components of the microbiota (H pylori)
Potential strategies for therapeutic microbiome manipulation:
- Antibiotics
- Bacteriophage
- Probiotics
- Prebiotics
- Synbiotics
- Nutritional therapy
- Microbiota restoration
Example additive microbiota therapies
A - vaginal commensale Lactobacillus jensenii engineered to produce antiviral protein cyanovirin-N: colonisation by recombinant bacteria inhibits host infection by SHIV in simian model
B - Lactococcus lactis genetically modified to produce anti inflammatory cytokine interleukin-10 (IL10): administration in mice with colitis shown to reduce inflammation during gut transit
C - Probiotic Escherichia coli engineered to synthesise N-acyl-phosphatidylethanolamines (NAPEs): host mediated conversion of NAPEs to N-acylethanolamides (NAEs) prevents obesity in mice (through inc. satiety)
D - Endogenous urease (Ure+) activity of mouse microbiota can exacerbate hyperammonemia caused by liver injury, depletion of native microbiota via antibiotics and polythene glycol: replacement with urease deficient (Ure-)microbiota can protect from hyperammonemia and associated neurotoxicity
Metabolic approaches to microbiome manipulations and therapies
Bacterial gut metagenome produces primary and secondary metabolites
Secondary metabolites are called ‘specialised metabolites’
Specialised metabolites can produce molecules that have effects in the body, e.g. GABA produced by bacteria can have neurological effects
Lactobacillus rhamnosus produces GABA: probiotic treatment increases GABA receptor expression in the hippocampus and reduces anxiety and depression behaviours in the mouse model
