Microbiome AV Flashcards
(16 cards)
outline the determinants of the gut microbiome (7)
- Mode of Delivery
○ Vaginal birth: Colonisation by maternal vaginal and fecal microbes (e.g., Lactobacillus, Bifidobacterium).
○ Caesarean section: Delayed colonisation, more skin/environmental microbes (e.g., Staphylococcus). - Early-Life Antibiotic Exposure
○ Disrupts microbial diversity and delays establishment of a stable microbiome.
○ Repeated exposure can lead to long-term dysbiosis and increased risk of immune and metabolic disorders. - Diet
○ Breastfeeding: Rich in human milk oligosaccharides (HMOs) — prebiotics that promote Bifidobacterium growth.
○ Formula feeding: Leads to a more diverse but less stable early microbiome.
○ Later diet: High-fibre diets promote microbial diversity; high-fat/high-sugar diets can reduce beneficial species. - Prebiotics and Probiotics
○ Prebiotics: Non-digestible fibres (e.g., inulin) that feed beneficial bacteria.
○ Probiotics: Live microbes (e.g., Lactobacillus, Bifidobacterium) that can transiently alter gut composition and function. - Environmental Exposure
○ Pet ownership, siblings, rural vs urban living → exposure to broader microbial communities, increasing diversity. - Geography and Lifestyle
○ Differences in diet, sanitation, antibiotic use, and lifestyle across populations (e.g., Western vs traditional societies) influence microbiome profiles significantly. - Host Genetics
○ Certain single nucleotide polymorphisms (SNPs) can affect immune responses, mucosal secretions, and metabolism, thereby shaping microbial colonisation.
Describe the links between the gut microbiome and cardiovascular system - dysbiosis and systemic inflammation
Disrupted gut barrier (“leaky gut”) allows translocation of bacteria or endotoxins (e.g., lipopolysaccharide, LPS) into the circulation.
This triggers systemic low-grade inflammation via cytokine production (e.g., IL-6, TNF-α), promoting:
* Endothelial dysfunction
* Plaque formation and instability
* Increased cardiovascular risk
Describe the links between the gut microbiome and cardiovascular system - Microbial metabolits and cardiovascular impact
Trimethylamine N-oxide (TMAO):
* Produced from gut microbial metabolism of choline, carnitine, and lecithin → converted in liver.
* Pro-atherogenic: enhances foam cell formation, vascular inflammation, platelet hyperreactivity.
Short-chain fatty acids (SCFAs) (e.g., acetate, propionate, butyrate):
* Derived from fibre fermentation.
* Modulate blood pressure, gut barrier integrity, inflammation, and lipid/glucose metabolism.
Amino acid metabolites (e.g., tryptophan, tyrosine):
* Involved in neurotransmitter synthesis (dopamine, serotonin), immune modulation, and CV health.
Describe the links between the gut microbiome and cardiovascular system - direct microbial involvement in atherosclerosis (evidence of what?)
Microbial DNA and bacterial components have been found in atherosclerotic plaques, suggesting direct microbial colonisation or translocation.
Describe the links between the gut microbiome and cardiovascular system - Gut-brain-cardiovascular axis
Evidence from animal study
Inflammation in the gut can lead to neuroinflammation.
This activates the sympathetic nervous system, increasing:
* Vasoconstriction
* Renin secretion → RAAS activation → angiotensin II → elevated BP
Animal studies:
* Faecal microbiota transplant (FMT) from normotensive to hypertensive rats lowers BP and reduces sympathetic tone (↓ noradrenaline).
What is the role of short chain fatty acids in cardiovascular health and disease
Short-Chain Fatty Acids (SCFAs) – Protective Role
○ Source: Produced by microbial fermentation of dietary fibre and endogenous substrates (e.g., mucus) in the colon.
○ Examples: Acetate, propionate, butyrate.
○ Mechanisms of Action:
* Bind to G-protein coupled receptors (GPCRs) on intestinal and immune cells (e.g., GPR41, GPR43, GPR109A).
* Promote vasodilation via peripheral vascular effects.
* Suppress lipolysis and macrophage activation in adipose tissue → reduce inflammation.
* Enhance intestinal barrier integrity and glucose homeostasis.
* Increase intestinal gluconeogenesis and modulate sympathetic nervous system activity.
○ Net effect: Cardioprotective, anti-inflammatory, and metabolic benefits.
What is the role of TMAO in cardiovascular health and disease
Trimethylamine-N-oxide (TMAO) – Pathological Role
○ Source:
* Diets rich in phosphatidylcholine, choline, and L-carnitine (e.g., red meat, eggs).
* These are converted by gut bacteria into TMA (trimethylamine).
* TMA is oxidised in the liver by flavin monooxygenases (FMOs) into TMAO.
a. TMAO and Atherosclerosis
* Increases macrophage scavenger receptors (e.g., CD36) → promotes foam cell formation.
* Impairs reverse cholesterol transport and reduces bile acid synthesis → cholesterol accumulation.
* Enhances vascular inflammation:
□ In animal models (e.g., ApoE⁻/⁻ and LDLR⁻/⁻ mice), TMAO increases inflammatory cytokine expression in endothelial and smooth muscle cells.
□ Promotes leukocyte adhesion to the vascular endothelium.
b. TMAO and Hypertension
* TMAO induces vascular smooth muscle contraction → raises blood pressure.
* Associated with endothelial dysfunction:
□ Reduces eNOS expression and NO bioavailability.
□ Decreases vasodilation (notably in elderly individuals with high TMAO levels).
* Increases oxidative stress (e.g., superoxide production) via reduction of eNOS
* DMB (3,3-dimethyl-1-butanol): Inhibits TMA formation and reverses TMAO-related vascular dysfunction in experimental models.
What are the therapeutic strategies and novel therapeutics for CVD (5)
dietary interventions
antibiotic thyerapy
probiotics
Faecal microbiota transplant
Targeted inhibition of TMA/TMAO pathway
How do dietary interventions act as a therapeutic strategy for CVD
Goal: Reduce dietary precursors of TMA (e.g. choline, carnitine).
Plant-based diets lower TMAO production due to reduced substrate availability and altered microbiota composition.
Polyphenols in red wine and other foods (e.g. resveratrol) may inhibit microbial TMA production.
How does antibiotic therapy act in CVD
Broad-spectrum antibiotics reduce gut microbial populations, thus decreasing TMAO.
Limitation: Not sustainable long-term due to resistance, microbiome disruption, and side effects.
Effect is reversible—TMAO levels rebound post-antibiotic.
How doe probiotics act as atherapeutic strategy for CVD
Specific probiotic strains (e.g. PLA04) reduce TMAO levels and vascular lesions in animal models.
Act by altering gut microbial composition, suppressing TMA-producing species.
How does faecal microbiota transplant act as a therapeutic strategy for CVD
Animal studies: Transferring microbiota from healthy or vegan donors to hypertensive or metabolic syndrome models reduces blood pressure and systemic inflammation.
Human relevance: Vegan donor FMT leads to distinct microbiome shifts but does not consistently reduce plasma TMAO or vascular inflammation.
Limitation: Variability in outcomes and unclear long-term effects.
How does targeted inhibiton of the TMA/TMAO pathway act as therapeutic targets in CVD (2 types)
TMA Lyase Inhibitors
* TMA lyase cutC/D enzymes convert choline to TMA in gut microbes.
* Inhibitors like DMB (3,3-dimethyl-1-butanol):
□ Block TMA production without killing bacteria.
□ Reduce TMAO, foam cell formation, platelet activation, and atherosclerosis in mice.
* DMB is found naturally in red wine and balsamic vinegar.
TMA Formation Inhibitors – IMC & FMC
* IMC (iodomethylcholine) and FMC (fluoromethylcholine):
□ Inhibit microbial choline metabolism at the source.
□ In mouse studies, plasma TMAO levels dropped to zero with chow + 1% choline + IMC/FMC.
□ Restored thrombotic risk to baseline (similar to chow-only mice), indicating therapeutic efficacy.
What are the mechanisms of microbial influence on drug action (direct and indirect effects)
Direct Effects
* Microbial enzymes (e.g. esterases, azoreductases, β-glucuronidases) can modify drug structure, altering:
□ Absorption
□ Activation/inactivation
□ Toxicity
Indirect Effects
* Microbial metabolites may:
□ Compete with drugs for host transporters and enzymes.
□ Modulate host gene expression, affecting drug metabolism enzymes (e.g. CYP450s).
□ Influence systemic drug exposure and immune responses.
What are the consequences of microbial drug interactions
Reduced drug efficacy
Increased or altered toxicity
Unpredictable pharmacokinetics in different individuals due to microbiome variability
What is the influence of the gut microbiome on ACEi like quinapril
Quinapril is a prodrug that must be converted to quinaprilat to be active.
Normally, this conversion is intracellular after absorption.
However, in spontaneously hypertensive rats (SHRs):
* The gut microbiome shows increased esterase activity, converting quinapril into quinaprilat in the gut lumen.
* Quinaprilat is lipophobic, so it cannot cross the gut barrier effectively → reduced bioavailability and efficacy.
* This shows how microbial pre-systemic metabolism can undermine therapeutic outcomes.
