Microbiome And Pharmogenetics Flashcards
1
Q
Environmental factors that influence the microbiome
A
- Food, alcohol
- Medicines
- Temperature, altitude
- Exercise
2
Q
Methodological issues with studying the microbiome.
A
- Microbiome genetic diversity is very significant- many taxa are not common across individual humans and populations.
- Sample sizes small
- Work is very dependent on stool sampling and DNA extraction methods -meta analyses harder
- Hard to find suitable experimental set ups - at least in humans.
3
Q
Paper that found environment seems more important for the Microbiome than the genetics.
A
- 24 pairs of 2nd-5th degree relatives with no household sharing- not similar microbiomes.
- 55 first- degree pairs with household sharing -similarity in microbiome .
- Unrelated pairs living together-similarities in microbiome.
4
Q
Things that contribute to microbiome composition.
A
- Vertical transfer
- Environmental
- Host genetics
- Horizontal transfer
5
Q
What are is the relationship between LNP and the microbiome.
A
- In LNP peoples, strong relationship between lactose intake and abundance of Bifidobacteria (produce B-galactosidase)
- In LP, no relationship - low levels. Competition between host and microbe.
6
Q
What are is the relationship between starch digestion and the microbiome.
A
- People with high CN, have higher levels of Ruminococcues ferments amylase-resistant starches. (Better starch digestion, and bacterial support for further digestion)
- In Low CN individuals- they cant do this
7
Q
Relationship between Parkinson’s disease and the microbiome.
A
- Known environmental and genetic risk factors- Can’t explain the disease risk.
- Recent studies on the microbiome have shown strong association between PD and the gut microbiome.- unknown relationship.
- Decreased SCFA -producing bacteria
- Increased abundance of Lactobacilli and Bifidobacterium, opportunistic bacteria within Cornybacteria _1, porphyrmonas
8
Q
Breaks hypothesis for the relationship between the microbiome and Parkinson’s.
A
- Disease triggered by pathogen in gut that spreads to brain.
- Misfolded alpha-synuclein hall mark of PDF
- Found in enteric neurons early in disease - spreads to brain
- Variants in the SNCA gene associated with idiopathic PD
9
Q
Commensals microbiome function
A
Induce protective response to prevent colonisation and invasion of pathogens.
10
Q
Why do we study the microbiome
A
To understand the role of microbes and how they influence human health.
11
Q
Define microbiome
A
The full collection of microbes and their genes
12
Q
Define microbiota
A
The distinct communities of microbial taxa associated with humans.
13
Q
Define mega genomics
A
The study of the collection of genomes within an environment or sample through DNA analysis.
14
Q
Define dysbiosis
A
An imbalance in the microbiome, resulting in adverse effects on the host body,
15
Q
Define operational taxonomic unit:
A
A cluster of sequences that identify a bacteria, allowing it to be classified.
16
Q
How do our microbiome originate ?
A
- Our microbiomes are largely maternal in origin and depending on how you were delivered, you would have been exposed to different microbiomes. This is because the first microbes we are exposed to are biologically our mothers.
17
Q
What factors influence the microbiome
A
- Age and sex
- Host genetics and Epigenetics factors
- Environmental exposure, such as pathogens
- Diets, alcohol consumption and smoking
- Lifestyle choices
- Medication usage
- Sleeping habits
- Stress levels
18
Q
General functions of Gut microbiome (8)
A
- Nutrient and mineral absorption
- Synthesis of enzymes, vitamins and amino acids
- Production of short chain fatty acids through the breakdown of complex fibers.
- Muscle functioning
- Prevention of chronic diseases and facilitating the treatment of disease
- Stimulation of the immune system
- Regulation of pH to deter pathogens
- Keeping the us and our gut lining health
19
Q
What is the Gut-brain axis (GBA)
A
Bidirectional communication between the central and enteric nervous systems
20
Q
What is the relationship between the microbiome and the GBA.
A
- Enteric nervous system (ENS): neural circuits embedded into the lining of the GIT.
- The ENS governs the function of the GIT including immune and endocrine functions, secretion, transport, blood flow and motor functions.
- Cognitive and emotional centres of the brain are linked to intestinal functioning and gut microbiota influence this interaction.
21
Q
Characterise the good bacteria in the GIT
A
- Beneficial bacteria that mainly reside on your skin and in your GIT, acting as resident flora.
- Different strain of beneficial bacteria have different functions
- Some of these strains are ingested in probiotics to treat or prevent disease.
- Examples Bifidobacteria + Lactobacillus
22
Q
Characterise the bad bacteria in the GIT
A
- Bacteria that act as a pathogen and make you sick. Some may result in severe diseases, such as pneumonia and meningitis.
- These reproduce rapidly and produce toxins
- When an infection enters the bloodstream, it can cause septicaemia. This allows the bacteria to spread, causing sepsis.
- Can be treated with antibiotics
- Examples: Streptococcus, Escherrichia coli
23
Q
Methods of manipulating our microbiome
A
- Antibiotics
- Probiotics
- Fermented food
24
Q
What are Faecal microbiome transplant
A
- When someone else’s stool is inserted into a patients GIT too give them a better microbiome after a reaccurant bacterial infection. Once patients receive the infusion, god bacteria populate the GIT and prevent pathogenic bacteria from persisting.
25
What methods are used in microbiome research?
1. 16S rRNA gene sequencing
2. Whole -genome shotgun sequencing
26
Characterise 16rRNA gene sequencing for bacteria
1. Target amplification- based approach that sequences the 16S rRNA gene in bacteria and archaea.
2. Does not provide a functional profile of microbial genes.
3. Taxonomic resolution at a genus levels
4. Have been more commonly used and there are well-curated database
5. Low risk of false positives
6. Cheaper since only the 16s rRNA gene is being sequenced.
27
Characterise whole-genome shotgun sequencing for bacteria
1. Untargeted- covers all genomic DNA, including bacteria, archae, fungi and viruses
2. Can provide information regarding functional potential
3. Taxonomic resolution at a species levels, but at high coverage can include strains and SNVs.
4. Database are new and still improving as more studies are conducted.
5. Higher risk of false positive
6. 2-3x the cost of 16S rRNA sequencing, but is more comprehensive and generates more date.
28
What is The human microbiome Project
1. Like the human genome project - but for microbes
2. A research initiative to improve understanding of the microbiota involved in human health and disease .
29
The Aim of the human microbiome project
The aim: to study the diversity, structure and function of healthy human microbiomes from approximately 300 adults in the USA
30
Key findings of the human microbiome project
There is no single “normal” or core microbiome and there is extensive diversity even among ‘healthy individuals.
31
The first phase of the human microbiome project
1. HMP1: characterisation of the microbes of healthy human subjects at five major body sites, using 16S and metagenomic shotgun sequencing.
2. Five sites; oral cavity, nasal cavity, skin, gastrointestinal tract and urn genital tract
32
The second phase of the human microbiome project
1. IHMP: characterisation of microbiome and human host from three 3 cohort of microbiome associated conditions, using multiple omics technology
2. Included studies of dynamic changes in the microbiome and host in three conditions; premature births, inflammatory bowel diseases and pre-diabetes
3. A multi-omic approach that could be used for future microbiome studies
33
African population remain underrepresented in human microbiome studies. Why?
1. Microbiome research has focused on western populations- greater resources, research institutions and infrastructure available.
2. Majority of African countries are resources - limited funding opportunities and research infrastructure. International collaborations will be required.
3. Access to research samples and sampling protocols can be limited.
34
Hypothesis for how the genetics shape the gut microbiome and how the microbiome affects the genetics .
1. Hypothesised that factors of our physiology (metabolism, gut motility and energy regulation) are governed by our genes ultimately, this affects the gut microbiome.
2. The gut microbiome also affects genetics by acting as a dynamic environmental factors within the host.
35
Key features that affect drug responses
1. Genetic variation
2. Environmental
3. Lifestyle
4. Age and sex
36
What is the therapeutic range for medication
The range between minimum effective concentration and minimum toxic concentration
37
Why is genetics important in drug therapy.
Pharmacogenetics testing implementation can inform the choice of treatments and drug dosage adjustments, thus decreasing the risk of ADRs and enhancing treatment efficacy.
38
Can pharmacogenetics studies done on one population be applied to another?
No the distribution of actionable PGx variants tends to vary across populations are important
39
Number of clinically relevant pgx variants carried per individual across populations.
Over 97% of study participants have a least 1 actionable PGx variant.
40
Examples of structural variants of genes important to pharmogenetics.
Gene deletion
Gene duplication and multiplication
Tandem arrangements and hybrid gene copies
41
Pharmacogenomoics resources
1. PharmVar - Pharmacogene variation consortium: is a central repository for pharmacogene (PGx) variation that focuses on haplotype structure and allelic variation.
2. CPIC- clinical pharmacogenomics implementation consortium : an international consortium of individual volunteers and a small dedicated staff who are interested in facilitating use of pharmacogenetic tests for patient care.
3. PharmGKB - Knowledge base: is a pharmacogenomics knowledge resource that encompasses clinical information including clinical guidelines and drug labels, potentially clinically actionable gene-drug associations and genotype-phenotype relationships.
4. PGRN - Pharmacogenomics Global research network : catalyze and lead research in precision medicine for the discovery and translation of genomic variation influencing therapeutic and adverse drug effects.
42
Key challenges and limitations hindering pharmacogenetics (9)
1. Most African ethnolinguistics groups are yet to be included in PGx studies.
2. Affordable technologies only assess known/common variants
3. Comprehensive NGS technologies are relatively expensive
4. Few PGx studies across Africa have performed functional assay to ascertain the impact of variants in key pharmacogenes.
5. Difficult to assess the impact of rare variants
6. Factors other than variants within ADME genes could alter drug response phenotypes
7. Infrastructure limitations and disparity in training / resource availability.
8. Lack of proper electronic health records across Africa
9. Limited access to essential medication across most clinical settings in Africa
43
There is a need for more PGx studies focused on African population to:
1. Characterise the PGx variation Landscape (SNV and structural variants) in understudied ethnolinguistics groups.
2. Discover novel variants / haplotypes in core and extended ADME genes
3. Address the lack of functional studies on multiple African -ancestry alleles
4. Facilitate implementation of genotype-guided therapy.
