22 Metagenomics and the Microbiome
22.1 Studying Communities of Microbes
22.1.1 What Is Metagenomics?
Metagenomics = Studying genetic material from environmental samples containing MANY different species
Meta = beyond or among Genomics = studying genomes
So: Studying the genomes of entire communities at once!
Think of it like:
Analyzing a whole forest instead of one tree
Studying a city instead of one person
Reading all books in a library at once
22.1.2 The Microbiome
Microbiome = All the microorganisms living in a particular environment
Examples:
Human gut microbiome: Trillions of bacteria in your intestines
Soil microbiome: Microbes in dirt
Ocean microbiome: Microbes in seawater
Skin microbiome: Bacteria on your skin
Key fact: There are more bacterial cells in/on you than human cells!
~30 trillion human cells
~40 trillion bacterial cells
You’re more microbe than human (by cell count)!
22.2 Why Study Microbiomes?
22.2.1 They’re Everywhere and Important!
In your body:
Help digest food
Make vitamins (K, B12)
Train immune system
Protect from pathogens
Affect mood and behavior!
In the environment:
Decompose dead material
Fix nitrogen (make fertilizer)
Clean up pollution
Cycle nutrients
Produce oxygen (ocean microbes!)
Without microbes: Life on Earth would collapse!
22.3 The Challenge: Unculturable Microbes
22.3.1 Most Microbes Can’t Be Grown in Lab
The problem:
Traditional microbiology: Grow bacteria on plates
But 99% of environmental microbes won’t grow in lab!
Called “unculturable”
Why they won’t grow:
Need specific conditions
Grow too slowly
Depend on other microbes
Unknown nutritional needs
Result: We were missing most microbial diversity!
22.3.2 The Solution: Culture-Independent Methods
Metagenomics breakthrough:
Don’t need to grow them!
Extract DNA directly from environment
Sequence all DNA together
Identify all microbes present
It’s like:
Instead of inviting each person to interview
Reading everyone’s ID cards at once
Getting census data without asking questions
22.4 How Metagenomics Works
22.4.1 The Workflow
1. Sample Collection
Collect environmental sample
Soil, water, feces, skin swab, etc.
Contains billions of microbes
2. DNA Extraction
Break open all cells
Extract all DNA
Mix of DNA from thousands of species!
3. Sequencing
Sequence all DNA fragments
Millions of reads
Don’t know which species each fragment comes from (yet!)
4. Analysis
Identify which microbes are present
How many of each?
What genes do they have?
What can they do?
22.4.2 Two Main Approaches
16S rRNA Sequencing (targeted):
Sequence only 16S rRNA gene
Present in all bacteria
Like a bacterial barcode
Tells you WHO is there
Cheap and fast!
Shotgun Metagenomics (whole genome):
Sequence ALL DNA
More expensive
Tells you WHO is there AND what they can do
Functional information
22.5 The Human Microbiome
22.5.1 We’re Walking Ecosystems!
Where microbes live on/in you:
Gut (most abundant): 100 trillion bacteria
Skin: Different microbes on different body parts
Mouth: Hundreds of species
Nose: Unique communities
Vagina: Dominated by Lactobacillus (usually)
It’s personal: Everyone has unique microbiome!
Like a fingerprint
Affected by diet, genetics, environment, medications
22.5.2 The Gut Microbiome
Most studied and important
Major bacterial groups (phyla):
Firmicutes (40-60%)
Bacteroidetes (20-40%)
Actinobacteria (smaller %)
Proteobacteria (smaller %)
Plus archaea, fungi, viruses!
What they do:
1. Digest Food:
Break down complex carbohydrates we can’t digest
Fiber, resistant starch
Produce short-chain fatty acids (healthy!)
2. Make Vitamins:
Vitamin K (blood clotting)
B vitamins (B12, biotin, folate)
We couldn’t make these without microbes!
3. Train Immune System:
Teach immune cells friend vs. foe
Without microbes: Allergies, autoimmune diseases
“Old friends” hypothesis
4. Protect from Pathogens:
Occupy space (no room for bad guys)
Produce antimicrobial compounds
Compete for resources
5. Produce Neurotransmitters:
Serotonin (mood)
GABA (calming)
Dopamine
“Gut-brain axis”!
22.5.3 Dysbiosis: When Microbiome Goes Wrong
Dysbiosis = Imbalanced microbiome
Associated with:
Obesity
Type 2 diabetes
Inflammatory bowel disease (IBD)
Allergies
Autism (controversial)
Depression and anxiety
Autoimmune diseases
Causes of dysbiosis:
Antibiotics (kill good bacteria too!)
Poor diet (low fiber)
Stress
Lack of sleep
C-section birth (miss mom’s microbes)
Formula feeding (vs. breastfeeding)
22.6 Environmental Metagenomics
22.6.1 Soil Microbiome
Incredibly diverse:
Teaspoon of soil: 1 billion bacteria
Thousands of different species
More diversity than gut!
What they do:
Decompose organic matter
Cycle nutrients (nitrogen, phosphorus)
Help plants grow
Carbon storage (climate change!)
Applications:
Agriculture (healthy soil = healthy crops)
Bioremediation (clean up pollution)
Carbon sequestration
22.6.2 Ocean Microbiome
Craig Venter’s Global Ocean Sampling:
Sailed around world
Sampled ocean microbes
Discovered MILLIONS of new genes!
Cyanobacteria (like Prochlorococcus):
Most abundant photosynthesizer on Earth!
Produce 20% of Earth’s oxygen
Tiny but critically important
Marine microbes:
Base of food chain
Carbon cycling
Climate regulation
Chemical diversity (drug discovery!)
22.7 Metagenomics Applications
22.7.1 Medicine
Fecal Microbiota Transplant (FMT):
Transfer healthy microbiome to patient
Cures C. difficile infection (90% success!)
Being tested for other diseases
Personalized Medicine:
Microbiome affects drug metabolism
Could predict treatment response
Tailor treatments to individual microbiome
Diagnostics:
Microbiome signatures for diseases
Early detection
Non-invasive testing
22.7.2 Agriculture
Improve Crop Yield:
Select beneficial soil microbes
Reduce fertilizer needs
Increase drought tolerance
Probiotics for plants!
Animal Health:
Livestock microbiome optimization
Reduce antibiotics use
Improve nutrition
22.7.3 Biotechnology
Bioprospecting:
Find new enzymes from microbes
Industrial applications
Laundry detergents
Biofuels
Waste Treatment:
Sewage processing
Decompose pollutants
Generate biogas
22.7.4 Environmental
Bioremediation:
Clean up oil spills
Remove heavy metals
Degrade plastics (potentially!)
Climate Change:
Understanding carbon cycle
Methane production/consumption
Ocean acidification impacts
22.8 The Human Microbiome Project
22.8.1 Mapping Our Microbial Partners
HMP (2007-2016):
NIH-funded project
Characterize microbiome of healthy humans
300 healthy people
Multiple body sites
Key findings:
Huge diversity (10,000+ species)
Everyone has unique microbiome
Core functions shared (even if species different)
Variation is normal
Impact:
Reference dataset
Enables disease studies
Launched microbiome research boom
22.9 Microbiome Manipulation
22.9.1 Can We Change Our Microbiome?
Methods:
1. Diet:
Fiber feeds good bacteria
Fermented foods (yogurt, kimchi, sauerkraut)
Prebiotics (food for probiotics)
Mediterranean diet linked to healthy microbiome
2. Probiotics:
Live beneficial bacteria
Yogurt, supplements
Evidence mixed (not all are helpful!)
Strain-specific effects
3. Antibiotics (when necessary):
Kill harmful bacteria
But also good ones
Use wisely!
4. Fecal Microbiota Transplant:
Extreme intervention
Very effective for some conditions
Being researched for other diseases
5. Exercise:
Associated with healthier microbiome
Increases diversity
Mechanisms unclear
22.10 Challenges in Metagenomics
22.10.1 Technical Difficulties
1. Complexity:
Thousands of species
Complex interactions
Hard to figure out who’s doing what
2. Computational:
Massive datasets
Need powerful computers
Analysis challenging
3. Causation vs. Correlation:
Microbiome difference ≠ cause of disease
Could be consequence
Hard to prove causation
4. Individual Variation:
Everyone’s different
Hard to define “healthy” microbiome
Personalized approaches needed
5. Functional Redundancy:
Different microbes can do same job
Focus on function, not just species
22.12 Mycobiome and Beyond
22.12.1 Not Just Bacteria!
Mycobiome (fungi):
Present in gut, skin, etc.
Less studied than bacteria
Candida and others
Role in health unclear
Archaeome (archaea):
Methane-producing archaea in gut
Less abundant than bacteria
Unique metabolism
Parasites and protists:
Also part of microbiome
Complex interactions
Often pathogenic but not always
22.13 The Future of Microbiome Research
22.13.1 What’s Coming
1. Precision Microbiome Medicine:
Analyze your microbiome
Personalized probiotic prescriptions
Targeted microbiome manipulation
2. Microbiome Editing:
CRISPR for microbiome
Edit bacterial genes in situ
Remove harmful functions
3. Synthetic Microbial Communities:
Design optimal microbiome
Engineer bacteria for specific functions
Living therapeutics
4. Biomarkers:
Microbiome signatures for diseases
Diagnostic tests
Track treatment response
5. Environmental Applications:
Climate change mitigation
Pollution cleanup
Sustainable agriculture
22.14 Key Takeaways
Metagenomics studies genetic material from mixed communities
Microbiome = all microorganisms in an environment
More bacterial cells than human cells in your body!
Most microbes can’t be cultured (99%)
Two approaches: 16S rRNA (who’s there) vs. shotgun (what they do)
Gut microbiome: Digests food, makes vitamins, trains immunity, affects mood
Dysbiosis = imbalanced microbiome, linked to diseases
Human Microbiome Project mapped our microbial partners
Diet, probiotics, FMT can modify microbiome
Applications: Medicine, agriculture, environmental cleanup
Everyone has unique microbiome
Microbiome research is exploding field with huge potential
Sources: Information adapted from Human Microbiome Project, microbiome research literature, and metagenomics studies.