christopher garris, harvard university immunology phd program
TRANSCRIPT
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Christopher Garris, Harvard University Immunology PhD Program
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What’s the Loop?
Mikael Häggström
• Small and Large Intestines
• Absorptive organs for nutrients and water
• Home to a TON of microbes
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Why Poop?
• Full of microbes
• Transits through the colon
• Easy to collect
Pixabay.com
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Plan for the Evening
What is a microbe?
Where do these bugs live?
How do we study these bugs?
Why are these bugs important for health?
What am I researching?
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What is a Microbe?
Madeleine Price Ball, wikipedia.org
A small organism
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Most Bugs Live in the Gut
Duncan Flock, wikipedia.org
• Present in both small and large intestine
• More bacteria in the colon
• Also present in lungs and skin (barrier tissues)
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Why live in the gut?
• Access to nutrients
Pixabay.com, Leyo wikimedia.org
• Bacterial “byproducts” promote a “healthy gut”
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Germ-Free Mice Demonstrate the Importance of Gut Microbes
Germ Free
Conventionally Raised
Servier Medical Art
Sterile Isolators
Intestine
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What’s Wrong with Germ Free Mice?
• Defects in the immune system
• Susceptible to infection
• Metabolic changes
Annie Steel, openclipart.org
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What is the Immune System?
• Protect against disease
• Distinguish self vs. Non-self (not always!)
Servier Medical Art
• Interactions of many cell types
Macrophage
Neutrophil
B Cell
Dendritic Cell
T Cell
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Absence of Certain “T Cells” in the Intestines
TH17
Ivanov et. al, Cell 2009
Germ
Fre
e
Germ
Free +
SFB
Normal
0
5
10
15
20%
Th1
7
Germ Free
Segmented Filamentous Bacterium (SFB)
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Susceptibility to Infection
Collins et. al, Infection and Immunity, 1978
LD 50 = Lethal dose for 50% of animals
Germ
Fre
e
Normal
100
101
102
103
104
105
106
107
Bac
teri
a LD
50
Germ Free
Conventionally Raised
Salmonella
1,000,000 times less bacteria!
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Metabolic Changes
• Animals are resistant to diet-induced obesity
Tebu.an, wikipedia.org; Backhed et. al 2007, PNAS
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So That’s Great… But I’m Not Germ Free, So Why Should I Care?
Ley et. al, 2005 PNAS
Obese Mouse
Microbial Communities are Different In Obesity
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So That’s Great… But I’m Not Germ Free, So Why Should I Care?
Germ Free Recipients
+
+
Obese Microbiota
Lean Microbiota
Turnbaugh et. al, 2006 Nature
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But That’s A Mouse, What About Humans?
• Decreased species diversity in obesity
• Proportions of certain bacteria groups are associated with obesity
• Fecal samples ≠ Cecal Samples
Turnbaugh et. al, Nature 2009
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A Review
Intestinal microbes predominantly live in the large intestine Germ-free mice are a system to study host-microbe mutualism
Microbes affect health in numerous ways • Immune System • Infection • Obesity
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Questions
Pixabay.com
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Intermission
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Plan for the Evening
What is a microbe?
Where do these bugs live?
How do we study these bugs?
Why are these bugs important for health?
What am I researching?
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Methods to Study Gut Microbes
Culturing
MarcoTolo, Greg Emmerich flickr.com
But you can’t culture everything!
A solution:
DNA Sequencing
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Why Do We Need To Sequence To Identify Bacteria?
• Most species cannot be grown in culture
• Competition between species
• Provides broader coverage
Pixabay.com
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How Do They Figure Out Bacteria Communities From Poop?
16S Ribosomal DNA Sequencing
Assembles Proteins Ribosomal RNA
Antilived, accessexcellence.org; David S. Goodsell RCSB Protein Bank
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Reconstructing Bacterial Relationships From Genetic Information
Don Hamerman, UIUC Institute of Genomic Biology, Tim Vickers
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Meta-Genomics
• “Above” the genome
• Measures differences between rDNA sequences
• Differences imply bacterial lineages
Greg Emmerich, Flickr
• Can identify the unculturable
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Initial Applications of Meta-Genomics
Brown R, ZooKeys, Pollo
Environmental Sampling
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Sequencing Can Reveal Bacterial Abundance
Ubeda et. al, 2010 JCI
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Sequencing Indicates Bacterial Community Structure
Ubeda et. al, 2010 JCI
Each color represents a type of bacteria
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Whole Genome Sequencing of Human Feces Yields Microbial Gene Content
Turnbaugh et. al, Nature 2009, National Institutes of Health
• Shared genes among diverse microbiotas
• Establishes a “core microbiota”
• Individual species may be less important than gene content
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Questions
Pixabay.com
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Well That’s Cool… But Don’t Bacteria Cause Disease?
Yes….. And No.
Volker Brinkmann, Max Planck Institute for Infection Biology, TJ Kirn, Vaishnava et. al, Science 2011
Spatial Segregation of Self from Bacteria
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Villi-fying Bacteria
Vaishnava et. al, Science 2011; Round et. al, 2010 PNAS
More Immune Activation with Defective Barrier
Some Bacteria Can Promote Immune Homeostasis
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Even Bacterial Products Can Control Inflammation
Round et. al, 2010 PNAS
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But Sometimes Microbes in the Gut Have a Dark Side
Mutant Mouse
Normal Mouse
Intestinal Inflammation Model
Co-house
Disease Transmissible! Elinav et. al, 2011 Cell
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Gut Bacteria Can Be Associated With Autoimmune Disease
Wu et. al, 2010 Immunity
+ Normal or Test Feces
Germ-Free
Measure of Arthritic Disease
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Plan for the Evening
What is a microbe?
Where do these bugs live?
How do we study these bugs?
Why are these bugs important for health?
What am I researching?
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What I Do
• Autoimmunity to Cancer
• Microbiota Education of the Immune System
• Immune Control of Cancer
• Microbiota Effects on Cancer Crab = Cancer
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Human Immune Responses to Cancer
Low High
Galon et. al, 2006 Science; Chen et. al, 2003 Clin. Cancer. Res.
Different Immune Cell Infiltrates – Different Prognosis
T Cell High
T Cell Low
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Microbiota And Therapy Response
• Chemotherapy can be affected by broad spectrum antibiotics
• Immunotherapy is also sensitive to broad spectrum antibiotics
Iida et. al, 2013 Science
+ Abx
- Abx - Abx
+ Abx
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Can Modifying Intestinal Bacteria Change Treatment Outcomes?
Genetic Models Antibiotics Intestinal Damage
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Potential for Microbes as Therapeutics
• Bacterial Infections
• Inflammatory Bowel Diseases
• Autoimmune Disease
• Cancer?
Algotruneman, openclipart.org
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Final Recap
Intestinal microbes are important for health Sequencing approaches enable us to study gut bacteria
Gut bacteria affect a variety of disease states
Poop is more interesting than you can ever imagine
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Thank you! SITN would like to acknowledge the following
organizations for their generous support.
Harvard Medical School Office of Communications and External Relations
Division of Medical Sciences
The Harvard Graduate School of Arts and Sciences (GSAS)
The Harvard Graduate Student Council (GSC)
The Harvard Biomedical Graduate Students Organization (BGSO)
The Harvard/MIT COOP
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Treg
Normal
Germ
Fre
e
Germ
Free +
SCFA
0
5
10
15
20
% T
reg