Margaret McFall-Ngai,Dept of Medical Microbiology and Immunology
Symbiosis ClusterUniversity of Wisconsin Madison
Interplay of Microbiome, Environmental Stressors, and Human HealthWashington, DC, April 2011
Origin and Evolution of the Microbiome
Outline
1. Humans as components of the animal kingdom -Who are we and how did we get here?
2. Evolution of the epithelium-immune-microbiota interaction
epithelium mucosal immunesystem
bacterial consortium Microbiota
MacPherson & Harris (2004) Nat Rev Immunol
Cretaceous
Jurassic
Triassic
Quaternary
Tertiary
MES
OZO
ICP
ALE
OZO
IC
Permian
Carboniferous
Devonian
Silurian
Ordovician
Cambrian earliest vertebrates
earliest jawed vertebratesLophotrochozoa
Ecdysozoa
earliest tetrapods
earliest mammals
Homo sapiens
225
65
550
Millions of years ago
ALL animal body plans diverged
Deuterostomia
CEN
OZO
IC
Bilateria
Deuterostomia
Protostomia
Metazoa
Porifera, Cnidaria, Ctenophora(sponges, corals, comb jellies)
Chordata (tunicates, lancelet, fish, human)
Hemichordata (acorn worms)
Echinoderms (sea urchin)
Lophotrochozoa
Ecdysozoa
Molluscs and others
Annelidsand others
Nematodesand others
Arthropodsand others
the vertebrates
Unicellular organisms
Over 96% of animal diversity
non-vertebrate
On their own complex
evolutionary paths
Bilateria
Deuterostomia
Protostomia
Metazoa
Porifera, Cnidaria, Ctenophora(sponges, corals, comb jellies)
Chordata (tunicates, lancelet, fish, human)
Hemichordata (acorn worms)
Echinoderms (sea urchin)
Lophotrochozoa
Ecdysozoa
Molluscs and others
Annelidsand others
Nematodesand others
Arthropodsand others
the vertebrates
Unicellular organisms
(Domazet-Loso and Tautz, 2008)
The evolutionary trajectory to humans in 19 steps -
Question: At which steps in evolution did the human genes evolve?
Method: All available proteins sequences were used to create a phylographic framework, within which the positions of human protein sequences (~23, 000) were identified.
Gen
e N
umbe
r10,000
1,000
10
11 2 3 4 5
100
Genome
Disease
6 7 8 9 10 11 12 13 14 15 16 17 18 19
Phylostrata
Animals
Mammals
Primates
Jawed Vertebrates
Origin of Human Genes/Genes Associated with Human Genetic Disease
(Domazet-Loso and Tautz, 2008) Phylostrata
(1,760/22,937)
Gen
e N
umbe
r10,000
1,000
10
11 2 3 4 5
100
Genome
Disease
6 7 8 9 10 11 12 13 14 15 16 17 18 19
Phylostrata
Animals
Mammals
Primates
Jawed Vertebrates
Origin of Human Genes/Genes Associated with Human Genetic Disease
(Domazet-Loso and Tautz, 2008) Phylostrata
(1,760/22,937)
Genes involved in genetic disease are biased toward ancient genes.
Thus, for an understanding of the human microbiome:
Can we derive basic principles of animal-bacterial interactions from an understanding of the patterns of evolution of genes?
Gen
e N
umbe
r10,000
1,000
10
11 2 3 4 5
100
Genome
Disease
15 16 17 18 19
Mammals Jawed Vertebrates
Origin of Human Genes/Genes Associated with Human Genetic Disease
Principally immune-related
Overrepresented in immune-related
Animals
Principally signaling
Overrepresented incell-cell
communication
(Domazet-Loso and Tautz, 2008)
6 7 8 9 10 11 12 13 14
Phylostrata
Bioinformatic approaches to evolution of animals Models of animal-bacterial associations - an evolutionary tool kit
Insights into human biology
“Given that over 90% of the disease genes have emerged before the bilaterian radiation, it seems justified to use the organisms that are evolutionarily very remote
as models for studying the function of disease genes”[Domazet-Loso and Tautz, 2008]
Bilateria
Deuterostomia
Protostomia
Metazoa
Porifera, Cnidaria, Ctenophora(sponges, corals, comb jellies)
Chordata (tunicates, lancelet, fish, human)
Hemichordata (acorn worms)
Echinoderms (sea urchin)
Lophotrochozoa
Ecdysozoa
Molluscs and others
Annelidsand others
Nematodesand others
Arthropodsand others
the vertebrates
Unicellular organisms
Environmental context for the evolution of animal body plans - what drove selection on the mucosa?
Environment of the oceans
> 99% of all the organic matter in dissolved (DOM) rather than particulate form[Hedges (1987) Nature 330:205)]
~ 105-106 bacteria/ml of seawater
Environment of the oceans
> 99% of all the organic matter in dissolved (DOM) rather than particulate form[Hedges (1987) Nature 330:205)]
~ 105-106 bacteria/ml of seawater
Evolution of animal body plans
-- selection for the uptake of DOM across the body wall in most, if not all, soft-bodied marine invertebrates
Challenge of opposite ‘goals’-- taking up DOM and preventingovergrowth of their tissues by the microorganisms thatshare the nutrient pool
Milestones in animal evolution
multicellularity
tissue layers (diploblastic - endoderm/ectoderm)
bilateral (triploblastic - +mesoderm)
complete gut
coelom
sponges
anemones
flatwormsribbonworms
insects vertebrates
mollusks
Milestones in animal evolution
multicellularity
tissue layers (diploblastic - endoderm/ectoderm)
bilateral (triploblastic - +mesoderm)
complete gut
coelom
sponges
anemones
flatwormsribbonworms
insects vertebrates
mollusks
EPITHELIA
INTERNAL TISSUELAYERS, ORGANS
one-way digestion,GUT REGIONALIZATION
GUT SEPARATED FROMBODY WALL
Thomas Bosch Christian-Albrechts University Kiel, Germany
Hydra spp.
Many responses of animals to the microbial world are ancient and conserved.
Hydra frozen section EM, TCG Bosch
www.visualsunlimited.com/requestform.jsp
Human small intestine
Hydra body column
Hydra – a new model in innate immunityHydra has two cell layers - epidermis (derived from ectoderm) and gastrodermis (derived from endoderm)
Fraune & Bosch (2010) BioEssays
Fraune & Bosch (2007) Proc.Natl.Acad.Sci USA
Fraune & Bosch (2009) Microbe
Fraune et al (2010) Proc.Natl.Acad.Sci USA
Analysis of bacteria associated with different Hydra species
Fraune & Bosch (2010) BioEssays
Fraune & Bosch (2007) Proc.Natl.Acad.Sci USA
Fraune & Bosch (2009) Microbe
Fraune et al (2010) Proc.Natl.Acad.Sci USA
Analysis of bacteria associated with different Hydra species
Environmental isolates & long-term lab cultures
Role of TLR-pathway in host-microbe interactions
Transgenic knock-down of MyD88
TLR signalling is required for host –microbe interaction
…From Hydra to man: TLR-2 knockout mutants have altered microbiota.
Cretaceous
Jurassic
Triassic
Quaternary
Tertiary
MES
OZO
ICP
ALE
OZO
IC
Permian
Carboniferous
Devonian
Silurian
Ordovician
Cambrian earliest vertebrates
earliest jawed vertebratesLophotrochozoa
Ecdysozoa
earliest tetrapods
earliest mammals
Homo sapiens
225
65
550
Millions of years ago
ALL animal body plans diverged
Deuterostomia
CEN
OZO
IC
Water-to-LandTransition
first evidence
Radiation of members of 7 of the ~36 animal phyla,
(representatives in all three subkingdoms)
Most vertebrates are aquatic.
Agnatha (80)
Chondrichthys (900)
Actinopterygii (25,000) Fishes
Actinistia + Dipnoi (8) Urodeles (415)
Anura (4300)
Amph
ibia
ns
Reptile
s
Birds
Mammalia (4500)
Aves(9100)
Gymnophiona (165)
Testudinia (260)
Lepidosauria(6800)
Crocodilia (22)
Mam
mals
Water-to-Land Transition
Land animals [and plants] require mechanisms:
of structural supportto respireto reproduceto avoid desiccation
Water-to-Land Transition
Land animals [and plants] require mechanisms:
of structural supportto respireto reproduceto avoid desiccation
require substantial remodeling of the mucosa
epithelium mucosal immunesystem
bacterial consortium Microbiota
MacPherson & Harris (2004) Nat Rev Immunol
The integration of microbiologyand host biology
= a revolution in biology
Our concept of the nature of the immune system
Cretaceous
Jurassic
Triassic
Quaternary
Tertiary
ME
SO
ZOIC
PA
LEO
ZOIC
Permian
Carboniferous
Devonian
Silurian
Ordovician
Cambrian
earliest vertebrates
earliest jawed vertebrates
Lophotrochozoa
Ecdysozoa
earliest tetrapods
earliest mammals
Homo sapiens
225
65
550
mya
ALL animal body plans diverged
Deuterostomia
CE
NO
ZOIC
adaptive immune system
Porifera(sponges)
EchinodermataChordata
Cephalochordata
Urochordata
Vertebrata
Agnatha
Cartilagenousfishes (sharks, rays)
Bony fishes
Amphibians
Reptiles
Birds
Mammals
The mechanism enabling somatic recombination appears at the agnathan - gnathostome transition.
Lophotrochozoa
Ecdysozoa
Deuterostomia
Vertebrates - 4%
Agnathan(jawless)
Gnathostome(jawed)
Invertebrates - 96%
Invertebrates Vertebrates
Binary associationsintra- or extracellular common rare
Stable, coevolved, consortial symbioses rare common
Basic differences in immunity between invertebrates and vertebrates may reflect the way they interact with microbes:
Correlated immunity: innate only innate + adaptive
Invertebrates Vertebrates
Binary associationsintra- or extracellular common rare
Stable, coevolved, consortial symbioses rare common
Basic differences in immunity between invertebrates and vertebrates may reflect the way they interact with microbes:
Correlated immunity: innate only innate + adaptive
Could a principal selection pressure on the evolution of the vertebrate adaptive immune system be the requirement of the host to maintaincoevolved communities in balance?
INVERTEBRATES VERTEBRATES
Association withmicroorganisms
Immune system:selection on, and function of
restrictive permissive
non-self control of a set recognition of communities
epithelium mucosal immunesystem
bacterial consortium Microbiota
MacPherson & Harris (2004) Nat Rev Immunol
Both bioinformatic approaches and functional studies provide evidence that animal-bacterial interactions
involve ancient, conserved characters.
Our new knowledge of the patterns and prevalence of these interactions demands that we question some of our
basic premises (e.g., the form and function of the immune system).
Conclusions
Thank you!
Questions?