the promise of the microbiome - science...(based on cell counts, we are 10 parts bacterial, 1 part...

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The Promise of the MicrobiomeFunction and Dysfunction in Humans and Beyond

Instructions for Viewers

Webinar Series

July 15, 2014

Brought to you by the Science/AAAS Custom Publishing Office

Sponsored by:

Participating Experts

David A. Relman, M.D.Stanford UniversityPalo Alto, CA

Jack A. Gilbert, Ph.D.Argonne National LaboratoryLemont, IL

Webinar Series

Rob Knight, Ph.D.HHMI / University of ColoradoBoulder, CO

The Promise of the MicrobiomeFunction and Dysfunction in Humans and BeyondJuly 15, 2014

The Promise of the Microbiome: Function and Dysfunction in Humans and Beyond

David A. Relman, Stanford UniversityScience Webinar

July 15, 2014

A bit of history Antony van Leeuwenhoek, 1683

(‘animalcules’)

“an unbelievably great company of living animalcules, a‐swimming more nimbly than any I had ever seen up to this time. The biggest sort. . . bent their body into curves in going forwards. . .” Razumov AS, 1932 (‘Great plate anomaly’) Moore W, 1975, 76; Savage DC, 1977

(cell counts, ecology)Relman et al.

The Tree of Life(based on rRNA sequences)

Bacteria

Eukarya

Archaea

Pace NR. A molecular view of microbial diversity and the biosphere. Science 1997; 276:734

macroscopic life

Site-specific distributions of bacterial phyla inhealthy humans

Size of circles is proportionate to average number of species-level phylotypes per individual

Dethlefsen L et al., Nature 2007; 449:811-818

Hundreds to thousands of strains (colon)

Diversity comparisons across 22 body sites, 279 healthy humans

Zhou et al. Genome Biology 2013, 14:R1

Sources of variation in patterns of diversity

Space (habitat, body site) Individual Health status Host genetics Environmental exposures Diet Chemical/drug/mechanical disturbance Other aspects of lifestyle? (e.g. geography) Other mammals/hosts

Time (esp. early in life) Relman et al.

Community stability landscape

Shift in community state variables

Shift in environmental parameters

Costello EK et al.,Science 336, 1255 (2012)

Fraction of shared ‘strains’* within individuals (37) versus time interval

weeks

Faith JJ et al, Science (5 July) 2013

*100% similar over 16S rRNA V1-V2

Our ‘extended self’: human-microbe mutualismOur ‘extended self’: human-microbe mutualism

Our benefits (incomplete list) Food digestion Nutrition (vitamins, energy) Xenobiotic processing Metabolic regulation, cometabolism Development: terminal differentiation of mucosa “Education”, regulation of immune system Epithelial “homeostasis”, barrier integrity Colonization resistance to pathogens

1683

Turnbaugh P et al, Nature 449:804-810, 2007; Dethlefsen L et al, Nature 449:811-818, 2007

(Based on cell counts, we are 10 parts bacterial, 1 part human…and based on numbers of unique genes, we are 150 parts bacterial, 1 part human…)

Disturbance

Disturbances remove or kill some fraction of the community, creating opportunities for remaining community members or new colonists…effects directed at community and/or host Increasingly prominent in “modern” societies?

Relman et al.

Clinical problems associated with the indigenous microbiota

Chronic periodontitis Crohn’s disease & other IBD Irritable bowel syndrome Tropical sprue Antibiotic-associated diarrhea Pathogen colonization Bacterial vaginosis Premature labor and delivery

Relman et al.

“pathogenic states”

“Community as pathogen”that is,

disease due to a community disturbance

Relman et al.

Clinical problems associated with the indigenous microbiota

Chronic periodontitis Crohn’s disease & other IBD Irritable bowel syndrome Tropical sprue Antibiotic-associated diarrhea Pathogen colonization Bacterial vaginosis Premature labor and delivery

Cause or effect?Initiating or propagating?Mono- or polyfactorial?

Relman et al.

Koch’s postulates (guidelines)“Die Aetiologie der Tuberculose”, Berlin, 1882

i. Parasite occurs in every case of the disease in question and under circumstances which can account for the pathological changes and clinical course of the disease

ii. Parasite occurs in no other disease as a fortuitous and nonpathogenic parasite

iii. After being fully isolated from the body and repeatedly grown in culture, the parasite can induce the disease anew (and be re-isolated)

Relman et al.

Molecular methods: criteria for causation*

• Association of “signature” with disease(specificity, sensitivity)

• Lower signature intensity (dose) in hosts, tissueswithout disease

• Signature intensity decreases with disease resolution,increases with relapse

• Signature predates disease• Correlation of signature with pathology• Nature of organism inferred from signature consistent

with known characteristics; phenotypes predicted• Reproducibility

(Fredricks DN, Relman DA. Clin Microbiol Rev 1996; 9:18-33)

* Adapted from Sir Austin Bradford Hill, 1965

e.g., sequences, transcripts, proteins, metabolites, phenotypes

Gut microbial ecosystem: Undernutrition

Science 339, 530 (2013)Science 339, 548 (2013)

Future of therapeutic interventions?

Fabricius of Acquapendente(1537–1619)

January 16, 2013

Relman et al.

Personalized culture collections

Engineered probiotic strains

Future of therapeutic interventions?

Relman et al.

Study of the human microbiome: Challenges

Tracking, understanding sources of variation Getting at function Assessing possible causation

…But learning about human biology, health and disease

Relman et al.

AcknowledgementsStanford University

Elies BikLiz Costello

Les DethlefsenWei-Ting LiuKatie ShelefDan DiGiulio

Diana ProctorSunje PampMiling Yan

& rest of Relman LabSusan Holmes (Statistics)

U. ColoradoAntonio Peña Rob Knight

U.C. San FranciscoGary ArmitagePeter Loomer

Michael Fischbach

Funding: NIH (NIDCR/OD/NIAID/NIGMS),US Navy, March of Dimes Foundation,

Keck Foundation, Helmsley Trust, Thomas & Joan Merigan Endowment

U.C. BerkeleyJill Banfield

U.C. San DiegoPieter Dorrestein

the promise of the microbiome - science...(based on cell counts, we are 10 parts bacterial, 1 part...

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