Human-microbe mutualism: stability and resilience in health and disease David A. Relman, Stanford University IOM Forum on Microbial Threats March 7, 2012
Our extended self : human-microbe mutualism (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 ) Our benefits Food digestion Nutrition (vitamins, energy) 1683 Xenobiotic processing Metabolic regulation, cometabolism Development: terminal differentiation of mucosa Education, regulation of immune system Epithelial homeostasis, barrier integrity Colonization resistance to pathogens Turnbaugh P et al, Nature 449:804-810, 2007; Dethlefsen L et al, Nature 449:811-818, 2007
Our extended self : human-microbe mutualism (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 ) Microbial benefits Nutrition Habitat Dispersal 1683 Turnbaugh P et al, Nature 449:804-810, 2007; Dethlefsen L et al, Nature 449:811-818, 2007
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
Clinical problems associated with the indigenous microbiota Chronic periodontitis Crohn s disease & other IBD Irritable Cause bowel or syndrome effect? Tropical sprue Antibiotic-associated diarrhea Pathogen colonization Bacterial vaginosis Premature labor and delivery Initiating or propagating? Mono- or polyfactorial?
Why interest in human microbiome? Human indigenous microbial communities as critical component of human biology; humans as superorganism Larger role in both health and disease than previously understood Determinant of individuality Novel approaches for therapy, prevention, dx? Microbiome as source of new antibiotics and abxr Microbiome in preventing pathogen invasion Convergence of complementary disciplines, tools, conceptual framework e.g., community as unit of study Turnbaugh P et al, Nature 449:804-810, 2007; Dethlefsen L et al, Nature 449:811-818, 2007
Outline Patterns of microbial diversity in humans Stability and resilience Implications for management of disease
Bacteria 80-100 phyla <1% cultivated modified from: Handelsman J, Microbiol Mol Biol Rev 2004; 68:669-85
Site-specific distributions of bacterial phyla in healthy humans Size of circles is proportionate to average number of species-level phylotypes per individual (in parentheses) Dethlefsen L et al., Nature 2007; 449:811-818
Distal gut species / strains seen in each individual over the course of 10 months? ~1600-2000 Dethlefsen et al, PNAS 2011; 108:4554-61 Seen before? ~7% (novelty among the rare taxa) Dethlefsen et al, PLoS Biology 2008; 6:e280
Why so few phyla on or within the human body? What are the factors that regulate or restrict human indigenous microbial diversity? external habitats animal-associated habitats
Sources of variation in patterns of diversity Space (habitat) Individual Health status Host genetics Environmental exposures (esp. early in life) Diet Chemical/drug/mechanical disturbance Other aspects of lifestyle? (e.g. geography) Other mammals/hosts Time (esp. early in life)
How robust (resistant, resilient, stable) are human indigenous microbial communities when perturbed? in health, disease? Effect of history on robustness? How might disturbance be exploited to restore a more desired fitness state?
C. S. Buzz Hollings hlp://www.flickr.com/photos/sfupamr/5515528060/sizes/l/in/photostream/ Social- ecological systems, Resilience theory, Complex adapkve behavior
Annual Review of Ecology and Systema9cs, Vol. 4 (1973), pp. 1-23 Resilience is the capacity of a system to absorb disturbance and reorganize while undergoing change so as to skll retain essenkally the same funckon, structure, idenkty, and feedbacks. (Walker, Holling, Carpenter, Kinzig; 2004) Resilience versus Stability
Study design Healthy subjects, no abx prev year 10-month study of ciprofloxacin disturbance; initial 2-months pre-rx Poop samples Dethlefsen et al. PLoS Biology 2008; 6:e280 Dethlefsen L, Relman DA. PNAS 2011; 108:4554-61 Les Dethlefsen
Study design V1-V3 PCR, 3 subjects, D, E, F ; 56, 52, 54 time points 11 Pre, 5 1 st Cp, 7 1 st WPC (+1w), 17 Interim, 5 2 nd Cp, 7 2 nd WPC (+1w), 3-5 Post ; 5,010,542 raw reads For D: >1,900,000 raw reads; 506,662 analyzed reads For E: >1,700,000 raw reads; 672,947 analyzed reads For F: 1,371,351 raw reads; 581,365 analyzed reads Fairly evenly distributed: Overall 10,870 mean ± 4,191 (SD) reads/sample; 9,048 reads/sample for subject D, 12,941 reads/sample for E, 10,766 reads/sample for F
Limited variability in taxonomic composition prior to disturbance Bray-Curtis distance log(abundance) relative to last day pre-cp Sampling day
Two adults, daily sampling for 6 and 15 months Caporaso JG et al., Genome Biology 2011, 12:R50
Two adults, daily sampling for 6 and 15 months Caporaso JG et al., Genome Biology 2011, 12:R50
Study design Healthy subjects, no abx prev year Ciprofloxacin twice, 6 months apart (pulse perturbation) Stool samples over 10 months Dethlefsen et al. PLoS Biology 2008; 6:e280 Dethlefsen L, Relman DA. PNAS 2011; 108:4554-61 Les Dethlefsen
The insurance hypothesis redundancy is a valuable commodity
Conclusions Human microbial diversity: few, shallow, wide radiations reflect selection, specialization, cooperation, and co-evolution with host Relative stability; resilience; history matters Long-term stability of human communities is not maintained by inertia, but by action of restoring forces within dynamic system Goals: improved diagnostic & predictive markers for health and disease, informed manipulation of microbiota; what functions matter, when? How to measure them?
Acknowledgements Stanford University Elies Bik Liz Costello Les Dethlefsen Jen Dinalo Clara Davis Long Katie Shelef & rest of Relman Lab Pat Brown Chana Palmer Susan Holmes Steve Quake UC San Francisco" Gary Armitage Peter Loomer" U Colorado" Greg Caporaso Rob Knight UC Berkeley" Jill Banfield U Pittsburgh" Mike Morowitz Funding: NIH (NIDCR/OD/NHGRI/NIAID), Doris Duke Charitable Foundation, US Navy, March of Dimes Foundation, Thomas & Joan Merigan Endowment