emerging science for environmental health sciences: the microbiome
TRANSCRIPT
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Emerging Science for Environmental Health Sciences: The microbiome
Ellen SilbergeldJohns Hopkins UniversityBloomberg School of Public HealthBaltimore MD
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Many ways of thinking about the interactive roles of the microbiome in environmental health
ā¢ Ecosystem microbiomes mediate fate and transport of environmental toxicants
ā¢ Host microbiomes participate in metabolism and toxicokinetics
ā¢ Ecosystem and host microbiomes are targets for environmental toxicants (antimicrobials as envrionmental contaminants)
ā¢ Horizontal gene transfer among microbes is responsive to environmental toxicants (resistance genes as environmental contaminants)
ā¢ Host microbiomes are involved in acute and chronic diseases
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Mutuality of Environmental Agents and the Microbiome
Environmental agents
Microbiome
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Many interesting new perspectives
ā¢ Itās evolution, stupid
ā¢ The 11th organ
ā¢ āmutualism with a costā
ā¢ Developmental microbiomics
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We didnāt discuss as much: The ecological perspective: not just for the landscape
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Language and definitions: we choose words by where we start
ā¢ The problem of antimicrobial resistanceā Not just a problem of good drugs/bad bugsā Not even just a problem of the microbiome
ā¢ Maybe studying the microbiome (as organisms) is not enough?
ā¢ Locating the resistomeā The microbiome and cloud computing
ā¢ Evolutionā The long viewā The crisis view
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Influential experiences: the hospital, evolutionary biology ā or, the modern livestock farm
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Willie Sutton and the laboratory of microbial evolution: where are the antimicrobials?
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Multidrug resistant E coli from domestic animals (Lindsay et al MDR 2011)
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Dreaming about the AR microbiome of the chicken gut
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Building the resistome: resistance genes move from poultry litter into soil
Nandi et al (2004) PNAS 101:7108
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The resistome as cloud computing
Resistome
bacteria
Microbiome
resistome
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āGenetic exchange communitiesā (Skippington and Ragan FEMS Micro Reviews 2011
ā¢ A collection of organisms that can share genes by HGT
ā¢ Not necessarily in close physical proximity (shared ecologies?)
ā¢ Not all microbes are equal ācliques and frenemies
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Global movement of dusts (and bacteria)
Griffin 2007
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Are we living in a new stage of animal:human:microbial evolution?
ā¢ Massive deployment of natural products as antimicrobial agents
ā Concentration
ā Inappropriate usesā¢ Rapid increases in plasmids
ā Complex multigene cassettes
ā Expansion of the resistomeā¢ Increased importance of horizontal gene transfer
as a driver of microbial evolution
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The interactive roles of the microbiome in environmental health
ā¢ Ecosystem microbiomes mediate fate and transport of toxicants in the environment
ā¢ Host microbiomes participate in host metabolism and uptake of toxicants
ā¢ Both ecosystem and host microbiomes are targets for some environmental toxicants
ā¢ Horizontal gene transfer among microbes is responsive to environmental toxicants
ā¢ Host microbiomes are involved in acute and chronic diseases
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Putting the microbiome into toxicology: the example of mercury
ā¢ Mercury is a major environmental health risk
ā¢ Environmental fate and transport of mercury is regulated by microbial metabolism
ā¢ Ecological food web transfers are dependent on microbial transformation
ā¢ Human toxicity varies with mercury species
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Mercury and the microbiome
ā¢ What you probably know:ā Mercury is biotransformed in ecosystems by
bacteria
ā Methylated mercury is more readily bioaccumulated and bioconcentration within ecological food webs
ā Methylmercury is one of the most widespread environmental toxicantsā¢ Exposuresā¢ Health impacts
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The mercury cycle
Slonczewski and Foster Microbiology
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Mercury methylation and demethylation by Desulfovibrio desulfuricans (and at least 8 other bacteria)
Macrocosm studies --Tan and Bartha (1998) AEM
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Mercury and the microbiome
ā¢ What you probably didnāt know:
ā Mercury is biotransformed by the gut microbiomeā¢ iHg Ć MeHg Ć iHg
ā Inorganic mercury as also highly toxicā Inorganic mercury affects the gut microbiome through
mucosal immune system (mast cells)
ā Mercury affects the environmental microbiome by driving antimicrobial resistance through horizontal gene transfer
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Mercury species and immunotoxicity
ā¢ iHg is more potent than MeHg inā Inducing autoimmune biomarkers and phenotypes
(murine)
ā Inhibiting host response to malaria (murine)
ā Increasing circulating autoantibodies (human)ā Altering cytokine production by PBMCs in vitro
(human)
(Silbergeld et al 2000; Silva et al 2004; Gardner et al 2010). Havaranisab et al 2007)
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Relative potency of iHg and MeHg in A.SW mice (Havarinasab et al 2005)
IFA analysis of intranuclear autoantibodies: Sera from mice exposed to iHg or MeHg. Arrow denotes antibrillarin
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Rio-Rato ANA Percentages
47%
24%1%
17%8% 2% 1%
01 101 201 401 801 1601 320
Rio-Rato ANoA Percentages
26%
1%
59%
7%
3%
1%3%
0
1 10
1 20
1 40
1 80
1 160
1 320
C)
E) F)
Tabatinga-AdultsANA Percentages
93%
1%4%
2%
0
1 10
1 20
1 40
c
Tabatinga-AdultsANoA Percentages
98%
2% 0%0%
0
1 10
1 20
1 40
Biomarkers of autoimmuity (ANA, ANOA) in persons exposed to inorganic Hg compared to MeHg (Silva et al 2004)
JacareacangaA N A
92.8
0.8 3.22.4 0.8
01:101:201:40 1:80
Jacareacang aA N o A
80
2.43.2
9.62.42.4
01:101:201:40 1:80 1:160
iHg ā miners MeHg ā fish eaters reference
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Millions are exposed to inorganic mercury in small scale gold mining (WHO 2011)
Mercury exposures in children living near or working in small scale gold mining
And maybe the rest of us are internally exposed after gut demethylation?
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Mercury and the gut microbiome ā impacts on bacteria (Summers 1999) and on the mucosal immune system (TLR4 and 5 signaling; macrophages, microglia)
Also effects on gut microbiome will affect Hg kinetics
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Mercury as a driver of antimicrobial resistance in bacteria and in the resistome
ā¢ Cross ā resistance
ā¢ Co-selection
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Metal and antimicrobial co-resistance by shared mechanism
Shared mechanisms of resistance Baker-Austin et al 2006
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Bacterial resistance by co-selection: mercury resistance genes (iHg and MeHg) along with tet(M) in transposon from S aureus (Soge et al 2008)
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Mercury exposure increases risks of carrying drug resistant E coli in French Guyana (Skurnik et al 2010)
Population Exposure carriage of mer or AMR genesā¢ Wayampi low AB high merA and AMR
(indigenous) high Hg
ā¢ Europeans high AB lower merA and lower AMRlow Hg
ā¢ Wayampi and Europeans with merA more likely to carry transposons with multidrug AMR gene cassettes
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Do we need to map metal contamination and antibiotic pressure to understand resistance? (Singer et al 2006)
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Antibiotics and antibiotic resistance genes as environmental pollutants (Martinez 2009)
ā¢ Antibiotics are mostly short lived in the environment but may be continuously added
ā¢ Antibiotic resistance genes are more stable
ā¢ AR genes may be ābioaccumulatedā by microbiomes and persistent within the microbiome
ā The ācost of resistanceā can be compensated for
ā Maintaining the resistome is prudent in a (human-made) sea of antimicrobial pressures
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Does this make a difference?
ā¢ Understanding environmental fate and transformation
ā¢ Rethinking toxicokinetics and biomarkers
ā¢ Adding a dimension to individual susceptibility
ā¢ Restoring immunology and evolution to environmental health sciences
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Can we unite the disciplines?
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Acknowledgements ā¢ Students and colleagues
ā Lance Price, Jay Graham, Amy Sapkota, Leila Lackey, Ana Rule, Amy Peterson, Meghan Davis, Carmen Arriolo, Jessica Leibler, Beth Feingold, Chris Hardy, Ricardo Castillo
ā Carol Resnick, Jackie Agnew, Steve Wing, Cynthia Whitener, Patricia Charache, Kellogg Schwab, David Smith, Robert Lawrence, Sam Josephs, Joseph Baumgartner, Michael Moore, Mark Pokras, Henrik Wegener, Peter Collignon
ā¢ Funding sourcesā FDA, CLF, Winslow and Baker Foundations, NIOSH
ā¢ Community baseā Delmarva Poultry Justice Alliance, International Food and
Commercial Workers Union