1. Toxic Exposures and the Microbiome Ellen Silbergeld Johns Hopkins University Bloomberg School of Public Health Baltimore MD 21218 esilberg@jhsph.edu www.smallerquestions.org

2. AAAS San Jose February 2015 Acknowledgements Rodney Dietert – co-author and co-developer of a new model for environmental health Martin Blaser and Clair Fraser – inspiration for thinking outside the box about the microbiome Markus Hilpert for reminding me about bioremediation

3. AAAS San Jose February 2015 MICROBIOME: “WHO ARE WE?” Martin Blaser EMBO 2006* The entirety of the microbial [bacterial] world within a defined domain or space, including all the genomes and genes of the members of the microbiome The microbial world, and its inputs and outputs The interactions (genomic, proteomic, etc) between the microbial world and its domain [host, organ system, ecological niche, etc] * ANSWER: WE ARE MOSTLY BACTERIAL CELLS 10:1

4. AAAS San Jose February 2015 Option 3: the ecological approach Mutualism and interdependence among organisms and the landscape Selection and evolutionary change within space and time Social organization and intra/inter community discourse

5. AAAS San Jose February 2015 Toxic exposures and the microbiome Target and transducer of toxicant actions Gatekeeper functions at the portal of entry Mediator of host/environment interactions –Susceptibility factors

6. AAAS San Jose February 2015 The microbiome as transducer of toxic exposures Bischoff 2011

7. AAAS San Jose February 2015 Gatekeeper at the portal of entry Portals of entry and routes of exposure: Wallace, US EPA TEAM study 1987

8. AAAS San Jose February 2015 The current paradigm: linking exposures and outcomes by opening the “black box” (NRC 1987)

9. AAAS San Jose February 2015 The standard model of how external exposures are transferred and transformed within the organism: ADME and PBPK Corley et al 1990 Absorption Distribution Metabolism Excretion Physiologically Based Pharmaco/toxico Kinetics

10. AAAS San Jose February 2015 The microbiome in the picture: Dietert and Silbergeld 2015

11. AAAS San Jose February 2015 The new “frontier” of ADME – the gut microbiome ( Klunemann et al Trends Biotechnol 2014).

12. AAAS San Jose February 2015 The expanded version: what are the implications for understanding and studying gene:environment interactions Whose genes? –Human or other organism –Microbiome Which genes? –Human genes don’t change –The microbial metagenome can change What is the relative contribution of human and microbial genes to metabolism of toxic agents [activation and detoxification]

13. AAAS San Jose February 2015 Most of the genetic information in “us” (human + microbiota) is bacterial NAS The Social Biology of Microbial Communities. 2012 NAP

14. AAAS San Jose February 2015 Does the gatekeeper modulate exposure:response relationships related to metabolism? Macrocosm studies --Tan and Bartha (1998) AEM Mercury methylation and demethylation by environmental bacteria [Desulfovibrio desulfuricans] that are also present in the human gut

15. AAAS San Jose February 2015 Not such a new story: bacteria and environmental remediation: Desulfitobacterium hafniense and polychlorophenols Villemur R, Phil Trans R Soc 2013

16. AAAS San Jose February 2015 Challenging our research designs: where is arsenic methylated? Current hypotheses –Methylation of inorganic arsenic occurs after absorption and distribution within the body –The overall patterns of arsenic and its metabolites are predictive of risks of toxicity –Polymorphisms in human genes encoding these metabolic pathways are associated with differential patterns of arsenic metabolism

17. AAAS San Jose February 2015 Human pathways of arsenic metabolism (Marnell et al 2003)

18. AAAS San Jose February 2015 Genetic polymorphisms in human arsenic methylating genes and arsenic metabolism Wu et al 2014 TAP

19. AAAS San Jose February 2015 Arsenic methylation status and risks of lung cancer Melak et al TAP 2014

20. AAAS San Jose February 2015 BUT bacteria within the human gut microbiome can also metabolize arsenic through the same pathway Kruger et al 2013

21. AAAS San Jose February 2015 Human gut microbiome ex vivo metabolizes iAs () Van de Wiele et al EHP 2010

22. AAAS San Jose February 2015 Disturbing the gut microbiome alters metabolism of arsenic in mice: Helicobacter infection of mice  Δmicrobiome  arsenic metabolism Lu et al 2013

23. AAAS San Jose February 2015 The host is still in the picture: the microbiome and its environmental niche in the gut Bischoff 2011

24. AAAS San Jose February 2015 The gate keeper is also a watchman: signaling between the host and the microbiome Hooper et al Science 336: 1268-73, 2012

25. AAAS San Jose February 2015 Altering the immune phenotype in mice alters the gut microbiome and arsenic metabolism Lu et al 2014

26. AAAS San Jose February 2015 So host genetics affect the microbiome

27. AAAS San Jose February 2015 Human genetic contribution to arsenic metabolism [Tellez Plaza et al 2011]

28. AAAS San Jose February 2015 RESEARCH QUESTIONS: What is the relative contribution of the gut [lung, skin, etc] microbiome to toxicant metabolism? How do we include the microbiome in epidemiological studies? What additional cofactors should we add to epidemiological studies? What opportunities does the microbiome present for interventions to protect exposed persons from toxicity?

29. AAAS San Jose February 2015 More complexity – adding the microbiome into systems toxicology

30. AAAS San Jose February 2015 “We’re not in Kansas anymore, Toto” [with apologies to Curt Klaassen]