Environmental Chemicals, the Human Microbiome, and Health Risk A Research Strategy (2018) / Chapter Skim
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6 Research Strategy
6 Research Strategy
Pages 84-105
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From page 84... ...
Thus, the com- whether and how the human microbiome might mittee determined that the research strategy should modulate health risks posed by exposure to enviaddress broadly the three general topics highlight- ronmental chemicals requires decisions regarding ed in its statement of task: the effects of environ- the specific chemicals to be investigated and the mental chemicals on the human microbiome, the appropriate exposure routes. The universe of chemrole of the human microbiome in modulating envi- icals that could be labeled environmental is large; ronmental-chemical exposure, and the importance it includes naturally occurring and synthetic chemiof population variability or variation in modulat- cals, chemicals produced as byproducts of industriing chemical–microbiome interactions.
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From page 85... ...
Moreover, in the absence of much more of those studies to investigate chemical–microknowledge than is available now, it is impossible biome interactions would be less expensive and to specify the numbers and types of chemicals that less time-intensive than studies of longer duration. would have to be investigated to provide an un- Longer-term studies will likely follow as microbiequivocal answer to the broad question regarding ome research develops a body of knowledge and the interaction between environmental chemicals inquiry.
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From page 86... ...
Scientific Value of the Research Experimental Approach As discussed in Chapter 2, the human microbiome has important effects on host biochemistry A research program that addresses the quesand physiology, and research over the last decade tion of how environmental chemicals affect the has associated disruptions in the microbiome with microbiome and the possible consequences could various disease outcomes. For example, regula- consist of defining toxicity end points for the mition of immune-system, nervous-system, and crobiome, identifying environmental chemicals metabolic functions occurs under the influence that can perturb (structurally and functionally)
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From page 87... ...
Second, although variability that structure, measures of the microbiome stress re- results from diet, age, or sex can be strictly consponse -- both general and specific to a particular trolled in rodents, it cannot be in human studies, so environmental chemical -- will be captured best experiments will need to be designed with considthrough metatransciptomic approaches. However, eration of the variation and variability associated the committee emphasizes that an integrated ap- with the human microbiome.
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From page 88... ...
, the dose to Other high-priority research would be aimed the microbiome could be substantially higher. Furat developing a high-throughput bioreactor sys- thermore, members of the microbial community tem that operates under physiologically relevant are not likely to exhibit the same dose–response conditions to screen environmental chemicals in relationship with an environmental chemical.
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From page 89... ...
outbred lines particularly allow assessment of the consistency of effects of chemical exposures in Linking Microbiome Perturbations by genetic and microbial gradients in such animals. Environmental Chemicals to Adverse The studies are not limited to rodents; for example, Health Outcomes zebrafish, fruit flies, or nematodes might be best suited to studies that require high-throughput analAnimal Studies ysis.
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From page 90... ...
toxicity to the microbiome are of paramount im- Overall, an additional barrier to research to unportance. Many of the antimicrobial experiments derstand how environmental chemicals might afthat the committee describes are likely to require fect the human microbiome is the unknown level of substantial investments of time and resources, functional redundancy that could exist within the are exploratory and thus unlikely to be supported human microbiome.
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From page 91... ...
Ultimately, linking the specific MODULATING EXPOSURES TO microorganisms, genes, and enzymes to a particu ENVIRONMENTAL CHEMICALS lar chemical transformation process is essential if substantive progress is to be made in addressing Another high-priority research topic is the ef- individual susceptibility and interspecies extrapofects of the human microbiome on exposure to lation questions at a mechanistic level and in unenvironmental chemicals. Specifically, what is the derstanding the degree of functional redundancy role of a microbiome in modulating absorption, within a microbiome.
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From page 92... ...
. The committee knowledge of microbiome roles in metabolism of notes that the initial focus of this research is on the environmental chemicals has progressed substan- gut microbiome because a large body of literature tially.
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From page 93... ...
A strategy for examining the role of the human microbiome in modulating chemical exposures would generate microbiome-based data to inform model prediction. The modeling results would be enhanced by integrating human microbiome databases to predict microbial metabolic capacity and by using human cohorts to validate model predictions.
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From page 94... ...
clusion as part of an integrated research strategy is critical for achieving the goal of assessing personIdentifying Specific Microbial alized microbiome status as a potential risk factor Enzyme Functions for environmental-chemical interactions. New chemical probes and chemical screening Barriers technologies are emerging that could reduce the experimental effort and time needed to isolate and Although the components of this research identify specific proteins and microorganisms that strategy for assessing the role of a microbiome in interact with environmental chemicals in the mi- modulating ADME of environmental chemicals crobiome.
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From page 95... ...
and a question is whether knowledge of popula • To address variations in microbiome struc- tion and life-stage variation and variability in the ture and function that are naturally present in hu- human microbiome will improve understanding of man populations, large experimental design matri- the susceptibility to environmental chemicals and ces might be required, whether animal models or of individual health risk. The subsections that folin vitro systems are used, and might require large low discuss the scientific value of the research and resource investments.
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From page 96... ...
For example, subtle variations in The goals of the research described are to un- low-biomass communities might impart important derstand the importance of human microbiome functional differences in metabolites or smallvariability and variation at any given life stage or molecule intermediates; conversely, because funcamong specific populations and ultimately to en- tional redundancy is probable in many microbial sure that studies consider such variation and vari- communities, variations in community composiability adequately and appropriately in assessing tion might not necessarily impart key functional the health risks to human populations posed by ex- differences.
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From page 97... ...
In the longer term, improved computational Scientific Value of the Research approaches, advances in data science, and innovative human-study design will advance understand- For most health risk assessment, animal moding of the implications of variation and variability els have been the basis for determining the toxic of the human microbiome. Specifically, the ad- effects of chemicals and estimating the potential vent of high-throughput DNA and RNA sequenc- for adverse health effects in humans.
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From page 98... ...
The research described be- • Functional characterization of human milow should produce new knowledge of microbial- crobiome samples in response to environmentalcommunity function that should allow assessment chemical exposure and conduct of comparative of the capacity of animal models to recapitulate analyses of functional profiles after transplantation the activities of human microbiomes. of microbiota into model organisms.
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From page 99... ...
microbiomes -- for example, with multi -omics approaches -- because of limitations related to TOOL DEVELOPMENT sample collection, sample type, sample quantity, and the preponderance of host components, such The research strategy developed by the comas human DNA, RNA, or protein that is usually mittee emphasizes the three main elements highassociated with tissue samples. Such microbiomes lighted in the statement of task: the effect of would include those from difficult-to-access host chemical exposure on the human microbiome, the sites or from sites that have small amounts of re- role that the human microbiome plays in environtrievable material, which potentially limit their mental-chemical exposure, and the importance of study with multiple analytic approaches.
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From page 100... ...
proaches to be used for understanding microbiome dynamics, the genomic, transcriptomic, and meta Microbial Reference Communities bolic databases and libraries need to expand their coverage of relevant strains, genes, enzymes, and Past initiatives of the Human Microbiome metabolite identities and functions. The vastness Project (HMP)
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From page 101... ...
For example, collaborations between the National It is not yet possible to predict the community- Institutes of Health (NIH) and EPA or state enviwide effects of most chemical exposures on the ronmental and public-health agencies that have a human microbiome; that is, how will the whole long history of assessing the health risks posed community structure be affected by a particular by environmental-chemical exposures are encourchemical exposure and with what temporal dy- aged.
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From page 102... ...
Ultimately, both ing potential collaborators and notes where the the near-term and longer-term research should lead resources could be leveraged to address the re- to the type of information that is needed to assess search described by the committee. The resources the importance of the microbiome as a contribuand related programmatic efforts present potential tor to the human health risks associated with expohigh-yield opportunities to advance the current un- sures to environmental chemicals and thus allow derstanding of the health consequences of environ- informed decisions to be made about the need for mental chemical–human microbiome interactions.
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From page 103... ...
2010) , with those in human microbiomes and might create an important new knowledge base.
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From page 104... ...
. Xenobiotic metabolism and gut microbiomes.
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From page 105... ...
Research Strategy 105 Wright, A.T., J.D.
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