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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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1

Introduction

The human body is host to a great number of diverse microorganisms, and researchers have only recently begun to appreciate the many influences of these microorganisms on human health. Rapidly advancing technologies now allow scientists to investigate the human microbiome—the microorganisms, their genes, and the environmental conditions that surround them—and to elucidate the important roles that it might play in a wide array of diseases, such as diabetes, asthma, and inflammatory bowel disease. Because the human microbiome has been shown to metabolize environmental chemicals and could itself be affected by chemical exposure, some have argued that it should be included as a component in human health risk assessment (Dietert and Silbergeld 2015). The US Environmental Protection Agency (EPA) and the National Institute of Environmental Health Sciences (NIEHS) recognize the possible importance of the human microbiome in human health and the complexity of incorporating interactions between the human microbiome and environmental chemicals into a risk-assessment framework. Given the complexity and resource constraints, EPA and NIEHS asked the National Academies of Sciences, Engineering, and Medicine to develop a research strategy to improve our understanding of the interactions between environmental chemicals and the human microbiome and the implications of those interactions on human health risk. As a result of that request, the National Academies convened the Committee on Advancing Understanding of the Implications of Environmental-Chemical Interactions with the Human Microbiome, which prepared the present report. This chapter briefly discusses the human microbiome and the risk-assessment framework and provides the committee’s statement of task, its approach to the task, and the report organization.

THE HUMAN MICROBIOME

Human microbiome is an all-encompassing term that refers to all microorganisms on or in the human body, their genes, and surrounding environmental conditions (see Box 1-2). The microorganisms are found in large numbers on skin and mucosal surfaces and can exist as attached, mixed-species biofilms and as detached, free-swimming cells—two distinct states of microbial life that strongly influence gene expression and microbial activity (Singh et al. 2010). The human microbiome collectively encodes more genes, by several orders of magnitude, than the human genome (HMP Consortium 2012a,b; Li et al. 2014). Because of the sheer amount of microbial life that colonizes the human body—the gut microbiota, for example, is composed of several trillion microbial cells—and its vast diversity, human beings are now regarded as ecosystems that are comprised of distinct ecologic niches or habitats, each housing a discrete collection of coevolved bacteria, archaea, viruses, and lower and higher eukaryotes (Oh et al. 2014) that interact extensively with each other and with the human host (Belkaid and Segre 2014).

Coevolution has led to interdependence: the human microbiome contributes a vast array of essential functions to the human host and influences a variety of physiologic, immunologic, and metabolic processes. For example, the gut microbiome

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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ferments dietary complex carbohydrates, and this results in the production of anti-inflammatory short-chain fatty acids that modulate adipose, skeletal, and liver tissue and improve glucose homeostasis (see Figure 1-1; Canfora et al. 2015). In contrast, gut microbial metabolism of L-carnitine produces trimethylamine, which is oxidized in the liver to trimethylamine-N-oxide, increased concentrations of which promote atherosclerosis (Koeth et al. 2013). The metabolic products of the microbiome, such as those described above, also shape the microenvironment, which exerts a strong selective pressure on microbial colonization. For example, Lactobacillus species in the vagina produce lactic acid, which promotes a low vaginal pH and inhibits several vaginal pathogens, including herpes simplex 2 virus (Conti et al. 2009), Neisseria gonorrhoeae (Graver and Wade 2011), and uropathogenic Escherichia coli (Juárez Tomás et al. 2003). Thus, research is showing that the human microbiome is fundamental in the maintenance of human health, and microbial perturbations are being linked to an ever-increasing array of neurologic, gastrointestinal, metabolic, oncologic, hepatic, cardiovascular, psychologic, respiratory, and autoimmune disorders (Lynch and Pedersen 2016).

**FIGURE 1-1** The gut microbiome plays important roles in human physiology and metabolism and functions as an ecologic niche that has an interface with the environment.

Since completion of the first phase of the Human Microbiome Project sponsored by the National Institutes of Health, three basic truths that are generally accepted as important for human biology have emerged, as described below.

First, the human microbiome has considerable body-site specificity. For example, the oral microbiome is distinct in composition and function from the microbiomes of the distal gut, various skin sites, and the vagina (HMP Consortium 2012a,b). Even within anatomic sites—for example, within the oral cavity or the vagina or along the length of the gastrointestinal tract—there are distinct patterns of microbiota composition. Although there is some consistency in bacterial phyla that inhabit the sites, species or strain variation related to age, geography, genetics, diet, and health status is also present (Lozupone et al. 2012; Greenhalgh et al. 2016).

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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Second, perturbations of the composition and function of niche-specific microbial communities are associated with disease, both locally at the site of the perturbation and distally. For example, studies in mice have shown that perturbations of the composition and function of the gut microbiome can lead to neurologic dysfunction characteristic of autism-spectrum disorder (Hsiao et al. 2013), and a perturbed gut microbiome in early life in humans has been associated with asthma development in childhood (Arietta et al. 2015; Fujimura et al. 2016). Furthermore, rodent studies have indicated that metabolites derived from gut microorganisms influence precursor immune cells derived from bone marrow (Trompette et al. 2014); these findings support a mechanism by which the gut microbiome might exert a systemic and pervasive effect on host immunity through programming of hematopoietic populations. The research indicates that the composition and activities of at least the gut microbiome have the potential to elicit both local and systemic effects, and this underscores the critical role that it plays in defining host health.
Third, increasing evidence indicates that the human microbiome expands and diversifies in a niche-specific manner from early life to the senior years, when it loses diversity. The precise timescale over which that occurs is still a matter of much debate; recent reports suggest appreciable functional diversification and microbial niche specialization as early as about 4–6 weeks of life (Chu et al. 2017). That finding implies that exposures before and around conception, during gestation, and throughout early development are likely to have a lasting effect and that those periods are fundamentally important. The senior years are also important when characteristic compositional instability and loss of community diversity correlate with declines in immunocompetence (Claesson et al. 2012).

The early research indicates the important role that the human microbiome might play in human health and raises the question of whether some consideration needs to be incorporated into risk assessment.

RISK ASSESSMENT

The 1970s saw a growing awareness and concern that some environmental chemicals could cause adverse health effects. Government programs were created to protect against harmful exposures, and agencies developed methods for estimating risks posed by chemical exposure. However, controversies arose over the various methods and their results, and Congress asked the National Research Council to evaluate risk-assessment practices. The request resulted in the report Risk Assessment in the Federal Government: Managing the Process, which established a framework for risk assessment (NRC 1983). Over the years, many articles and reports have been published on risk assessment, including some from the National Academies, the most recent being Science and Decisions: Advancing Risk Assessment (NRC 2009). However, the core elements of risk assessment—hazard identification, dose–response assessment, exposure assessment, and risk characterization—have remained the same.

Animal toxicology studies have traditionally provided the data for hazard identification and dose–response assessment for exposures to environmental chemicals, but epidemiology (human) studies have provided the primary evidence on some chemicals, such as arsenic and formaldehyde. In vitro assays and computational approaches are also being developed in light of scientific and technologic advances in biology and related fields and substantial increases in computational power. The hope is that the new approaches can predict toxicity on the basis of an understanding of the biologic processes that lead to adverse effects.

Regardless of the approaches used to provide data for various risk-assessment elements, none has explicitly considered or incorporated the human microbiome. As noted above, the gut microbiome can affect chemical metabolism, and there is growing evidence that perturbations of the human microbiome can affect health. Those findings lead to many important questions; the answers to which could have profound implications for risk assessment. Are potentially adverse health effects

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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of chemicals that can be transformed by the human microbiome or can directly affect its composition and function being missed or mischaracterized because the human microbiome is not being explicitly considered? Because animals and humans have intact microbiomes, are any adverse effects that would involve the microbiomes already being captured in animal and human studies? If animal and human microbiomes differ substantially, do the differences themselves need to be considered? If a microbiome component needs to be incorporated into a risk-assessment framework, how should that be done? One question leads to another, and the complexity soon becomes clear. EPA and NIEHS recognized the challenges and asked the National Academies to develop a research strategy to improve understanding of the interactions between environmental chemicals and the human microbiome and the implications of the interactions for human health risk.

THE COMMITTEE AND ITS TASK

The committee that was convened as a result of the request included experts in microbiology, metabolomics, clinical medicine, exposure science, toxicology, and risk assessment (see Appendix for the committee’s biographic information). As noted, the committee was asked primarily to develop a research strategy but was also asked to identify possible barriers to understanding and to describe opportunities for collaboration. The committee’s verbatim statement of task is provided in Box 1-1.

THE COMMITTEE’S APPROACH TO ITS TASK

To accomplish its task, the committee held five meetings, which included two open sessions to hear primarily from sponsor representatives and a few invited speakers on various topics. The committee found, as it began to draft its report, that different people attach different meanings to various terms. To ensure clarity in this report, Box 1-2 contains the committee’s definitions of several terms used throughout the report. Regarding the terms variability and variation, the committee acknowledges that there clearly is overlap of the terms as it defines them. However, the key distinction between the terms is that variability is used when one would not expect there to be substantial differences between states or conditions, such as the microbiome compositions of the same body sites of healthy people, and that variation is used when one would expect there to be differences between states or conditions, such as the microbiome compositions of different body sites, life stages, or species.

BOX 1-1 Statement of Task

An ad hoc committee will develop a research strategy to better understand the interactions between environmental chemicals and human microbiomes, including the intestinal, skin, and lung microbiomes, and the implications of those interactions on human health risk. The committee will assess the state of the science regarding the health implications of chemical metabolism by microbiota and chemical exposure on microbiota diversity and function. It will also assess what is known about how effects might differ depending on, for example, life stage or interindividual differences. The committee will then develop a research strategy that identifies the types of studies needed to improve understanding of how different microbiome communities can affect chemical absorption and metabolism, how population variation in microbiome activity might affect individual chemical exposure, and the effect of chemical exposure on microbiome functions and possible implications for human health risk. The committee will also identify methodological or technological barriers to advancing the field, discuss possible opportunities for coordination or collaboration, and indicate which research investments might provide the most information for improving understanding of microbiome implications for human health risk.

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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BOX 1-2 Definitions of Selected Terms

Biomass refers to the quantity of microorganisms as a cell count or density in a given region or sample.

Environmental chemicals are chemicals that have entered the environment as a result of human activity and are subject to regulation (see Chapter 6 for further discussion).

Ex vivo refers to an experimental process that is carried out by removing biologic specimens or materials—such as primary cells, tissues, or organs—from an organism and using them directly in an artificial setting.

Gnotobiotic animal describes an animal maintained in the absence of any microorganisms (that is, germ-free conditions) or a germ-free animal that is colonized with a microbial strain or a defined multispecies community of microbes.

In vitro refers to an experimental process that is carried out in an artificial setting by using biologic specimens or materials that have not been directly isolated from an organism—such as immortalized cell lines, laboratory microbial strains, or purified proteins—or by using microbial communities outside their typical setting or by using any combination of those components.

In vivo refers to an experimental process that is conducted in a whole organism, such as a rodent or primate.

Metabolomics is the scientific study of small molecules (metabolites) that are created from chemicals that originate inside the body (endogenously) or outside the body (exogenously) (NASEM 2016).

Metagenome refers to all genomes or genes encoded by a microbiota.

Microbiome refers to “the entire habitat, including the microorganisms (bacteria, archaea, lower and higher eukaryotes and viruses), their genome (i.e., genes), and surrounding environmental conditions” (Marchesi and Ravel 2015). The term microbiome is often used in conjunction with a specific body site—such as the gut, skin, or respiratory microbiome—or as an all-encompassing term to refer to all microbiomes on or in the human body, that is, the human microbiome.

Microbiota or microbial community is a collection of microorganisms in a habitat.

Resilience is the ability of a microbial community to maintain or return to a steady state in the presence of or after some stress on or perturbation of its composition or function.

Variability refers to a measurable distribution of a state or condition that would typically be considered nominally homogeneous. For example, differences in the function or composition of the gut microbiome in a population of healthy adults would be described as variability.

Variation refers to differences between or patterns of change in two or more conditions or states. For example, differences between species, life stages, or body niches would be described as variation.

Although not included in Box 1-2, exposure and dose are used in this report. NRC (2012) noted that exposure can be considered as “stressors, receptors, and their contacts in the context of space and time.” For the present report, the stressors of primary concern are environmental chemicals, and the receptors in the case of external exposures might be populations, individual humans, laboratory animals, or their microbiomes. In the case of internal exposures, the receptors might be host cells, tissues, organs, or individual microbes. As discussed in Chapter 5, some expansion of exposure-science concepts might be needed to incorporate the possible role of the human microbiome in modulating the health risks associated with exposure to environmental chemicals. Like NASEM (2017), this report uses the term exposure primarily but also uses dose in conventional phrases, such as dose–response relationship.

Several points should be noted regarding the focus of the present report. First, this report is not a comprehensive review of all microbiome research and is focused on answering the questions set forth in the committee’s task. Accordingly, the research

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Suggested Citation:"1 Introduction." National Academies of Sciences, Engineering, and Medicine. 2018. Environmental Chemicals, the Human Microbiome, and Health Risk: A Research Strategy. Washington, DC: The National Academies Press. doi: 10.17226/24960.

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strategy that the committee proposes is directed at addressing questions about the interaction of the human microbiome with environmental chemicals and the implication of the interactions for human health risk. It is not a research strategy for directly investigating associations between the human microbiome and various diseases. Second, the statement of task asks for a research strategy to improve understanding of “how population variation in microbiome activity might affect individual chemical exposure.” To address that point, the committee has focused on understanding how exposure is modulated by the microbiome and how variation in microbiome activity affects chemical–microbiome interactions or human health risk, which is referred to explicitly in the opening statement of the committee’s task and is seen as the ultimate goal of the overall research strategy. Third, although the committee acknowledges that some interactions of environmental chemicals and the human microbiome might be beneficial, the primary focus of the present report is on the potential for adverse effects of such interactions because that is the traditional focus of risk assessment. Fourth, the committee acknowledges that the report appears to focus on the gut microbiome and the bacterial components of the human microbiome, but that focus reflects the current state of the science and the sparseness of the literature on other body-site microbiomes and on the viral and fungal components of the human microbiome.

ORGANIZATION OF THE REPORT

The committee’s report is organized into six chapters and one appendix. Chapter 2 further describes the human microbiome and focuses on its variation and variability. Chapter 3 explores how the human microbiome can affect chemical exposure. Chapter 4 discusses methods for studying the human microbiome, and Chapter 5 continues the discussion of risk assessment and the impetus to include a human-microbiome component. Chapter 6 presents the committee’s research strategy and discusses possible obstacles to the research and opportunities for collaboration. The Appendix provides biographic information on the committee members.

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