Summary and Assessment

ENDING THE WAR METAPHOR: THE CHANGING AGENDA FOR UNRAVELING THE HOST-MICROBE RELATIONSHIP

The History of Medicine

2000 B.C.—Here, eat this root.

1000 A.D.—That root is heathen. Here, say this prayer.

1850 A.D.—That prayer is superstition. Here, drink this potion.

1920 A.D.—That potion is snake oil. Here, swallow this pill.

1945 A.D.—That pill is ineffective. Here, take this penicillin.

1955 A.D.—Oops…bugs mutated. Here, take this tetracycline.

1960–1999—39 more “oops.” Here, take this more powerful antibiotic.

2000 A.D.—The bugs have won! Here, eat this root.

—Anonymous (WHO, 2000)

In 1967, U.S. Surgeon General William H. Stewart told a White House gathering of health officers that “it was time to close the book on infectious diseases and shift all national attention (and dollars) to what he termed ‘the New Dimensions’ of health: chronic diseases” (Garrett, 1994; Stewart, 1967). In the ensuing years, Americans became intimately acquainted with a range of emerging infections including Legionnaire’s disease, toxic shock syndrome, AIDS, Lyme disease, West Nile encephalitis, and SARS. Complacency has given way to concern regarding a spectrum of microbial threats—including antimicrobial-resistant pathogens, emergent and reemergent diseases with pandemic potential, and outbreaks of exotic viruses such as monkeypox—propelled by a seemingly inevitable convergence of biological, environmental, ecological, and socioeconomic factors (IOM, 2003a,b). At the same time, the association of various chronic dis-



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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Summary and Assessment ENDING THE WAR METAPHOR: THE CHANGING AGENDA FOR UNRAVELING THE HOST-MICROBE RELATIONSHIP The History of Medicine 2000 B.C.—Here, eat this root. 1000 A.D.—That root is heathen. Here, say this prayer. 1850 A.D.—That prayer is superstition. Here, drink this potion. 1920 A.D.—That potion is snake oil. Here, swallow this pill. 1945 A.D.—That pill is ineffective. Here, take this penicillin. 1955 A.D.—Oops…bugs mutated. Here, take this tetracycline. 1960–1999—39 more “oops.” Here, take this more powerful antibiotic. 2000 A.D.—The bugs have won! Here, eat this root. —Anonymous (WHO, 2000) In 1967, U.S. Surgeon General William H. Stewart told a White House gathering of health officers that “it was time to close the book on infectious diseases and shift all national attention (and dollars) to what he termed ‘the New Dimensions’ of health: chronic diseases” (Garrett, 1994; Stewart, 1967). In the ensuing years, Americans became intimately acquainted with a range of emerging infections including Legionnaire’s disease, toxic shock syndrome, AIDS, Lyme disease, West Nile encephalitis, and SARS. Complacency has given way to concern regarding a spectrum of microbial threats—including antimicrobial-resistant pathogens, emergent and reemergent diseases with pandemic potential, and outbreaks of exotic viruses such as monkeypox—propelled by a seemingly inevitable convergence of biological, environmental, ecological, and socioeconomic factors (IOM, 2003a,b). At the same time, the association of various chronic dis-

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary eases with microbial infection (e.g, peptic ulcer with Helicobacter pylori, liver cancer with hepatitis B and C viruses, and Lyme arthritis with Borrelia burgdorferi) has deepened respect for the destructive potential of infectious agents (IOM, 2004). Infectious diseases continue to cause high morbidity and mortality throughout the world, particularly in developing countries. In 2001, infectious diseases accounted for an estimated 26 percent of deaths worldwide (Kindhauser, 2003). Moreover, there are indications that the tide of human conquest over microbial pathogens is turning. Over the last 30 years, 37 new pathogens have been identified as human disease threats, and an estimated 12 percent of known human pathogens have been recognized as either emerging or reemerging (Merell and Falkow, 2004). Having fallen steadily since the turn of the century, the number of deaths attributable to infection in the United States began to increase in the early 1980s, due in large part to the HIV/AIDS pandemic (Armstrong et al., 1999; Lederberg, 2000). In the face of these challenges, the metaphor of “war” on infectious diseases—characterized by the systematic search for the microbial “cause” of each disease, followed by the development of antimicrobial therapies—can no longer guide biomedical science or clinical medicine. A new paradigm is needed that incorporates a more realistic and detailed picture of the dynamic interactions among and between host organisms and their diverse populations of microbes, only a fraction of which act as pathogens. To explore the crafting of a new metaphor for host-microbe relationships, and to consider how such a new perspective might inform and prioritize biomedical research, the Forum on Microbial Threats of the Institute of Medicine (IOM) convened the workshop, Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship on March 16 and 17, 2005. Workshop participants reviewed current knowledge and approaches to studying the best-known host-microbe system—the bacterial inhabitants of the human gut—as well as key findings from studies of microbial communities associated with other mammals, fish, plants, soil, and insects. Participants and discussants also considered the evolutionary and environmental origins of pathogenesis and reviewed recent findings describing how hosts recognize and respond to pathogens. Additional presentations and discussions addressed the complexity of microbial communities and ecological relationships among pathogens, such as zoonoses, that infect multiple hosts. Finally, participants examined the prospects for manipulating host-microbe relationships to promote health and mitigate disease. The workshop’s primary goal of replacing the war metaphor for infectious disease intervention represents an expansion of the Forum’s focus on microbial threats to health. The perspective adopted herein is one that recognizes the breadth and diversity of host-microbe relationships beyond those relative few that result in overt disease.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary ORGANIZATION OF WORKSHOP SUMMARY This workshop summary report is prepared for the Forum membership in the name of the editors as a collection of individually authored papers and commentary. Sections of the workshop summary not specifically attributed to an individual reflect the views of the editors and not those of the Forum on Microbial Threats, its sponsors, or the Institute of Medicine (IOM). The contents of the unattributed sections are based on the presentations and discussions that took place during the workshop. The workshop summary is organized within chapters as a topic-by-topic description of the presentations and discussions. Its purpose is to present lessons from relevant experience, delineate a range of pivotal issues and their respective problems, and put forth some potential responses as described by the workshop participants. Although this workshop summary provides an account of the individual presentations, it also reflects an important aspect of the Forum philosophy. The workshop functions as a dialogue among representatives from different sectors and presents their beliefs on which areas may merit further attention. However, the reader should be aware that the material presented here expresses the views and opinions of the individuals participating in the workshop and not the deliberations of a formally constituted IOM study committee. These proceedings summarize only what participants stated in the workshop and are not intended to be an exhaustive exploration of the subject matter or a representation of consensus evaluation. THE RISE AND FALL OF THE WAR METAPHOR More than a century of research, sparked by the germ theory of disease and rooted in historic notions of contagion that long precede Pasteur and Koch’s 19th-century research and intellectual synthesis, underlies current knowledge of microbe-host interactions (Lederberg, 2000). This pathogen-centered understanding attributed disease entirely to the actions of “invading” microorganisms, thereby drawing the lines of battle between “them” and “us,” the injured hosts (Casadevall and Pirofski, 1999). Although it was recognized in Koch’s time that some microbes did not cause disease in previously exposed hosts (e.g., milkmaids who had been exposed to cowpox did not become infected with smallpox), the fact that his postulates1 could not account for microbes that did not cause 1   Koch’s postulates include the following: (1) the bacteria must be present in every case of the disease, (2) the bacteria must be isolated from the host with the disease and grown in pure culture, (3) the specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host, and (4) the bacteria must be recoverable from the experimentally infected host.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary disease in all hosts was not generally appreciated until the advent of vaccines and the subsequent introduction of immunosuppressive therapies in the 20th century (Casadevall and Pirofski, 1999; Isenberg, 1988). By then, the paradigm of the systematized search for the microbial causes of disease, followed by the development of antimicrobial and other therapies to eradicate them, had been firmly established in clinical practice. The considerable impact of this approach, further enabled by improvements in sanitation, diet, and living conditions in the industrialized world, served to cement the belief that humanity was engaged in a war against pathogenic microbes, and that we were winning (Lederberg, 2000). By the mid-1960s, experts opined that, since infectious disease was all but controlled, researchers should focus their attention on other difficult medical challenges, such as heart disease, cancer, and psychiatric disorders. This optimism and complacency was shaken with the appearance of HIV/AIDS in the early 1980s, and was dealt a further blow with the emergence and spread of multidrug-resistant bacteria. As these experiences began to lead researchers to reexamine the host-microbe relationship, additional reasons to do so began to accumulate: pandemic threats from newly emergent (e.g., SARS) and reemergent (e.g., influenza) infectious diseases; lethal outbreaks of Ebola, hantavirus, and other such exotic viruses; and a new appreciation for the associations of various chronic diseases with prior microbial infections, as noted above. Forum member Joshua Lederberg has envisioned the future of humanity and microbes as “episodes of a suspense thriller that could be entitled, Our Wits Versus Their Genes” (Lederberg, 2000). Our wits have so far afforded us increased longevity and reduced mortality from infectious disease, but the defenses we have mounted to make these gains are no match, over the long run, for the rapidly changing and adaptable genomes of microbial pathogens. We are vulnerable not only to emerging infectious diseases, but also to less treatable strains of pathogens (e.g., Staphylococcus aureus, Streptococcus pneumoniae) once seemingly conquered. The global health threat and economic burden posed by microbial resistance to therapeutics was highlighted in a recent Forum workshop, in which participants concluded that the management of microbial resistance over the long term would require “a sea of change…in how we view the ecology and evolution of infection” and the recognition of resistance “as an integral part—not an aberrant part—of the ecology of microbial life” (IOM, 2003b). However, doing so will require a far greater understanding of the evolutionary processes that underlie the development of resistance. Changes in global ecology, climate, and weather are also increasing human vulnerability and exposure to microbial threats, as are more localized factors such as economic development, land use, travel, poverty, and war. A convergence of biological, environmental, sociopolitical, and ecological factors, depicted in Figure S-1, can be seen to influence the host-microbe relationships that lie at the core of disease emergence.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary FIGURE S-1 The Convergence Model. At the center of the model is a box representing the convergence of factors leading to the emergence of an infectious disease. The interior of the box is a gradient flowing from white to black; the white outer edges represent what is known about the factors in emergence, and the black center represents the unknown (similar to the theoretical construct of the “black box” with its unknown constituents and means of operation). Interlocking with the center box are the two focal players in a microbial threat to health—the human and the microbe. The microbe-host interaction is influenced by the interlocking domains of the determinants of the emergence of infection: genetic and biological factors; physical environmental factors; ecological factors; and social, political, and economic factors. SOURCE: IOM (2003a). PATHOGENESIS REVISITED The vast majority of microbes do not produce overt illness in their hosts, but instead establish themselves as persistent colonists that can be described as either low-impact parasites (e.g., causes of asymptomatic infection), commensals (or-

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary ganisms that “eat from the same table,” deriving benefit without harming their hosts), or symbionts (establishing a mutually beneficial relationship with the host) (Blaser, 1997; Merrell and Falkow, 2004). These states, while separate, represent part of a continuum—one that extends to pathogenesis and disease—that may be occupied at any point by a specific microbial species through the influence of environmental and genetic factors (Casadevall and Pirofski, 2000, 2002, 2003). Persistent colonization of a host by a microbe is rarely a random event; such coexistence depends upon a relationship between host and microbe that can be characterized as a stable equilibrium (Blaser, 1997). In the case of microbes that cause persistent, asymptomatic infection, physiological or genetic changes in either host or microbe may disrupt this equilibrium and shift the relationship toward pathogenesis, resulting in illness and possibly death for the host (Merrell and Falkow, 2004). Early views of pathogenesis and virulence were based on the assumption that these characteristics were intrinsic properties of microorganisms, although it was recognized that pathogenesis was neither invariant nor absolute (Casadevall and Pirofski, 1999). Over the course of the last century, the identification of increasing numbers of microbial pathogens and the characterization of the diseases they cause has begun to reveal the extraordinary complexity and individuality of host-pathogen relationships. As a result, it has become exceedingly difficult to identify what makes a microbe a pathogen. One response to this dilemma has been to define pathogenesis from the perspective of the host, who experiences disease only when the presence of a microbe (whether protozoan, bacterial, or viral) results in damage—whether that damage is actually mediated by the pathogen itself, or by the host’s immune response to it (Casadevall and Pirofski, 1999, 2003). A broader view, reflected in many workshop presentations and discussions, considers how pathogens coexist within host-microbial communities and places infectious disease within an ecological context. This perspective acknowledges the ecological and evolutionary impact of advancing civilization—and particularly the “war on disease”—on host-microbe systems, and promotes a more realistic, deeper, and nuanced understanding of the relationships upon which these systems depend (Lederberg, 2000). The time has come to abandon notions that put host against microbe in favor of an ecological view that recognizes the interdependence of hosts with their microbial flora and fauna and the importance of each for the other’s survival. Such a paradigm shift would advance efforts to domesticate and subvert potential pathogens and to explore and exploit the vast potential of nonpathogenic microbial communities to improve health.2 2   Refer to p. 27 first paragraph under the section “Raising Awareness of the Host-Microbe Relationship” for further information on the paradigm shift.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary IT’S A SMALL WORLD: MICROBIAL COMMUNITIES OF THE GUT The gastrointestinal (GI) tract represents an important and challenging system for exploring how microbial communities become established within their hosts, how their members maintain stable ecological niches, and how these dynamics relate to host health and disease (see Chapter 1). The complex, dynamic, and spatially diversified microbial community, or microbiota, of the human gut is believed to be comprised of at least 1013 microorganisms (Xu and Gordon, 2003). This estimation includes more than 800 species of bacteria (Bäckhed et al., 2005; Gordon, 2005) (most of which have not yet been successfully cultured in the laboratory), fungi, numerous viral species including bacteriophages, (Breitbart et al., 2003) archaea (e.g., methanogens), and eukaryotes (e.g., helminths and protozoa) (Dominguez-Bello, 2005; Fagarasan et al., 2002; Hylemon and Harder, 1998; Xu and Gordon, 2003). The collective genomes of the microbiota in the human gut, known as the microbiome, is approximately one hundred-fold larger than that of its host (Bäckhed et al., 2004; Savage, 1977; Xu and Gordon, 2003). Therefore, as Bäckhed et al. have recently argued, “It seems appropriate to view ourselves as a composite of many species and our genetic landscape as an amalgam” of the human genome and the microbiome (2005). The complexity of the human gut microbiota has been studied using culture-based assays and, more recently, a variety of molecular methods. These include fluorescent in situ hybridization, terminal restriction fragment length polymorphisms, microarrays, and direct sequencing of 16S libraries (Breitbart et al., 2003). The latter has revealed the presence of only 8 of 55 known bacterial divisions in the human gut, but great diversity among them at the strain and subspecies level exists (Bäckhed et al., 2005; Winter et al, 2004). This pattern suggests strong selection pressure on these microbes and coevolution between them and their host—a conclusion supported by findings that reveal how Bacteroides thetaiotaomicron, a prominent intestinal anaerobe, maintains a stable ecological niche despite dietary shifts and attacks by bacteriophage and the human immune system (see Gordon in Chapter 1). Knowledge of the viral components of the gut microbiota is comparatively limited; however, a recent study of viral genotypes in human feces (Breitbart et al., 2003) suggests that bacteriophages play an important role in shaping the gut microbiome (Bäckhed et al., 2005). Methanogenic archaea in the gut appear to orchestrate the final step in processing plant polysaccharides, but their role in determining the structural and functional stability and diversity of the gut microbiota is largely unexplored (Bäckhed et al., 2005; Gordon, 2005). The Molecular Basis of Mutualism The gut microbiota acts as an exquisitely tuned metabolic “organ” within the host, according to presenter Jeffrey Gordon (see Chapter 1) (Bäckhed et al., 2004;

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Casadevall and Pirofski, 2000; Xu and Gordon, 2003). Microbes and mammals have coevolved mutually beneficial (symbiotic) relationships, typically based on nutrient sharing, in which the microbiota perform functions that their hosts have not evolved. For example, mammals are inherently limited in their ability to break down polysaccharides, which represent an abundant energy source in a plant-based diet (Hooper et al., 2002). Instead of producing the enzymes for carbohydrate hydrolysis, mammals recruit a diverse community of microorganisms that allow them to make efficient use of a broad range of foodstuffs; the microbes, in turn, gain access to abundant, readily fermentable carbon sources. An especially complex version of this exchange occurs among ruminants, who obtain nutrients solely by digesting the bacteria that feed upon the grass and other fodder swallowed by their mammalian hosts, as described by presenter Maria Dominguez-Bello (see Chapter 3). Thus over the course of evolution, symbiotic gut bacteria have become master physiological chemists, employing a broad range of strategies to manipulate host genomes, Gordon observed. Identifying the host genes targeted by gut microbes and the mechanisms by which they manipulate host gene expression could lead to novel approaches for preventing and controlling a variety of diseases and promoting human health. To explore such host-microbe interactions at a molecular level, researchers have introduced genetically mutable components of the human intestinal microbiota into germ-free animals (Bäckhed et al., 2004; Hooper et al., 1998, 2001, 2002; Rawls et al., 2004; Xu and Gordon, 2003); several such studies are described in Chapter 1. Examination of the transcriptional response of germ-free mice to colonization with B. thetaiotaomicron reveal that the bacterium modulates the expression of host genes known to influence a wide range of intestinal functions in addition to nutrient absorption, including mucosal barrier formation, xenobiotic metabolism, angiogenesis, and postnatal intestinal maturation (Hooper et al., 2001; Xu and Gordon, 2003). Related studies show that in addition to mediating energy harvest from the diet, the gut microbiota also influences energy storage by the host, and thereby, individual predisposition toward obesity (see Gordon in Chapter 1) (Bäckhed et al., 2004). Additional research being performed in germ-free animals involves the initial establishment of microbiota in the gut (in humans, during the early days of infancy), its influence on host development (e.g., immunity), and the mechanisms by which hosts perceive and respond to the presence of colonizing microbes. Presenter Karen Guillemin (see Chapter 1) pursues these fundamental questions in germ-free zebrafish, an experimental system that simplifies analyses of microbial influence on host development while closely approximating GI tract and immune system maturation, as well as gut microbiota diversity, in mammals. Although this approach has demonstrated the pervasive influence of the microbiota over a variety of events in the maturation of the GI tract, it raises further questions regarding the potential for individual developmental variation arising from differences in microbiota from one member of a species to another. In humans, such

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary variation could accrue among contemporaries who live in different environments, as well as over the course of history. Microbe-Microbe Interactions The complex web of interactions that must occur among the denizens of the gut is even less well studied than those that take place between microbe and host, but undoubtedly no less important to gut function and development. Microbe-microbe relationships include nutritional interactions—such as the previously described metabolism of the end products of bacterial fermentation by archaea—and genetic exchanges that occur through transformation, phage transduction, and conjugation (see Salyers in Chapter 1). For example, Bacteroides species recently have been shown to acquire and transfer antibiotic resistance genes among distantly related bacteria (e.g., Escherichia coli) that colonize the same ecological niche (Whittle et al., 2002; Wilson and Salyers, 2003). While important as a mechanism in the spread of antibiotic resistance, with its attendant impact on public health, Salyers emphasized it as merely an indicator, the “tip of the iceberg” of pervasive genetic exchange among members of endogenous microbial communities. In light of this discovery, further study of the gut as a “cauldron of microevolution” is clearly warranted (Gordon, 2005; Salyers, 2005; Wilson and Salyers, 2003). Key questions to be investigated include how and where microbial gene transfers occur, the extent to which such transfers have contributed to the evolution of pathogens, and the potential for such transfers to influence phenomena other than antibiotic resistance, such as host metabolism and microbial virulence. IT’S A SMALL UNIVERSE: INSIGHTS FROM OTHER HOST-MICROBE SYSTEMS The host-microbe environment of the human gut is complex, compelling, and likely to yield important scientific and medical insights, but the same can be said for microbial communities in plants, insects, and the soil (dubbed “nature’s GI tract” by presenter Jeffrey Gordon) that have received considerably less attention. One workshop contributor highlighted recent findings in these systems that suggest the importance of inter-microbe communication (see Handelsman in Chapter 2); another noted similarity between the strategies used by plant and animal pathogens and compared the defenses mounted against them by their disparate hosts (see Staskewicz in Chapter 2). Moreover, the gut is but one site of microbial colonization in mammals; recent studies of oral microbial communities in humans (Smoot et al., 2005) are discussed later in this summary and in Chapter 5 (see Relman), and new data are emerging rapidly on the microbial communities of the human female genital tract.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Camouflage and Communication in Microbial Communities Many momentous discoveries in microbiology—the germ theory of disease, the discovery and characterization of viruses, the techniques of cell culture, and the analysis of cell differentiation—were first achieved by plant biologists, but were not recognized at the time by their peers in other disciplines (Handelsman, 2005). Thus, while it is not surprising that studies of plants and their associated microbial communities have added considerably to knowledge of host-microbe relationships, these findings have not been widely appreciated nor have they been well integrated with current understanding of the human gut microbiota. There is a need to take a broader view to include perspectives from other biological systems. Many significant biological control processes were originally recognized in plants—such as RNA silencing—only to be demonstrated decades later to be conserved and operational in mammalian systems as well. Research by presenter Jo Handelsman offers a new opportunity to apply insights derived from host-microbe studies in plants, in this case, toward a new understanding of the importance of microbial signaling to host health. Handelsman and coworkers demonstrated that inter-microbe communications that lead to disease could be disrupted, and that beneficial lines of communication could be protected against pathogenic saboteurs (see Chapter 2). For example, they observed that plant diseases can be suppressed by treatments that modify the microbial community of the root to make it more like the community in the soil, a conclusion which they have dubbed the “camouflage hypothesis” (Gilbert et al., 1994). These studies have led to further examinations of the interactions between endogenous microbes and disease outcomes in other host-microbe systems, with the most recent example being the gut of the gypsy moth caterpillar (Broderick et al., 2004). In the relatively simple gypsy moth system, the Handelsman lab has begun to explore how signaling within microbial communities influences their ability to protect their hosts from disease and other perturbations (Handelsman, 2005). Among their discoveries in examining the gypsy moth “metagenome”—a representative collection of genomic clones derived from its gut microflora—is the presence of at least one gene associated with quorum sensing (also known as autoinduction), a bacterial system that monitors population density and coordinates gene expression with population growth (Bassler 1999; Dunn and Handelsman, 2002; Greenberg 1997; Handelsman, 2005; Hastings and Greenberg, 1999). The researchers are currently pursuing experiments to gauge the impact of this gene on gut community structure and robustness. Microbial Disease in Plants and Animals Research presented by Brian Staskawicz (see Chapter 2) suggests that microbial pathogens that colonize in animals share common strategies with those

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary that infect plants (Staskawicz et al., 2001). Both sorts of pathogens can deliver proteins into host cells that mimic, suppress, or modulate host defense signaling pathways and enhance pathogen fitness, and both are recognized by similarly sophisticated host surveillance systems. Striking architectural similarities between surface appendages of plant and animal pathogenic bacteria suggest common mechanisms of infection, while structural differences reflect the profound differences between plant and animal cells, most notably the presence or absence of a cell wall. Plants lack the mobilized immune surveillance system and capacity for adaptive immunity present in animals. However, the form of innate immunity evident in plants, which responds to the presence of pathogen effector proteins, is in many ways comparable to innate mammalian mechanisms that recognize conserved molecular patterns on microbial surfaces (Staskawicz, 2005). Host surveillance proteins in plants, encoded by resistance (R) genes, are thought to mediate pathogen recognition by functioning as receptors for specific phytopathogen effector proteins (Baker et al., 1997). Interaction between these components triggers a rapid defensive reaction, known as the hypersensitive response, characterized by tissue death at the site of infection (Baker et al., 1997). This localized reaction limits the spread of infection and often precedes the development of nonspecific resistance throughout the plant, a phenomenon known as systemic acquired resistance. Striking structural similarities have been noted among R genes derived from several plant species that confer resistance to diverse bacterial, fungal, viral, and nematode pathogens. This suggests common patterns of defensive signaling among plants (Baker et al., 1997). Conserved cellular defense responses in plants may also be analogous to certain innate immune responses to pathogens in vertebrates and insects, suggesting that these defense pathways are highly conserved and may be inherited from a common ancestor (Baker et al., 1997). Animals, plants, and yeast have been found to share structural (and in the case of plants and animals, functional) homology in a key enzyme (caspase) that regulates programmed cell death upon infection with a pathogen (Rojo et al., 2004). A prevalent protein class involved in plant disease resistance, the nucleotide-binding/leucine-rich repeat (NB/LRR) proteins, contains significant homology with Toll-like receptor (TLR) proteins associated with innate immunity in insects and mammals; more specifically, plant NB/LRR disease resistance proteins share homology with mammalian intracellular protein receptors NOD13 and NOD2, which function as intracellular receptors of bacterial peptidoglycan and which participate in the inflammatory cascade that causes Crohn’s disease (Staskawicz, 2005; Staskawicz et al., 2001). The prepon- 3   NOD proteins are defined as proteins carrying Nucleotide-Oligomerization Domains (NODs) that are involved in the regulation of immune responses and apoptosis. NOD1 and NOD2 are involved in host recognition of small molecules that are components of bacterial peptidoglycan and activate nuclear factor kappa-B (NF-κB) in response to sensing these molecules.

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary Because intended use determines how a probiotic is regulated, another FDA entity, the Center for Food Safety and Applied Nutrition (CFSAN), regulates probiotics and prebiotics marketed as dietary supplements or food ingredients. Most prebiotics fit the FDA definition of a dietary supplement (“a product taken by mouth that contains a dietary ingredient intended to supplement the diet”), and to date, so do all probiotic products on the market. Although this situation is expected to change, workshop participants noted, there is little incentive for manufacturers of probiotics currently marketed as dietary supplements to develop them as biotherapeutics, given the rigors and expense of the associated review and regulation process. This situation confuses many consumers, who struggle to understand the vague health claims associated with probiotics and other dietary supplements, and who may (especially if they are ill) misinterpret such claims as proof of therapeutic efficacy. But unless serious adverse events can be shown to result from the use of a dietary supplement, the FDA cannot remove the product from the market. It was noted that a similarly confusing situation currently exists for European consumers, but that many countries in Europe are currently considering legislation to require proof for all health claims. Although the dietary supplement/biotherapeutic dichotomy may remain a part of U.S. regulation of probiotics for some time, presenter Julienne Vaillancourt of OVRR/CBER expects the regulatory process for biotherapeutics to expand and change to reflect new knowledge. In fact, she identified several issues that need to be addressed in revisions to current regulations; these include the need to define and set guidelines for the evaluation of colonization and potency as they relate to biotherapeutics, and also to establish protocols for investigating the potential pathogenicity of probiotic strains. In addition, it was observed that although the most promising populations of beneficial microbes adhere to mucosal surfaces, most probiotics currently on the market have been isolated from stool samples that contain very few mucosal-adherent bacteria. Moreover, the vast majority of probiotic efficacy trials are conducted on the basis of the analysis of stool samples. Thus, it is not only clear that guidelines and regulations governing probiotics must be revised to reflect recent research findings, but also that this goal is a fast-moving target. Lorenzo Morelli predicted the advent, within two to three years, of new products such as targeted probiotics or biotherapeutics that enhance production of specific cytokine or suppress specific pathogens, as well as new genotype-based methods of surveying microbial populations and assessing host-microbe interactions. By their very nature, such innovations will demand adjustments to current regulatory practices for probiotics. PURSUING A NEW PARADIGM With the development of genomic and bioinformatic tools, and with the expectation that the future will bring even more powerful technologies for resolving

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary the vast diversity of microbial communities, researchers can at last begin to study host-microbe relationships in their complexity. There is much to be discovered about the composition of microbial communities, how they assemble and self-regulate, and the means by which their members communicate with each other and with their hosts. Even in the relatively familiar and well-studied territory of the human gut, many basic questions remain unanswered. The following list of such queries, posed by David Relman and elaborated upon by several workshop participants, could equally be applied to a variety of other endogenous microbial communities and host-microbe ecosystems including, but not limited to: How variable is the composition of the gut microbiota among human populations? What is the role of timing in determining the acquisition and composition of the gut microbiota, and how does initial exposure and host genetics influence this process? What drives the development of the immune response with respect to the temporal exposure to different pathogens? How variable is the gut microbiota across space? Is the gut an assembly of microhabitats? Is it continuously variable? What is the role of the individual host or host species in dictating the nature of the commensal microflora? Will this specificity permit the manipulation of either host or microbial community to benefit both? How do microbial communities self-regulate? What mechanisms enable endogenous communities to exchange information with their hosts, and vice versa? How can the presence of phages, viruses, and archaea in the gut microbiota be characterized in terms of diversity and population sizes? What ecological roles do these organisms play in this and other microbial communities? What is the role of polymicrobial interactions, biofilms, and other communities of indigenous microbes (e.g., skin)? What do microbial community members do? What do pathogens do when they are not being pathogens (e.g., do their toxins have an ecological role)? Interdisciplinary Research on Host-Microbe Interactions Participants noted that the understanding of host-microbe relationships could be greatly advanced by the expansion and implementation of key recommendations of the IOM report, Microbial Threats to Health (2003a), that encourage an integrated and cooperative research effort by human and animal health communities on infectious disease threats. It was recognized that these goals would be furthered by engaging the plant research community and that the collaborative research agenda on infectious disease should incorporate host-microbe ecology. Interdisciplinary infectious disease centers such as those proposed in the Micro-

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary bial Threats to Health report could support research on such topics as the ecology of microbial communities across species and among multiple hosts and the response of microbial communities to novel ecological pressures and opportunities for host colonization. Much more needs to be learned about the roles of eukaryotic viruses in these processes—discussion of the possible roles played by DNA or RNA viruses were virtually absent in this workshop, reflecting a major gap in our understanding. Connection among such centers on an international scale would further advance research goals by providing a “critical mass” of researchers to address the extreme complexity of scientific inquiry at the community and ecosystem level. A logical partner for international collaboration (as well as an example upon which to base U.S. programs) is the European network for research on the prevention and control of zoonoses, Med-Vet-Net (Med-Vet-Net, 2005). Founded in 2004, Med-Vet-Net comprises 300 scientists from 8 veterinary and 7 public health institutes, along with the Society for Applied Microbiology (UK), who are linked by a variety of structures intended to improve scientific collaboration and the dissemination of knowledge. Opportunities for Global Survey of the Gut Microbiome Workshop presentations and discussions clearly demonstrated both the feasibility and promise of conducting a microbial survey of human and animal microbiota. As noted by Bäckhed et al. (2005), “experimental and computational tools are now in hand to comprehensively characterize the nature of microbial diversity in the gut, the genomic features of its keystone members, the operating principles that underlie the nutrient foraging and sharing behaviors of these organisms, the mechanisms that ensure the adaptability and robustness of this systems, and the physiological benefits we accrue from this mutualistic relationship.” The technical feasibility of microbial genomic surveillance now makes it possible to conduct global surveys of gut microbiota and also to monitor how these microbial communities respond (in terms of structure and composition) to environmental change. Indeed, it was observed, the collection of this data could be viewed as an extension of the human genome project to encompass the “organismal metagenome.” In addition to advancing understanding of the etiology and epidemiology of infectious disease, this project may shed light on microbial influence on a host of chronic disorders, including GI conditions, allergy, asthma, diabetes, and obesity. Participants also considered the collection, organization, and analysis of survey data on the gut microbiome. To assemble an encyclopedic representation, samples must be obtained from humans and animals across a broad range of geographic, nutritional, and health environments, as well as from several anatomical microenvironments. Standards for sampling methods would need to be established, and it was agreed that attempts should be made to identify and obtain

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Ending the War Metaphor: The Changing Agenda for Unraveling the Host-Microbe Relationship - Workshop Summary appropriate samples that may already exist in clinical and research communities—an effort that, in addition to reducing the time and expense of data collection, could also strengthen ties among potential collaborators in studies of host-microbe interactions. Finally, participants emphasized the importance of archiving sample material so that trends can be followed over time, and also to permit future analyses based on improved technologies. RAISING AWARENESS OF THE HOST-MICROBE RELATIONSHIP Our “war” on infectious microbes has restricted the spread of several pathogens and drastically reduced the burden of human disease, but the metaphor appears to be reaching the end of its usefulness. Recent findings on host-microbe interactions in a variety of settings, which highlight the many benefits of some microbes—as well as the potential for exploiting those benefits to further advantage—reveal the limitations of pure antagonism toward the microbes among us. At best, the war metaphor is a limiting mental shortcut that distracts from abundant opportunities to improve human and animal health. At worst, it represents a dangerous influence on disease control practices that have accelerated the development of antimicrobial resistance among human and animal pathogens, and perhaps also increased virulence in some pathogens. Put simply, the war metaphor must be replaced or, as comically (yet ominously) predicted in the epigraph to this summary, the bugs will win. We hosts are far better served by recognizing microbes as the allies they (mostly) are, and by making the best of our intimate alliances with them. Such a message, which does not invoke the threat of catastrophe, will be difficult to send. The notion of microbes as the “enemy” will not fade quickly, especially given the relative complexity of the ecological perspective that would supplant the “us vs. them” paradigm. The most optimistic scenario for changing this opinion may be to begin within the infectious disease research community, where scientists who tend to focus on interactions between individual microbes and hosts could be encouraged to better understand and incorporate the concepts of community and ecosystem dynamics in their studies. A better-informed research community could then help to influence governmental and other funding agencies to recognize the importance of studying and funding proposals to examine host-microbe relationships to human health. Recognition of the commercial potential of probiotics could also encourage federal support for research, regulation, and the development of strain collections, reagents, and good manufacturing practices. A similar “sea change” could occur if medical professionals encourage their patients to appreciate the benefits associated with the microbial flora and fauna that exist on and in us, and indeed to recognize that without these microbes, life as we know it would not exist. Many physicians are exercising new caution in prescribing antibiotics and some are able to explain their reasons for doing so to

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