Perspective

Honor Thy Gut Symbionts Redux

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Science  08 Jun 2012:
Vol. 336, Issue 6086, pp. 1251-1253
DOI: 10.1126/science.1224686

Abstract

Exploring our gut microbial communities with new tools is allowing us to revisit old questions; to develop new concepts about our evolution, postnatal development, systems physiology, individuality, and definitions of health; and to further delineate the impact of our changing life-styles. It is also allowing us to envision exciting new ways for addressing global health problems. This area is inherently interdisciplinary, offering a wealth of opportunities to create new fields, partnerships, and educational initiatives. It is captivating to the public and carries substantial expectations. As such, participating scientists need to sponsor proactive, solution-focused discussions of its societal implications.

Captivating. Awe-inspiring. In a number of ways, a refreshing and humbling departure from our anthropocentric worldview. These and other phrases can be applied to the exploding area of basic and applied research devoted to the human gut microbiome that is presented, dissected, and critiqued in these companion issues of Science and Science Translational Medicine (16) (see Box 1 for definitions of microbiome and other terms used in these articles). The field of metagenomics, emanating from the technology and computational tools spawned by the Human Genome Project, along with a more ecologic focus in microbiology, is allowing us to see ourselves as intimately connected with the microbial world. Integrating microbes into our concept of “self” contextualizes our views of human development, our sense of individuality, and our connections to family and environment in new and different ways (7, 8). Whether thinking about the impact of humanity’s discovery of fire and cooking food, our formation of communities with domestication of animals and crops, our current exploding populations migrating from rural to urban settings, or our increasing hygiene and use of antibiotics, we are prompted to consider that there is another dimension to our human evolution and human condition. This other dimension, involving the collection of gut microbial species (microbiota) and their genes (microbiomes) is affecting our concepts of “healthy,” of disease risk, and of how Western life-styles are affecting us.

Looking Back

For some, learning about our gut microbiomes brings back childhood memories of reading Paul deKruif’s The Microbe Hunters (9), the historical narrative portraying the early heroes of microbiology. In the pages of that book, we saw our relationship with microbes portrayed in warlike, rather than in mutually beneficial, terms. Even though we now know that we are a splendid amalgamation of microbial and human cellular and genetic parts—more microbial than human in many ways—reading that book was to experience the thrill of the hunt for things unknown, the challenge of crafting a framework for not only identifying new microbes but for establishing what they do, and the triumphs of overcoming and ultimately preventing the diseases they cause.

The current quest to understand the factors that forge the assembly, determine the stability, and effect the adaptations of our gut microbiomes is also thrilling, but it can be humbling, too. The system is incredibly complex and dynamic: Modeling and predicting system properties seems daunting, even if we reduce complexity by using gnotobiotic animal models. We also need to think deeply about the evolutionary significance of our gut communities, for example, in the context of the origins and functions of our innate and adaptive immune systems, the mammary gland and lactation [e.g., (10)], and the history of our migrations and social and cultural development. Furthermore, our scientific predecessors, using the technologies available to them, pursued the very same questions that captivate us today. A century ago, the importance of food in influencing gut bacterial communities was established when defined diets were administered to monkeys and dogs (11, 12). At that time, scientists began creating germ-free animal models and discovered that most of the animals soon became sick without their microbes (13). A half a century ago, advances in anaerobic culturing techniques yielded detailed catalogs of bacteria in the gut microbiota, but no overarching principles of how human gut communities take root (14). These methods provided definitions of succession in the mouse gut during postnatal life (15), revealed the importance of diet and host factors in shaping this process (16), and demonstrated that different bacterial populations were associated with the intestinal epithelium compared to the lumen (17). The concept of an “autochthonous biota” of species specialized for stable colonization of the host was introduced (18).

The State of the Art

Box 1

GLOSSARY OF TERMS

  • Gut microbiota. The community of microbes that lives in an individual’s gastrointestinal tract. The term encompasses members of Bacteria, Archaea, Eukarya, and their viruses.

  • Gut microbiome. The aggregate collection of genomes and genes present in a gut microbiota.

  • Gnotobiotics. From the Greek gnosis (known/knowledge) and bios (life). Animals reared under sterile (germ-free) conditions are classified as gnotobiotic, as are animals that are raised under germ-free conditions for a period of their lives and then colonized with various collections of microbes.

  • Metagenomics. Culture-independent studies of the structures and functions of microbial communities. Some limit the term to DNA- and RNA-level analyses, whereas others extend it to include proteins and metabolites. High-throughput screening of expression libraries, generated from cloned microbial community DNA fragments, is defined as functional metagenomics.

  • Pathobiont. As opposed to a pathogen, refers to a member of a microbiota that under certain conditions of disturbance to the host and/or microbiota can cause pathology.

  • Dysbiosis. Concept coined by Metchnikoff to describe a state of microbial imbalance in the gut (33). Refers to a change in the structural and/or functional configuration of the microbiota that produces a disruption in the homeostasis between a host and the microbial community it harbors.

  • Prebiotic. Food ingredient that supports the growth and expression of a beneficial biological property or properties of one or more resident gut symbionts.

  • Probiotic. A live microorganism that when ingested provides benefit to the host, either directly through interactions with host cells or indirectly through effects on members of the microbiota.

The explosive growth in metagenomics has driven, and in turn has been driven by, the democratization of DNA sequencing. Smaller, more highly parallel instruments can now fit on bench tops, where they can be directly accessed by students. Progress requires that we harness the power of this democratization, so that many individuals, representing a variety of disciplines, can create and test a wide variety of hypotheses by using a broad range of innovative study designs and methods. Because so much about the gut microbiome has yet to be described and the questions reflect so many facets of our lives and life choices, discovery efforts can and should extend beyond a limited number of research institutes and universities and encompass faculty, postdocs, doctoral students, undergraduates, and high school students in many countries [e.g, (19) and OMI (Open Microbiome Initiative), www.openmicrobiome.org].

A highly visible part of recent gut microbiome exploration has been the massive catalogs of genes and species produced by large international consortia powered by large genome sequencing centers [e.g., MetaHIT (20, 21) and the National Institutes of Health (NIH) Human Microbiome Consortium (www.hmpdacc.org)]. To date, their surveys have focused on a few hundred adult Europeans and North Americans. These efforts, together with the efforts of smaller groups, have produced terabases of DNA sequence, realization of the need for annotation standards (22), and an appreciation of the urgency of establishing and maintaining databases that can receive and archive these data sets. Other outcomes include a spectacular increase in the number of available genome sequences from culturable human microbial symbionts; an effort to develop ways to culture the majority of microbial diversity present in the guts of individuals representing various ages, physiologic phenotypes, cultural traditions, or disease states of interest; as well as high-throughput methods for identifying genetic determinants needed to establish human gut symbionts in their habitats [e.g., (23, 24)]. One unfortunate outcome has been a belief, predicated on little evidence, that very deep sequencing of gut microbiomes is somehow always better. This belief produces economic barriers and barriers to broader, more diverse scientific involvement and distracts focus from the fact that the depth of sampling required is dependent on effect sizes and results claimed. Such focus on depth affects study design by inhibiting adequate sampling of biological variation, whether through detailed time-series studies of individuals [e.g., (25)] or by surveying larger numbers of humans.

The good news is that, together with increasingly powerful computational resources and a growing suite of open source software tools (26), it is becoming much easier to describe the organismal and gene content of gut communities and their intra- and interpersonal variations. As discussed from a variety of perspectives in these companion review articles (16), this capacity also presents a grand challenge: namely, to find ways to move beyond the allure, relative ease, and stimulation of describing the component parts of gut microbiomes to assaying and understanding function. It also represents a challenge to government funding agencies, foundations, and other private-sector organizations as they ponder how to thoughtfully and effectively invest their resources. Issues include how to maintain diversity in the manner in which science is performed, the balance between basic and applied questions, disciplinary breadth, and, for want of a better word, nimbleness.

The Road Ahead

The path forward to addressing basic and applied questions about the gut microbiome is so inherently interdisciplinary that it provides a splendid opportunity to craft new alliances, spawn new fields, and transform how we educate ourselves. Examples include partnerships with engineers to create small, ingestible, autonomous or nonautonomous robotic devices capable of retrieving samples, luminal or mucosal, from multiple defined locations along the gut safely, without disturbing the sampled microbiota. Systems biologists could be recruited to devise new ways to measure and model the thermodynamic properties and costs of a microbiota from the perspectives of the host, the microbial community, and the supraorganism (holobiont). Studies of the microbiota could help protect and promote the vitality of an endangered species—the glycobiologist. The microbiota offers a rich opportunity to identify, solve the structures, and characterize the catalytic sites and mechanisms of enzymes that mediate biologically important and novel chemical transformations. This field should stimulate advances in quantitative proteomics, including exploration of covalent modifications of proteins that could capture the metabolic output of the gut microbiota and “imprint” it in the host epi-proteome. It could create timely unions with immunologists and nutritionists to more fully understand the impact of nutritional status and nutrient processing on innate and adaptive immunity. Neurobiologists will hopefully be enlisted to examine the interactions between the gut microbiota and the peripheral and central nervous systems, including potential modulatory effects of diet and immune status. Calls have already been made to join with representatives of different subdisciplines of anthropology to create a new area, the anthropology of microbes, to more fully understand how the different ways we live affect our microbial ecology and to examine impediments and enablers of microbiome-related studies (27).

Educational institutions and governmental agencies should appreciate how studies of the human gut microbiome create a means to inspire students to expand their knowledge of the human condition and to devote themselves to identifying new ways to address some of the most vexing global health problems we face this century, including how to enhance the nutritional health of infants and children. This appreciation should encourage institutions in economically well-developed countries to form mutually beneficial partnerships with those in economically less- or least-developed countries in order to create innovative educational programs, different facets to student exchange, strategies for capacity building, and effective solutions to health disparities.

Importantly, the public is captivated. This fascination comes from new perceptions about ourselves, carries new expectations, and creates a need for participating scientists to not only describe their results in a clear and sober fashion but to approach translation from bench to bedside carefully and mindfully.

There are a number of important ethical, legal, safety, and regulatory issues related to microbiome research [e.g., (2830)]. The consequence of not considering these issues could be a set of reactionary responses on the part of a number of elements in society that are not based on fact and born from lack of a thoughtfully considered, objective framing of issues, proposed solutions, and educational outreach by those involved in this work. One example is provided by preclinical research platforms now being implemented to determine the effects of foods we currently consume on the gut community, as well as foods that we envision creating in the future. A hope is that these platforms will support proof-of-concept, proof-of-mechanism, proof-of-efficacy, and/or proof-of-safety tests of the interactions between (i) food ingredients and methods of food preparation and preservation; (ii) gut microbiota obtained from various human populations; and (iii) human metabolic, immunologic, and other physiological activities. Coupled with new methods for generating clonally arrayed, sequenced bacterial culture collections from selected human microbiota donors, these platforms offer the promise of yielding next-generation prebiotic and probiotic therapeutics designed to intentionally manipulate microbiome and host properties.

Data packages produced from these preclinical models will likely be a challenge for regulatory agencies, both in terms of their stated missions, current structures, and the applicable laws that guide their decisions. To what extent will next-generation prebiotics, probiotics, and combinations of the two (synbiotics) be classified as drugs? What type of information about dosing, safety, biomarker validation, and clinical end points will be needed to approve a phased series of proposed clinical studies for next generation pre- or probiotics? The ability to produce and test purified consortia of cultured, sequenced candidate probiotic species derived from human donors who may or may not be related to potential treatment recipients by biology or by shared living environments raises questions about who should be the initial human participants for early phase studies. These efforts will inevitably raise questions about ownership of microbes as well as concepts and strategies concerning intellectual property. The goal may be to administer a probiotic species or species consortium, or synbiotic, shortly after birth to an infant or to a mother just before or immediately after parturition. The goal may be to achieve benefits in the context of a diet or diets consumed by a given human population or by a broad range of populations. How will expanding knowledge of diet-microbiota interactions affect claims for the health benefits of foods in consumer populations with different gut microbial community configurations and on strategies for differentiation of food products? The result could herald a new epoch of precision nutrition but will also put increasing focus on foods as drugs for disease prevention as well as treatment. The effects of this focus on the strategic plans and investments of food, dairy, and pharmaceutical companies will be important to follow. Thus, with so much opportunity and hope associated with the gut microbiome, it would be wise to address these issues now rather than later, through a process that takes lessons from the group of individuals who, illustrating the precautionary principle, gathered together in 1975 to discuss recombinant DNA research and its implications (31, 32).

References and Notes

  1. Acknowledgments: Work cited from the author’s lab was supported by grants from the NIH, the Bill and Melinda Gates Foundation, and the Crohn’s and Colitis Foundation of America. The author declares no competing interests.
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