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Addressing Infectious Disease Challenges by Investigating Microbiomes Emily P. Balskus* Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States ABSTRACT: Microbial communities occupy essentially every habitat on earth and have profound effects on our environment and human health. The National Microbiome Initiative will provide a framework for interdisciplinary microbiome research. The challenges inherent in discovering and understanding microbiome functions, especially those associated with infectious disease, present countless opportunities for chemists.
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perturbations, will persist throughout almost all of adulthood. Interestingly, the period in which the gut microbiome is established parallels an important time frame in the development of the human immune system. Although the factors influencing both of these processes are not yet well understood, it is conceivable that exposure to particular types of microbes at this time primes the host immune system in ways that affect its ability to tolerate and respond to pathogens. The developmental trajectory of the gut microbiota may therefore influence individuals’ susceptibility to infectious agents, including viruses, bacteria, fungi, and protozoans. In addition to interacting with the host immune system, infectious agents also encounter the members of the human microbiome. A growing body of evidence suggests that the composition and metabolic activities of microbial communities located throughout the body can provide critical defense against pathogen invasion. Microbiomes can be remarkably resistant to invasion by external microbes, including pathogens. This phenomenon, which is known as colonization resistance, may be perturbed upon administration of antibiotics, increasing susceptibility to infection. Clostridium dif f icile is perhaps the most notable example of a pathogen that is associated with the loss of colonization resistance. C. dif f icile infections occur after the administration of antibiotics, which may kill anaerobic bacterial species that perform activities that would normally prevent pathogen colonization. The presence of specific commensal organisms and their associated metabolic activities may also limit the virulence of pathogens. Conversely, pathogens can detect and utilize microbiota-derived molecules to promote growth or aid the establishment of infection. A better understanding of the mechanisms underlying colonization resistance and other microbiome−pathogen interactions may reveal new strategies for treating or preventing infections. An exciting recent development in infectious disease therapeutics is the “rediscovery” of fecal microbiota transplant (FMT) as a treatment for recurring C. dif f icile infection. This practice, which can be traced back to ancient Chinese medicine, was introduced to modern medical practice in the late 1950s.
n May 13th, 2016, the White House announced the launch of the National Microbiome Initiative (NMI), a collaborative effort among government agencies, academics, industry, and philanthropic organizations aimed at enhancing our understanding of earth’s many microbial communities. An investment of $121 million in federal funding and an additional $400 million from additional stakeholders will support interdisciplinary research, the development of platform technologies, and additional educational and public outreach activities that will expand the workforce for microbiome studies (https://www.whitehouse.gov/the-press-office/2016/05/12/ fact-sheet-announcing-national-microbiome-initiative). The creation of the NMI presents an especially exciting opportunity for chemists. Knowledge of the molecular mechanisms underlying how microorganisms in communities interact with each other, their surrounding habitats, and other organisms, along with innovative tools to measure and manipulate these processes, is needed to address challenging societal problems, including climate change, energy, food security, and health care.1−3 By expanding the funding and visibility of microbiome research, the NMI will enable chemists of all disciplines to make critical contributions to this exciting research area. Communities of microorganisms, or “microbiomes”, exist everywhere there is life on earth, including the oceans, soils, and atmosphere. For 3.5 billion years, microbes such as bacteria, archaea, and viruses have shaped this planet and all of its inhabitants. We know that these organisms and their associated metabolic activities are critical to the health of the environments they occupy, including the human body. Trillions of microbes live in and on humans, with the largest number residing in the gastrointestinal tract.4 Collectively these organisms possess over 100 times more genes than the human genome. We coevolved with microbes, so it is logical that the presence of these organisms and their associated metabolic activities would influence human health and disease susceptibility. Notably, research over many decades has revealed many strong connections between the human microbiome and infectious disease.5 Humans are colonized with microbes at birth. During the first three years of life, the types of organisms present in the human gut change, ultimately reaching a stable state that is unique to each individual and, in the absence of major © XXXX American Chemical Society
Received: June 7, 2016
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DOI: 10.1021/acsinfecdis.6b00100 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
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As C. dif f icile infections have become an increasingly serious problem over the last 20 years, FMT use has increased. In 2013, a randomized study found FMT superior to the standard of care vancomycin for the treatment of recurrent C. dif f icile infection.6 The success of FMT in this setting has provided perhaps the strongest evidence supporting microbiome modulation as a strategy for treating human disease and has generated much excitement for the prospect of using this approach to treat other gut microbiome-associated disorders. This technology has also formed the basis for a rapidly growing sector of the biotech industry, with multiple companies developing new C. dif f icile therapies based on FMT. It is also important to understand the interplay between the human microbiome and antibiotics. Antibiotic treatment causes collateral damage to beneficial microbes. Our renewed appreciation of the microbiome’s importance in human health and correlations between the rise in antibiotic use and various diseases has raised concerns about the consequences of the overuse of antibiotics, particularly early in life. For example, exposure to antibiotics at critical periods could contribute to a loss of microbes needed for immune system development, altering the susceptibility to autoimmune disease. Antibiotic exposure also increases susceptibility to infectious disease by killing members of the microbiome that provide colonization resistance and decreasing natural barriers to pathogen colonization, as is the case for C. dif f icile. The human microbiome’s role in mediating the spread of antibiotic resistance is also a topic of much interest given the seriousness of this public health threat. The human gut microbiota is recognized as a reservoir of antibiotic resistant genes and a site of increased horizontal gene transfer relative to other microbial communities. Understanding the factors that promote the transfer of antibiotic resistant genes from environmental organisms to the gut microbiota, between members of this community, and from gut microbes to pathogens could help to limit the spread of these elements. Finally, the recent appreciation that microbiomes of “built environments” (homes, work places, and hospitals) may contribute to the spread of antibiotic resistant genes highlights the need to understand how the design of these structures influences the residence and movement of microbes. Despite this growing appreciation of the many connections between the human microbiome and infectious disease, our understanding of the specific mechanisms underlying these phenomena is in its infancy. From both a phylogenetic and a functional perspective, all microbiomes contain vast amounts of uncharacterized microbial diversity. While advances in DNA sequencing technology and gene markers for phylogeny allow us to catalog microbes present in communities readily, we still have not cultivated the vast majority of organisms found in most habitats. We also have a poor understanding of the chemical functions performed by microbial communities, including both the biochemical transformations required for microbial growth and survival as well as those required for communication with other organisms. For example, over 50% of the genes in human gut microbiomes encode proteins that cannot be given even a broad annotation.7 This vast knowledge gap leaves us unable to predict the chemistry that will take place in microbial communities accurately using the vast amounts of sequencing data we have acquired. We also lack the ability to monitor these chemical processes in the complex environments in which they take place. Finally, we are unable to manipulate these assemblages rationally, either by removing specific
organisms or by modulating individual microbial activities. Together these obstacles limit our understanding of how microbiomes work and, in the context of infectious disease, prevent us from harnessing the full therapeutic potential of these organisms. What scientific and technological advances will enhance our understanding of microbiomes? Techniques that allow a highthroughput functional characterization of microbial genes and proteins will improve our knowledge of the chemical capabilities of microbes and increase our ability to extract information about the biochemistry associated with microbial communities. We also need new, nondestructive approaches for measuring, imaging, and studying microbiome processes in community settings at appropriate scales.8 To decipher the contributions of individual organisms and activities to communities, we need the ability to manipulate specific organisms as well as metabolic activities with high specificity. This could be accomplished using narrow-spectrum antibiotics or small molecules that inhibit specific microbial metabolic pathways. The development of these transformative technologies will require cooperation between scientists and engineers from many disciplines who can bring a diversity of tools and perspectives. Recognizing that chemists are uniquely positioned to contribute to the development of these research tools, the American Chemical Society has partnered with the American Society for Microbiology, the American Physical Society, and the Kavli Foundation to sponsor the Kavli Microbiome Ideas Challenge (http://www.kavlifoundation.org/sciencespotlights/why-its-time-map-microbiome#.V08sfvkrIdU). This effort will support the development of innovative tools and methods that will be applicable across many distinct microbial ecosystems. The research supported by this effort, and the NMI more broadly, will advance the move from a descriptive to a mechanistic understanding of all microbial communities, including the human microbiome and its roles in preventing or mediating infectious disease. It will also provide an exciting training opportunity for a new generation of microbiome researchers, including chemists.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acsinfecdis.6b00100 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acsinfecdis.6b00100 ACS Infect. Dis. XXXX, XXX, XXX−XXX
