Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
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Workshop Overview
Workshop Overview
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MICROBIAL ECOLOGY IN STATES OF HEALTH AND DISEASE Introduction Individually and collectively, resident microbes play important roles in host health and survival. Shaping and shaped by their host environments, these microorganisms form intricate communities that are in a state of dynamic equilibrium.
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Still, the dramatic rise in the global pervasiveness of many of these apparently noncommunicable diseases over the past half-century has fueled intense interest in the possibility that local and global alterations in our microbial ecology may be contributing to the 2 For the purposes of this workshop overview, microbiota is a collection of microorganisms -- including Archaea, Bacteria, Fungi, Protozoa, and Viruses -- that exist in the same place at the same time (see Robinson et al., 2010)
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on the formation, function, and stability of microbial communities; and research challenges and opportunities for this emerging field of inquiry. This meeting built and expanded upon many of the topics explored at a 2002 Forum workshop, The Infectious Etiology of Chronic Diseases (IOM, 2004)
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. As noted by David Relman, chair of the Forum on Microbial Threats, the important biology accomplished by the net actions of interacting microbial communities is really the norm on our planet, yet we are only just beginning to explore and ppreciate a the principles that might define these communities.
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. Coupling these techniques with concepts developed in the field of macroecology, r esearchers are able to create a rich, multidimensional picture of the ecology of microbial communities (Robinson et al., 2010; Boyle and Gill, 2012)
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. In addition to long-term selective forces that hone microbe–host interdependencies, indigenous microbes are subject to shifting environmental conditions over the lifetime of the host.
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fischeri migration into host tissues. Thus, the host responds transcriptionally upon initial symbiont contact, which facilitates subsequent colonization (Kremer et al., 2013)
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fischeri with host tissues induces the expression of several genes (e.g., proteases, chitinases such as EsChitotriosidase, and lysozyme) whose products, when supplemented with components already present in the mucus (NO and EsPGRP2)
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Plant roots provide a structured and nonhomogeneous habitat for tens of thousands of species of icrobes. m Within this complex environment, microhabitats of nutrient, water, pH, and oxygen gradients shape -- and are shaped by -- root-associated microbial communities (Ramirez-Puebla et al., 2013)
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that are involved in establishing feeding sites in plant roots (6) , and nematodes secrete other compounds (organic acids, amino acids, and sugars)
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Dynamic interactions Bacterial colonization of the zebrafish gut triggers an innate immune response by the host, in the form of neutrophils -- which are not present in the intestinal tracts of germ-free fish, Guillemin noted (Bates et al., 2007)
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12 MICROBIAL ECOLOGY IN STATES OF HEALTH AND DISEASE FIGURE WO-4 Monoassociation with zebrafish gut bacterial isolates elicits a wide range of neutrophil influx (MPO+ cells/gut)
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Inquiry into the sources of variation in the zebrafish gut microbiome are informed by ideas developed over decades by plant and animal ecologists. According to one influential theoretical framework, three basic processes drive community variation over short time frames and coarse taxonomic resolutions: • Dispersal (movement in space)
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. FIGURE WO-6 Positive and negative selection of colonizing microbial species in the gut.
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In his presentation, Tuskan described his group's efforts to characterize the sources of genetic diversity among these microbial communities and to relate community composition to function (Figure WO-7)
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. This observation supports a conception of microbiota acquisition that he called the "lottery hypothesis" where plants recruit microbial inhabitants of the root endosphere from the wider range of microbes present in the immediate environment of the rhizosphere -- which, in turn, represents a subset of the far larger pool of potential endosymbionts available in the various environments in which the plant grows.
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In addition, certain endophytic bacteria are known to partner with the mycorrhizal fungi that form symbiotic associations with plant roots. Through pairwise inoculation experiments with Populus fungal isolates, the ORNL team identified "mycorrhizal helper bacteria" among their collections of Populus bacterial isolates.
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. Community composition changed over time (panel C)
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. Consequently all animals -- including humans -- D may share certain fundamental principles of interaction with their resident microbiota, Douglas said.
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Hibernation-Related Dynamics of a Vertebrate Gut Microbiome Mammals found in all classes hibernate during periods of unfavorable environmental conditions, during which they experience profound changes in physiology, morphology, and behavior (Carey et al., 2003)
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. Carey's group studies the 13-lined ground squirrel Ictidomys tridecemlineatus, which undergoes an annual hibernation cycle (see Figure WO-11)
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To explore how the gut microbiota responds to the extreme transitions during the annual hibernation cycle, she and her group compared the sequences of 16S rRNA genes from the microbiota occupy ng the squirrels' intestinal lumen during summer, early winter, late winter, i and spring (Carey et al., 2013) (Figure WO-11)
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. At the level of bacterial species and strains, the exact mix present on any given individual is as "unique as a fingerprint" -- reflecting the influence of factors ranging from genetics and life history to diet (Spor et al., 2011; Human Microbiome Project Consortium, 2012; Yatsunenko et al., 2012)
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or absence (–) of Helicobacter pylori, can lead to permanent and marked perturbations in community composition.
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. Despite the variation of community structure between individuals, each human microbiome -- the collection of genes encoded by members of a m icrobiota -- xhibits shared functional attributes that influence host physiology, e immunity, and metabolism (Human Microbiome Project Consortium, 2012)
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As summarized in this section, researchers at the workshop described efforts to build upon initial characterizations of the structure and function of the microbiome by mapping the spatial and temporal dynamics of host-associated microbiota; elucidating the means by which host genetics, life history, and environmental exposures may influence community structure and function; and expanding our view of our microbiota to include fungi and viruses. Workshop presentations on the inflammatory bowel diseases (IBDs)
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. As previously noted, the primary microbial community inoculum at birth is the mother's microbiome.26 Following vaginal delivery, an infant's microbiome 26 Recent research suggests that the microbial communities of an infant's mecomium may also play a role in microbial colonization during the first month of life (Moles et al., 2013)
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. Following initial colonization events, the gut microbiota of human adults undergoes consecutive changes in composition and function, increasing in diversity and stability until a relatively constant adult gut community is established (Lozupone et al., 2012)
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By the third trimester, a healthy pregnant woman's gut microbiota has changed markedly, perhaps in response to immunological changes known to inhibit rejection of the fetus. In its structure and function, the late-pregnancy microbiome resembles that of an individual who exhibits weight gain and inflammation associated with type 2 diabetes.
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Various hypotheses, including contributions to immune system and neurological development, and "pathogen deflection" by providing pathogen binding sites that resemble the intestinal epithelium, have been advanced to explain the presence of these oligosaccharides in human milk. Mills and coworkers have explored the possibility that the oligo saccharides in human breast milk enrich specific populations of microorganisms in the infant gut leading to early colonization events in the newborn infant that are beneficial to the infant.
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[and] it goes systemic, it can kill you." A healthy immune response is both plastic and diverse, Eberl observed, reflecting the complexity of the microbial world and the necessity to establish a dynamic equilibrium through adaptation; if it is too weak, the microbiota overgrows and invades host tissues; if it is too strong, the host suffers inflammatory "collateral damage." An example of the latter has been observed in a Drosophila mutant lacking regulation of a key inflammatory pathway such that it kills most species of endogenous microbes -- except for a single toxic strain that eventually kills the fly (Ryu et al., 2008)
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. The nature of the immune response is not purely regulatory or inflammatory, but more generally adjusts to the nature of the trigger it faces, like a spring that is pulled by the intensity of the microbial challenge.
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. Indigenous Microbes and the Ecology of Chronic Diseases In his keynote remarks, Martin Blaser, of New York University, acknowledged the "world of diversity" that has been revealed by early studies of our microbiomes and emphasized the ancient origins of our resident microbial communities (Dr.
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. In inflammatory bowel disease (IBD)
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. This is but one of many examples of the influences of the gut microbiome.
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be giving Helicobacter pylori back to children to replace their ancient microbe that
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Accumulating evidence suggests that the human gut microbiota becomes established during the first 3 years of life and is shaped by a variety of factors, including host genetics, diet, and other environmental exposures (Lozupone et al., 2012; Yatsunenko et al., 2012)
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Based on the observation that sub-therapeutic antibiotic treatment (STAT) of livestock stimulates weight gain and increases feeding efficiency (particularly among animals treated at young ages)
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children -- could produce sufficient change in the mouse gut microbiome to alter body composition; as demonstrated in the mouse model, preliminary results suggests lifelong effects. Blaser observed that studies in other fields may help to illuminate these results.
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(2008) suggested that decreased microbial diversity due to antibiotic treatment may contribute to the development of "antibiotic-associated" Clostridium difficile infection and diarrhea.
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Expanding Perspectives on Host–Microbe Interactions While considerable research on the role of the microbiome in human health and disease has focused on the resident bacteria of the human gut, studies of other mucosal surfaces and the skin, and of other resident microbes, have broadened our understanding of the complex interplay between the host, environment, and microbial communities. The presentations summarized below reflect expanding 35 Estrogens leave the liver as bile conjugates and circulate to the gastrointestinal tract, from which they are excreted -- unless they are deconjugated through the action of the resident bacteria, causing estrogen to be reabsorbed, Blaser explained.
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. Their results reveal five distinct types of microbial communities, all of which contained significant numbers of lactic acid–producing bacteria -- but not necessarily lactobacilli (Figure WO-20)
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Panel A is a heat map of percentage abundance of microbial taxa found in the vaginal microbial communities of 394 reproductive-age women. Panel B is a representation of vaginal bacterial community groups within each ethnic group of women.
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If the different states identified by Forney and colleagues reflect different risks to invasion or disease, he observed, then for a particular woman disease risk will also vary with time "depending upon what day it is and what the events are that are driving the changes we are seeing," Forney observed. To better understand the relationships between community composition, stability, and disease, we need to appreciate "what functions are being performed by the microbial communities that are important to maintaining health and the ecological interactions necessary to maintain them," he concluded.
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. In the case of OPC, mucosal tissues defend against fungal invasion through an adaptive immune response involving CD4 T cells.39 Despite considerable efforts to find a similar protective role for adaptive immunity against VVC, it was suspected -- and then demonstrated -- that this disease did not arise from insufficient defense by the host against invasion, but rather by an immune "overreaction" to the presence of a commensal -- "collateral damage," as Eberl described it (Fidel, 2007; Yano et al., 2010, 2012)
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"Symptomatic infection of vaginal candidiasis is associated with an acute inflammatory response, not of the adaptive immune system, but of the innate immune system," Fidel stated. "The whole idea of protection and susceptibility to infection has gone through a paradigm shift over the past several years now, going away from some deficiency in adaptive immunity to issues of innate immunity being responsible for both protection and susceptibility." But, as his research demonstrates, both models -- involving the same host and microbe -- can exist simultaneously in different contexts.
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This finding should provoke further exploration of the role of niche-specific microbial communities in local immune responses and the potential for cross-talk between host sites, Belkaid added (see Belkaid and Naik, 2013)
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. He described recent 40 Crohn's disease is one of the inflammatory bowel diseases (IBDs)
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By contrast, in situations where commensalspecific T cells become dysregulated because of impaired regulatory pathways and/or barrier function, these T cells could drive chronic pathology such as inflammatory bowel disease or psoriasis. SOURCE: Belkaid et al.
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In another study, infection of mice with a different latent herpesvirus "armed" the natural killer (NK) cells of the innate immune system, 41 Murine gammaherpesvirus 68 and murine cytomegalovirus -- herpesviruses that are genetically highly similar to the human pathogens Epstein–Barr virus and human cytomegalovirus (Barton et al., 2007)
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. These research results suggest that "the fundamental nature of the immune response is determined by this latent virus, or maybe other parts of the host v irome," according to Virgin.
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Some of these viruses may cause disease; others may translocate into the blood; some may damage the intestinal epithelium, enabling molecules associated with pathogens and recognized by cells of the innate immune system to move into host tissues, causing systemic inflammation that is the hallmark of AIDS. Based upon these observations, Virgin and coworkers are now studying such possible effects of AIDS-associated virome expansion in humans and primates.
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Mucus covers the entire living surface of some organisms, such as coral, and in humans, mucus lines the lungs, sinus and oral cavities, and the gastrointestinal tract. A variety of microorganisms can be found in mucosal surfaces, which provides the microbes with structure and nutrients.
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Indeed, he pointed out, antibodies recognizing a common fungal cell wall component, mannan, are currently used to identify cases of Crohn's disease. "This suggests that in inflammatory bowel disease, there is novel exposure to fungi," observed Underhill (Underhill and Braun, 2008)
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"There may be some predictive utility here." Host–Microbe Interactions in the Inflammatory Bowel Diseases The term inflammatory bowel disease is used to describe a constellation of conditions associated with chronic or recurrent inflammation of the gastrointestinal tract. Two clinically defined forms of IBD are ulcerative colitis and Crohn's disease, which "are chronic remittent or progressive inflammatory conditions that may affect the entire gastrointestinal tract and the colonic mucosa, respectively, and are associated with an increased risk for colon cancer" (Kaser et al., 2010)
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The presentations summarized below explore the complex interplay of these factors in the pathogenesis of IBD. The Influence of the Mucosal Immune System and Gut Microbiota on IBD Recent discoveries in genetics, microbiology, and immunobiology have helped to illuminate the complex interactions between host, microbiota, and environmental factors that contribute to the development and persistence of IBD (Figure WO-27)
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WORKSHOP OVERVIEW 57 FIGURE WO-25 Worldwide Crohn's disease incidence rates and/or prevalence for countries reporting data (A) before 1960, (B)
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. NOTES: IBD, samples from patients with either Crohn's disease or ulcerative colitis (Frank et al., 2007)
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By responding to host and pathogen-derived lipids, NKT cells are able to initiate and control a variety of different inflammatory events. NKT cells are critical because they function as the earliest phases of the immune response -- at the cusp between innate and adaptive immunity.
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. Genetics of Susceptibility in Microbiota-Associated Complex Diseases Based on family studies, metagenomic analyses of Crohn's disease and ulcerative colitis have confirmed earlier assumptions that genetic predisposition
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changes that provide protection from later life environmental triggers that are capable of activating NKT cells and causing inflammation and disease. In the absence of these essential microbial exposures during early life (as associated with early-life use of antimicrobials)
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Reduced taxonomic diversity in the gut microbiome is now recognized as one of the hallmarks of IBD, along with characteristic increases and decreases in specific bacterial clades that may define specific subtypes of these disorders, Xavier said. Examining the functional implications of these shifts, he and colleagues discovered that they were accompanied by striking declines in carbohydrate and amino acid metabolism, short-chain fatty acid synthesis, and DNA maintenance, accompanied by increased secretory and invasive activity (Morgan et al., 2012)
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These processes all occur within microbes and rely on transport of small molecules to and from the lumen. The resulting tissue-destructive environment provides nutrients such as nucleotides and amino acids, which allow for increased growth of auxotrophic "specialists." Bacterial clades of interest are indicated in orange, bacterially mediated processes increased in IBD in red, and processes that decrease in green.
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. Exploration of the human microbiome is just one extension of the work initiated by environmental microbiologists over a half a century ago to reveal the vast diversity and complexity of the microbial world around us (Robinson et al., 2010)
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. While noting that we have much to learn about whether and how to manipulate established microbial communities to achieve such goals, several speakers described efforts to lay a foundation for future microbiota-directed therapies -- and in one case, to successfully treat potentially lethal dysbiosis through "ecological" intervention.
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During infancy and early childhood, a healthy gut microbiota helps to avoid dysbiosis that can lead to disease later in life. In adulthood, corrective strategies to deal with emergent dysbiosis and associated diseases such as inflammatory bowel disease, obesity, and type 2 diabetes include modulating the microbiota using probiotics and prebiotics, antibiotics, bariatric surgery, or "drugging the microbiota." Drugs targeted to microbial enzymes could also be used to boost the efficacy and reduce the toxicity of therapeutics.
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These inquiries not only reveal novel and potentially useful compounds, he observed, but also provide "a new window into the biology of the organisms that produce these molecules, and maybe new ways of understanding why they make them." The process of discovering natural products traditionally began with an environmental sample, such as soil, from which a wealth of small molecules -- produced by microbes -- could be isolated and characterized. Today, however, insight into the genetic architecture underlying the synthesis of these molecules presents the opportunity to rapidly identify sets of natural product genes in microbial genomes and connect them to the molecules they ultimately manufacture (Walsh and Fischbach, 2010)
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Fischbach's lab has begun to focus on the human microbiome because "many of the most interesting biosynthetic gene clusters that we found were not in exotic soil and marine microorganisms; they were in [human] gut and skin and oil bacteria." Experiments on candidate gene clusters have borne out the hypothesis that these molecules mediate host–microbe interactions and have led to the discovery of several intriguing small molecules that the Fischbach lab is currently investigating.
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. Antimicrobial Peptides: Innate Defense Against Infection The arsenal of proteins produced by the innate immune system represents another untapped resource for understanding and potentially manipulating host– microbe interactions (Figure WO-33)
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"Anywhere on the body where a bacterial or fungal organism could creep in from the outside, weWO-33_R02492 Figure find an array of antimicrobial peptides," Zasloff observed. Zasloff also noted that AMPs appear to be highly adapted to the host organism's macroenvironment, as well as to the microenvironment of the specific tissues where they are expressed: "They are different, how they're regulated is different, what stimulates their expression is different, [and]
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the most perfect solution to its coexistence with microbes." Diagnostic Information from the Skin Microbiome Human skin surfaces are complex ecosystems that provide diverse environments for our resident microorganisms, observed speaker Julie Segre, of the National Human Genome Research Institute (Dr. Segre's contribution may be found on pages 401-412 in Appendix A)
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. Genomic surveys of the skin microbiome detected far greater microbial diversity -- on the genera and species levels -- than had previously been appreciated by studies limited to culturable organisms, Segre observed.
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Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection Over the past two decades, Clostridium difficile infections in humans have become among the most common hospital-acquired infections in the United States. Linked to more than 14,000 deaths (U.S.)
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In addition, an ineffective immune response may also contribute to the pathogenesis of recurrent C difficile infection (Kyne et al., 2001)
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Transplantion of fecal microbiota from a healthy donor into an individual with CDI can restore the healthy gut microbiota in the patient's diseased colon, thereby probably preventing further outgrowth of C difficile and leading to resolution of symptoms.
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difficile infections in two patients, each of whom had failed to re cover after at least three courses of antibiotics. Sequencing performed before
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For example, efforts to alter microbiota function by introducing microbial communities, rather than a specific species, will be difficult to monitor, he said. "You are no longer saying we either did or did not have this organism, or did or did not see a fall in this particular well-understood end point," Relman explained.
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This notion was raised in presentations and discussions throughout the workshop, culminating in a lively conversation on the need to consider the ollateral damage to the beneficial microbes associated with antibiotic use; c whether and how we should restrict the use of antimicrobial interventions -- from a ntibiotics and antiseptics to the widespread use of hand sanitizers -- and how to convey such messages to a germ-phobic public. Amplifying Blaser's suggestion that current levels of antibiotic exposure in children may lead to lifelong repercussions such as asthma, obesity, and increased susceptibility to infectious diseases, Belkaid speculated that "the sum of the infection and the antibiotic treatment is very likely to be [much]
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you are washing your hands after going to the bathroom, before you prepare food, or eat food." Manipulation of Our Microbiomes Given mounting evidence of the biological costs of antibiotic therapy -- long considered a medical triumph -- workshop participants were at best cautiously optimistic regarding prospects for the strategic manipulation of microbiota to improve host health. While the use of probiotics to treat IBD (as described by Keller)
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Such hypothetical debates typify this emerging field of inquiry, during what Relman called "a lush time in the early phase of a science before the reality sets in and we come back down to some reasonable level of balance." In the meantime, he observed, "It is a pretty exciting time in this area of work, and it's made exciting by the fact that we have the means of discovering complexity that offers untold possible explanations and mechanisms. But we don't know enough about any of it to realize that much of it may be wrong." Advancing Research Several workshop participants emphasized the importance of assembling multidisciplinary teams and to train the next generation of scientists.
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, "[m] icrobial communities are at the heart of all ecosystems" -- thus, biomedical, environmental, agricultural, and bioenergy research all share "a common challenge: to predict how functions and composition of microbial communities respond to disturbances" (Shade et al., 2012)
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2009. Increasing incidence of paediatric inflammatory bowel disease in O ntario, Canada: Evidence from health administrative data.
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2013. Session I: Annual cycles of extreme dietary change shape gut microbiota and their hibernator hosts.
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2012. The impact of the gut microbiota on human health: An integrative view.
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2007. Molecular-phylogenetic characterization of microbial community imbalances in human inflam matory bowel diseases.
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2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
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2011. Genetics and pathogenesis of inflammatory bowel disease.
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2012. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
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2008. Metagenomic approaches for defin ing the pathogenesis of inflammatory bowel disease.
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2009. The gut microbiota shapes intestinal immune responses during health and disease.
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Inflammatory Bowel Diseases 14(8)
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2012. Human gut microbiome viewed across age and geography.
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