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Host Tissues May Actively Respond to Beneficial Microbes Some bacteria are viewed as having a dynamic and positive, rather than passive and harmful, relationship with their hosts Richard P. Darveau, Margaret McFall-Ngai, Edward Ruby, Sam Miller, and Dennis F. Mangan ome bacteria help to maintain health Crohns and Colitis Foundation of America, the and otherwise benefit multicellular orUniversity of Washington School of Dentistry, ganisms. Traditionally, microbioloSonicare/Phillips Oral Healthcare, Inc., and the gists attributed these benefits to pasHack Estate. The workshop agenda and other sive and nonspecific effects—arguing, information may be viewed at http://www for example, that a host’s resistance to further .adminw.com/bmw/. bacterial colonization reflects occupation of During the workshop, participants reexammost niches on tissue surfaces by benign bacined current knowledge of the physical organiteria. Other metabolic activities, such as those zation of host-associated microbial communithat produce acids, also help to preclude ties, the role of bacteria in host development and colonization by pathogens and thus discourage metabolism, innate host defense recognition, infections. Yet another traditional mechanisms of probiotics, and belief holds that, as long as nontheories of host-microbe coevolupathogenic bacteria remain in certion. Many scientists working in The past tain niches and cause no harm, this area believe that the past parparadigm is the host immune system tolerates adigm is shifting, with bacteria beshifting, with their presence and does not elimiing viewed as having active and nate them. However, recent dedynamic rather than passive relabacteria being velopments indicate that the retionships with their hosts. Thus, viewed as lationships between the usual they say that using the term “comhaving active microbiota and the host are more mensal” to refer to nonpathogenic and dynamic active and specific than previously microbiota of animals perpetuates rather than thought. a misleading and naive view of the passive A group of about 100 scientists complexity of these interactions. with backgrounds in evolutionary NIH officials will draw on these relationships biology, ecology, pathogenic midiscussions for guidance when with their hosts crobiology, immunology, or cell planning new programs. and developmental biology convened in October 2001 at the Consortia in Oral Cavity Could Typify “Beneficial Microbial Workshop,” which was Those Found More Widely cochaired by Sigmund Socransky of the Forsyth The many and varied microbial associations Institute, Boston, Mass., and Margaret McFallwithin the oral cavity include some that appear Ngai of the University of Hawaii (UH) in Honocritical for maintaining health, according to lulu. The workshop was sponsored by the NaSocransky. For instance, DNA probe studies of tional Institute of Dental and Craniofacial 40 taxa of oral bacteria obtained from subginResearch (NIDCR) of the National Institutes of gival plaque samples of healthy individuals and Health (NIH), VSL Pharmaceuticals, Inc., the S Richard P. Darveau is a Research Professor at the University of Washington School of Dentistry, Seattle; Margaret McFallNgai is a Professor and Edward Ruby is Professor at the University of Hawaii; Sam Miller is Professor at the University of Washington, Seattle; and Dennis F. Mangan is Chief, Infectious Diseases and Immunity Branch at National Institute of Dental and Craniofacial Research, Bethesda. 186 Y ASM News / Volume 69, Number 4, 2003 others with periodontal disease indicate FIGURE 1 that several bacterial taxa, including those associated with gingival health, co-occur in the periodontal crevice. This group, designated the “green cluster,” includes Capnocytophaga species, Campylobacter concisus, Eubacterium nodatum, and Streptococcus constellatus. Although the host-associated consortium within the oral cavity is one of the best described, it includes many asyet unculturable and thus poorly characterized bacteria. Bacteria adhere to tooth surfaces to form dental plaque, an oral host-associated microbial biofilm, according to Paul Kolenbrander of NIDCR and Richard Lamont of the University of Washington, Seattle. Highly specific interactions occur between bacterial adhesin proteins and carbohydrate or protein receptors found on the surfaces of other bacteria. For example, a 26-amino-acid fragment of the SspB polypeptide made by Streptococcus gordonii is critical for its association with Porphyromonas gingivalis, another bacterium in the oral cavity. These and other interactions form complex arrays of different oral bacteria, which are also linked to tooth surfaces (Fig. 1). Microbial symbioses, including those Innate host defense status in clinically normal periodontal tissue. Clinically healthy tissue with humans, fall within a larger evoluexpresses low levels of E-selectin and a gradient of IL-8 (represented in shades of red) tionary context, according to McFallthat facilitates the transit of neutrophils through the tissue and into the gingival crevice where they protect the host from infection. These mediators are made in response to a Ngai. If anything, such intimate, highly organized bacterial biofilm, termed dental plaque. This representation is adapted coevolved relationships with microorfrom Whittaker et al. 1996 and Tonetti et al., 1994. ganisms are the rule rather than the exception among animals. Among vertebrates, for example, 8 of the 10 major organ lying tissue are actively involved in maintaining systems have components in which bacterial a stable, long-term relationship. cells may outnumber host cells. However, biologists rarely focus on such aniFor instance, such metabolic cooperativity is mal-bacterial associations, despite their wideextensive within the female reproductive tract, spread occurrence and apparent importance. according to Sharon Hillier of the Magee-WomThis comparative neglect in large part reflects an’s Research Institute in Pittsburgh, Pa. Cells the way in which scientific fields developed within the vaginal epithelium convert glycogen historically, according to McFall-Ngai. For to glucose, thereby providing nutrients useful instance, bacteriology separately emphasized for beneficial, lactic acid-producing microorpathogenic and environmental microbiology, ganisms. These bacteria employ a set of highly while immunology tended to focus on issues specific molecular mechanisms to optimize such as nonself recognition. Thus none of these growth, indicating that these microorganisms fields provided a natural home for studying coare not passively occupying those niches. evolved, beneficial associations of bacteria with Rather, the microbial community and its underanimal hosts. Emerging shifts in these concep- Volume 69, Number 4, 2003 / ASM News Y 187 Representative models of monospecific beneficial bacterial associations with invertebrates Host species Extracellular Euprymna scolopes (sepiolid squid) Hirudo medicinalis (medicinal leech) Heterorhabditis bacteriophora (entomophagous nematode) Bugula neritina (bryozoan) Intracellular Glossina spp. (tsetse fly) Sitophilus spp. (weevil) Bankia setacea (shipworm) Bacterial species Function Vibrio fischeri Aeromonas veronii Bioluminescence Nutrition (?) Photorhabdus luminescens Endobugula sertula Predation/antibiosis Sodalis glossinidiu Unnamed symbiont Unnamed symbiont Nutrition Nutrition Cellulose and N2 fixation Polyketide synthesis tual frameworks, along with new techniques and models for studying cooperative interactions, promise to open this vast frontier of biology. Microbial Cooperativity with Host Tissues Can Be Critical Species within mixed microbial communities communicate more extensively with one another than was previously appreciated. Many of these host-associated microbial consortia are recognized as highly organized communities within biofilms rather than mere collections of microorganisms. For instance, microorganisms within such biofilms demonstrate a high order of physical and physiological organization, and may be divided between areas of high and low biomass interlaced with water-filled channels of different sizes. Moreover, these channels can serve as conduits, bringing oxygen to otherwise anoxic microbial communities. Such physical structures also allow diverse bacterial species to benefit from their juxtaposition, thereby facilitating a physiological cooperativity not seen in mixed populations of planktonic microorganisms, according to John Breznak at Michigan State University, East Lansing. He and his colleagues determined that hydrogen gas transfers between members of the interacting microbial populations in termite hindguts require spatial relationships which lead to predictable patterns of species distributions. Optimizing spatial relationships among different microbial species depends on mechanisms for sensing and responding to environmental cues, according to Peter Greenberg of the University of Iowa, Iowa City. Thus, microorgan- 188 Y ASM News / Volume 69, Number 4, 2003 isms in biofilms depend on quorum sensing to regulate gene expression and cell growth. His group and others are providing evidence that this mechanism contributes significantly to the maintenance of such highly organized microbial communities. Microbial-Host Associations Result in Normal Functions and Morphology Studies using germ-free or gnotobiotic mice provide dramatic evidence that “commensal” bacteria can directly participate in normal tissue development and functions. For instance, components of the host immune system, including Peyer’s patches, the lamina propria, and the intraepithelial space, do not develop unless ordinary microbiota are allowed to colonize the intestines of gnotobiotic mice. Recent developments in genomics-based technologies are enabling microbiologists to study more subtle but dramatic molecular effects of such bacteria on mammalian tissue development. For example, when bacteria colonize the intestinal lumen of germ-free mice, host genes encoding specific sugar modifications are activated, leading the mouse epithelium to change. For instance, fucose sugars are added to glycolipids in these tissues. Thus, enteric bacteria can play an active and specific role in host tissue maturation steps. Specific interactions can occur between nonmammalian hosts and associated bacteria. Among invertebrates, interactions with bacteria are often binary—that is, involving only one microbial symbiont. Just as fruit flies and nematodes provide relatively simple models for studying development, binary symbiotic associations with invertebrates offer valuable opportunities for manipulating and studying host-microbe relationships (Table 1). Consider the luminous bacterium Vibrio fischeri. It induces the development of the lightemitting organ of the bobtail squid (Fig. 2). The bacteria trigger a number of specific developmental events in the squid, including the loss of an external layer of ciliated epithelium and an increase in the density of microvilli in the internal bacteria-associated tissue, as reviewed by Edward Ruby at UH. FIGURE 2 Symbiosis between the Hawaiian sepiolid squid Euprymna scolopes (A) and the luminous bacterium Vibrio fischeri (B). V. fischeri cells colonize the bilobed light-emitting organ (C) located in the mantle of the bobtail squid. The bacteria provide the host with light for its counterillumination behavior during nocturnal feeding. A large population of the extracellular bacterial symbionts resides within the organ in crypt spaces lined by microvillus epithelial tissue (D). (Images from M. McFall-Ngai.) Ongoing studies using bacterial mutants and measuring host gene expression are uncovering some of the mechanisms underlying the molecular dialog that initiates this development program in the squid. Understanding the basis for the bacteria-directed effects on development and morphology in this and other associations may well lead to the discovery of additional bacteria that are involved in normal tissue and organ functions in humans as well as other species. Detecting Host-Associated Microbial Communities Advances in our understanding of how the innate host immune system detects and responds to bacteria are providing another impetus for reevaluating how cooperative bacterial associations affect health and development. Host responses to microorganisms vary considerably and depend upon the structures with which they interact, according to Brain Henderson of the Eastman Dental Institute in London, U.K., who provided an overview of this subject. Host cells depend on several key pattern-recognition receptors, including lipopolysaccharide-binding protein (LBP), CD14, and the tolllike family of membrane receptors (TLR), according to Henderson. For example, different host TLRs recognize specific microbial components: thus, TLR2 recognizes lipoteichoic acid Volume 69, Number 4, 2003 / ASM News Y 189 and lipoproteins; TLR4 intereacts with lipopolysaccharide (LPS); TLR5, with bacterial flagella; and TLR9, with bacterial DNA motifs. In addition, each such TLR interaction appears to trigger a distinct type of host response, activating different host cell-signaling pathways. Cellsurface expression of TLR may vary, as may serum-soluble microbial recognition host components such as LBP and sCD14s. They further contribute to the exquisite microbial specificity of the innate host response system. When this innate system detects particular host-associated microbial communities, it can profoundly influence specific tissues where those communities form, according to Richard Darveau of the University of Washington, Seattle. For instance, a host surveillance system tracks gingival tissues. Even when those tissues are healthy, they are bathed in low levels of E-selectin, intracellular adhesion molecule (ICAM), and interleukin-8 (IL-8) (Fig. 1). Among them, IL-8 forms a gradient of expression that is greatest near the bacteria/epithelial cell interface and decreases deeper into periodontal tissues. These molecular findings are consistent with other observations indicating that neutrophils steadily stream through normally functioning, healthy gingival tissue, collect in the gingival crevice, and prevent oral infections. However, this flow of neutrophils can be disrupted when the ordinary periodontal microbiota changes. It appears that normal bacterial colonization of the periodontium serves to maintain this tissue as an effective, disease-preventing host interface. Probiotics Represent a Practical Application of Microbial Communities Probiotics represent one area in which bacterial interactions with hosts are being put to practical and even therapeutic use. Probiotics consist of live bacterial infusions that are administered orally for the treatment of inflammatory bowel disease, according to Balfour Sartor of the University of North Carolina, Chapel Hill, and Claudio Fiocchi of Case Western Reserve University in Cleveland, Ohio. Thus, probiotics are administered to patients—replacing pathogenic microbial communities with beneficial ones—as one way of modulating the destructive host response that occurs in inflammatory bowel disease. 190 Y ASM News / Volume 69, Number 4, 2003 However, the mechanisms underlying probiotic action are far from well understood. For example, host responses may depend on specific microbial signature compounds, and outcomes from infusing patients with live microorganisms may depend on those microbes releasing specific chemicals necessary for altering dysfunctional molecular dialogues between host tissues and resident microbiota. Inducing beneficial hostbacterial interactions could provide opportunities for discovering immunomodulating drugs. Bacteria May Coevolve with their Hosts Some microbe-host associations apparently evolved through coordinate adaptations between the partners, according to Vaughn Cooper of the University of Michigan, Ann Arbor. Coevolutionary theory predicts that the species with the shorter generation time in such pairs will undergo a greater amount of adaptive change over time. Therefore, a dynamic dialogue between bacteria and their hosts suggests that the symbionts are continually adapting to the biochemical and genetic environment of the individual hosts with which they are associated. Such adaptations may not always be beneficial to the host and could contribute to common diseases such as inflammatory bowel disease and periodontitis, conditions that include both human and microbial genetic components. The human immune system may have evolved not so much to recognize nonself components such as bacteria, but rather conditions that signify “danger,” according to Polly Matzinger of NIH. While this danger concept was proposed to explain how autoimmune disorders can develop, it now is also being applied to explain the role of the immune system in the context of beneficial associations of the host with bacteria. No longer are scientists constrained to viewing these bacteria as merely foreign entities that human (or other animal) tissues learn to tolerate. Instead, under certain circumstances host tissues may promote associations with bacteria because those interactions benefit the host and thus do not represent a danger. Indeed, a key function of microbial pattern recognition receptors involved in innate immunity may be to maintain healthy relationships with our ordinary microbiota and to promote mature tissue development, rather than to prevent infections. ACKNOWLEDGMENTS Richard Darveau was supported by an IPA assignment to the NIDCR during the organization of this workshop. SUGGESTED READING Akira, S., K. Takeda, and T. Kaisho. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2:675– 680. Costerton, J. R., Z. Lewandowski, D. E. Caldwell, et al. 1995. Microbial biofilms. Annu. Rev. Microbiol. 49:711–745. Darveau, R. P., A. Tanner, and R. C. Page. 1997. The microbial challenge in periodontitis. Periodontology 14:12–32. Hooper, L. V., M. H. Wong, A. Thelin, L. Hansson, P. G. Falk, and J. I. Gordon. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291:881– 884. Kroes, I., P. W. Lepp, and D. A. Relman. 1999. Bacterial diversity within the human subgingival crevice. Proc. Natl. Acad. Sci. USA 96:14547–14552. Leadbetter, J. R., T. M. Schmidt, J. R. Graber, and J. A. Breznak. 1999. Acetogenesis from H2 plus CO2 by spirochetes from termite guts. Science 283:686 – 689. McFall-Ngai, M. J. 1998. The development of cooperative associations between animals and bacteria: establishing détente among domains. Am. Zool. 38:593– 608. Ruby, E. G. 1999. The Euprymna scolopes-Vibrio fischeri symbiosis: a biomedical model for the study of bacterial colonization of animal tissue. J. Mol. Microbiol. Biotechnol. 1:13–21. Savage, D. C. 1997. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31:107–133. Socransky, S. S., A. D. Haffajee, M. A. Cugini, C. Smith, and R. L. Kent, Jr. 1998. Microbial complexes in subgingival plaque. J. Clin. Periodontol. 25:134 –144. Tonetti, M. S., M. A. Imboden, and N. P. Lang. 1998. Neutrophil migration into the gingival sulcus is associated with transepithelial gradients of interleukin-8 and ICAM-1. J. Periodontol. 69:1139 –1147. Whittaker, C. J., C. M. Klier, and P. E. Kolenbrander. 1996. Mechanisms of adhesion by oral bacteria. Annu. Rev. Microbiol. 50:513–552. Get the Picture. Take Advantage of This ASM Member Subscriber Online Tool: Table/Figure Searching ASM member online subscribers can get direct access to tables, graphs, slides and other images. Whether you are preparing for a presentation or conducting research, the Table/Figure Search is a vital resource you’ll turn to time and again! Feature includes: • Key Word Search of Table Titles/Footnotes and Figure Legends • Thumbnail Images or Larger JPEG Images • Links to Full Text or Abstracts We’re Getting You the Information You Need Faster. ASM Journals are designed to help you find the information you need to improve the quality of your research. All ASM online journals offer the following powerful features for online member subscribers: • The ability to search across all ASM journals, plus over 300 non-ASM journals • CiteTrack- a personalized research service that tracks when articles of interest are published online • Full text searching functions, including searching by a journal’s table of contents section • Hypertext links to abstracts (and some full text) of most cited articles Visit all 11 ASM Journals Online at www.journals.asm.org Volume 69, Number 4, 2003 / ASM News Y 191