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ILAR Journal, 2015, Vol. 56, No. 2, 159–162 doi: 10.1093/ilar/ilv007 Article Pathogens, Commensal Symbionts, and Pathobionts: Discovery and Functional Effects on the Host Mathias Hornef Mathias Hornef, MD, is a full professor at the Institute for Medical Microbiology at the RWTH University Clinic in Aachen, Germany. Address correspondence and reprint requests to Mathias W. Hornef, Institute for Medical Microbiology, RWTH University Clinic, Aachen, Germany or email [email protected]. Abstract During the last decade, we have witnessed a stunning increase in information on the composition of the microbiota; its influence on a variety of host functions; and associations with the susceptibility to inflammatory, metabolic, and autoimmune diseases. We have thus obtained insight into the potentially harmful consequences of an altered microbiota and also learned about the many beneficial functions of commensal bacteria. The present review aims at summarizing for the reader the general concept of pathogenic and commensal bacteria and their particular features. It also discusses the more recently defined pathobionts, members of the microbiota that exert specific effects on the host’s mucosal immune system associated with the development of clinical disease. Key words: commensal; microbiota; pathobiont; pathogen; symbiont Identification and Definition of Pathogenic \Microorganisms The wish to understand the etiology of devastating epidemic communicable diseases led to the discovery of pathogenic microorganisms during the second half of the 19th century. Robert Koch (1843–1910), Louis Pasteur (1822–1895), and many others recognized during the “golden age of microbiology” the causal role of pathogenic microorganisms in the etiology of infectious diseases and cultured and characterized the causative agents. Bacillus anthracis, the cause of anthrax; Mycobacterium tuberculosis; Yersinia pestis; Neisseria gonorrhoeae; Vibrio cholerae; Clostridium tetani; Corynebacterium diptheriae; and Shigella dysenteriae were among the first pathogenic bacteria identified to cause longknown communicable diseases. These bacteria all fulfilled the third Koch’s postulate, which stated that causative isolates are able to evoke a similar disease in healthy animals, defining the ability of pathogens to mediate disease in a healthy host (Loeffler 1884). The overwhelming importance of infectious disease at the time and the wish to find strategies to prevent and treat these often fatal diseases by hygienic measures, vaccination, or later antibiotic treatment focused much attention on the identification and characterization of pathogenic microorganisms during the following decades. In addition, researchers started to analyze the mechanisms of microbial pathogenesis (i.e., the molecular basis of the disease-promoting ability of pathogens). These studies soon led to a better understanding of how individual microorganisms are able to cause the symptoms of the respective infectious disease. In addition, the results provided clues about how to counteract the dreadful action of pathogenic microorganisms. For example, the identification of the critical role of toxins in the pathogenesis of diphtheria or tetanus by Kitasato Shibasaburo (1853–1931) and Emil von Behring (1854–1917) in Berlin and Emile Roux (1853–1933) and Edmond Nocard (1850–1903) in Paris paved the way to specific protection using antitoxin antibodies by passive or active vaccination. Another example is the discovery of the critical role of capsule expression by pathogenic bacteria. Frederick Griffith (1877–1941) demonstrated in his famous experiment in 1928 that genetic transfer of the ability to generate a capsule rendered Streptococcus pneumoniae isolates able to induce © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: [email protected] 159 160 | Hornef invasive pneumococcal disease (Griffith 1928). The capsule protects the bacteria from humoral immune defenses and uptake by phagocytes. Again, the induction of capsule-specific antibodies by the later-developed vaccines containing capsule material from selected pneumococcal serotypes provided protection from invasive infection. Capsule polysaccharide-based vaccines are still standard to prevent pneumococcal infection. Research during the last century extended the picture of the broad array, important function, and sophisticated nature of virulence factors produced by individual bacterial pathogens in order to overwhelm the immune system and impair cellular and organ functions. For example, the release and reuptake of siderophores allow the acquisition of iron, which is highly restricted at most body sites of the host. Also, expression of surface molecules with high affinity to host cell structures facilitates firm attachment and cell or organ tropism. The release of a large variety of enzymes facilitates degradation of matrix molecules and spread through host tissue and the specific degradation of antimicrobial host factors such as complement or immunoglobulins. The assembly of sophisticated export and translocation machineries allows the release or even direct injection of bacterial effector proteins into host cells and the manipulation of their function (e.g., to inhibit or induce internalization and facilitate intracellular survival). Finally, more recent work has demonstrated that the induction of inflammation induces the release of electron acceptors for respiration and energy production that can preferentially be used by enteropathogenic bacteria, such as Salmonella. With progress in modern medicine, the introduction of intensive care units with respiratory ventilation, the use of joint and vascular implants, iatrogenic immunosuppression and transplantation, and an extended life expectancy, a new group of bacteria emerged that causes significant morbidity and mortality, not in healthy individuals, but in hospitalized patients or individuals with preexisting medical conditions. For example, pneumonia caused by Pseudomonas aeruginosa is typically found in patients under prolonged supportive care and respiratory ventilation. P. aeruginosa is able to produce an extracellular matrix, alginate, that facilitates firm attachment and protection from host antimicrobial agents (as well as most antibiotics). Infections of foreign bodies (e.g., joint or cardiac valve implants) are frequently caused by so called coagulase-negative staphylococci, among them Staphylococcus epidermidis. Many coagulase-negative staphylococci have the ability to strongly adhere and colonize the surface of foreign bodies, such as catheters and implants. Again, bacterial growth on implant surfaces, named biofilm, renders the bacteria resistant to antibiotic treatment. A third example is Clostridium difficile, an important causative agent of antibiotic-associated diarrhea. Following antibiotic treatment and suppression of the competitive enteric microbiota, C. difficile proliferates and secretes toxins. Although P. aeruginosa, coagulase-negative staphylococci, and C. difficile play an important role in the clinical management of hospitalized patients, these bacteria do not formally fulfill the third Koch’s postulate. They fail to infect healthy individuals but require a certain degree of immunological (or microbiota) impairment to induce disease. To indicate this somewhat restricted pathogenic ability, the term opportunistic pathogens has been coined. Commensal Microorganisms Despite the major focus on pathogenic microorganisms, the ubiquitous presence of apparently nonpathogenic bacteria was noted during the early days. In 1676, Antoni van Leeuwenhoek (1632–1723) visualized motile microorganisms in swabs from his own oral mucosa using a primitive microscope. Similarly, Louis Pasteur (1822–1895) 200 years later noticed the omnipresence of nonpathogenic bacteria on body surfaces but also in the environment during his attempts to keep bacterial culture media sterile and disprove the hypothesis of spontaneous generation of microbial life. Given the ubiquitous presence and high density of evidently nonpathogenic bacteria, he wondered whether they may play an important role in the host’s physiology (Pasteur 1885). Also, the Russian researcher Elie Metchnikoff (1845–1916) was intrigued by the possible beneficial effect of commensal bacteria and propagated the potential life-prolonging effect of lactic acid producing bacteria, inspiring later research activities on probiotics (Metchikoff 1908). Similarly, Albert Döderlein (1860–1941) promoted the protective function of the colonization of the vaginal mucosa with lactobacilli. Lactobacilli reduce the local pH, which protects from colonization by pathogenic microorganisms. Because both the microbial organisms and the host benefit from this mutualistic interaction, these commensal bacteria represent true symbionts. An important step in a better understanding of the functional role of these commensal bacteria in the intestinal tract was the generation of germfree animals (i.e., chickens or rodents bred in the absence of viable bacteria) in the first half of the 20th century. These experiments elegantly demonstrated the functional role of the microbiota. In the intestine, the microbiota synthesizes essential nutrient constituents such as vitamins, facilitates access to complex nutritional polysaccharides, and drives the development of the mucosal immune system. Also, the ability of the naturally occurring commensal bacteria to outcompete pathogens during the early phase of infection (named “colonization resistance”) was demonstrated (Spees et al. 2013). However, the characterization of the influence of the host and environment on the microbiota remained a problem. Many members of the microbiota are highly fastidious (i.e., require mostly undefined supplements for growth), making cultural characterization a difficult task. Only the development of affordable and high throughput sequencing techniques was able to overcome this technical limitation. PCR-based amplification and alignment of the variable 16S rDNA regions to a large database of 16S rDNA sequences from known bacteria displayed a more representative image of the overall bacterial composition. Metagenomics (i.e., sequencing of all DNA present) or transcriptomics (sequencing of all mRNA generated) further characterized the genetic equipment and bacterial gene expression, respectively, and allowed an indepth understanding of the diversity and complexity of the commensal bacterial communities and the host microbial interplay (Turnbaugh et al. 2007). The next step to also functionally characterize features of individual commensal bacteria (i.e., metabolic products, enzymes, etc.), however, will nevertheless require techniques to culture and genetically manipulate commensal bacteria and test their function in germfree animals or animals carrying a highly defined microbiota. Probiotic bacteria are defined by the World Health Organization (WHO) as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (WHO 2001). Most probiotic bacteria represent typical commensal bacteria and as such are principally able to fulfill beneficial functions and outcompete pathogenic microorganisms. Some probiotic strains were originally isolated from individuals that remained healthy under conditions of pathogen exposure. The E. coli Nissle strain, for example, was isolated in 1917 by Albert Nißle (1874–1965) from a soldier that remained healthy surrounded by fellows suffering from diarrhea (Nißle 1918). The problem starts with the prolonged in vitro culture and expansion of ILAR Journal, 2015, Vol. 56, No. 2 probiotic strains to produce well-controlled and distributable aliquots. During this in vitro culture, the bacteria lose their ability to effectively outcompete other pathogenic or commensal bacteria for nutrients and space and therefore fail to establish prolonged colonization after single administration. This explains the frequent administrations and high doses required to obtain a measurable effect. In contrast, fecal transplantation (i.e. the direct transfer of a complete “healthy” non-cultured enteric microbiota into a host suffering from C. difficile infection) has been shown to be highly efficacious (Kassam et al. 2013). Evidently, the problem associated with this particular scenario is the risk to transmit pathogenic microorganisms. | 161 bacterium Porphyromonas gingivalis was associated with systemic signs of inflammation and insulin resistance (Arimatsu et al. 2014). Thus, although pathobionts coexist in the absence of overt disease in the healthy, immunocompetent host and significantly support maturation of the immune system, their influence might, under certain circumstances, drive autoimmunity and promote the development of clinical disease. A better characterization of these bacteria, their prevalence in humans, and their functional influence on the host might provide new insight into the pathogenesis of chronic inflammatory disease and provide new strategies in the clinical management of patients. References Pathobionts: At the Edge Between Physiology and Pathology The better understanding of the enteric microbiota and mucosal immune system during the past decade taught us that the interrelationship between enteric bacteria and the mucosal immune system does not represent a passive coexistence. It is rather characterized by a constant, dynamic, and intimate interaction between the highly dynamic and competitive microbiota and the efficient mucosal immune system. What looks like peaceful coexistence represents a constant struggle and the result of a highly efficient innate and adaptive mucosal immune system, in combination with constant epithelial renewal and rapid tissue repair. Individual members of the microbiota express specific and sophisticated mechanisms that support colonization, such as energy production from mucus degradation or the ability to very closely interact with the surface epithelium. Of note, this close interaction is critical to maintain the epithelial barrier and contributes to the full maturation of the immune cell compartment. This constant challenge thus seems to educate the immune system to prepare for the interaction with pathogenic microorganisms (Abt et al. 2012). On the other side, the maturation and stimulation of individual immunological traits appear to promote tissue destruction in the event of autoimmune or autoaggressive diseases (Lee et al. 2011). Interestingly, studies that aim to identify individual bacterial members of the microbiota that have the ability to promote immune maturation or inflammation repeatedly identify similar species or groups of organisms. These microorganisms have been named pathobionts to describe their potential pathogenic influence on the host (Cerf-Bensussan and Garoriau-Routhiau 2010). A firm and testable definition of pathobionts has not been provided. In contrast to opportunistic pathogens, however, their influence on the host occurs indirectly via stimulation of the immune system. Good examples are segmented filamentous bacteria (SFBs) that have long been noted to exert a particularly potent stimulation on the host’s mucosal immune system (Gaboriau-Routhiau et al. 2009; Talham et al. 1999). This effect might be due to their very close interaction with the intestinal epithelium. More recently, SFBs were found to stimulate bacteria-specific TH17 T cells (Goto et al. 2014; Yang et al. 2014). TH17 T cells provide protection from bacterial enteric infection, but on the other hand drive inflammation in a mouse model of multiple sclerosis (Ivanov et al. 2009; Lee et al. 2011). Bilophila wadsworthia was identified to drive mucosal inflammation in mice deficient in IL-10 (Devkota et al. 2012), and bacteria of the Prevotellaceae and adherent invasive E. coli (AIEC) were both associated with gut inflammation in NACHT, LRR, and PYD domains containing protein (Nlrp)6 and toll-like receptor (Tlr)5 knockout mice, respectively (Chassaing et al. 2014; Elinav et al. 2011). Finally, colonization with the oral Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, Wherry EJ, Artis D. 2012. 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