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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
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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.
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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.
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