'Til death do us part': Coming to terms with symbiotic relationships

Stanford University, and VA Palo Alto Health Care System, Building 101, Room B4-185, 3801 Miranda Avenue 154T, Palo Alto, California 94304, USA.
Nature Reviews Microbiology (Impact Factor: 23.57). 11/2008; 6(10):721-4. DOI: 10.1038/nrmicro1990
Source: PubMed
Symbiotic interactions of microorganisms are widespread in nature, and support fundamentally important processes in diverse areas of biology that range from health and disease to ecology and the environment. Here, David Relman discusses the selection of articles in this Focus issue, which reflects the exciting advances in our understanding of intimate partnerships between organisms and their environments.


Available from: David A Relman, Aug 24, 2014
The term symbiosis was first used by Heinrich Anton de
, a German botanist, in 1879 to describe the relation-
ships between fungi and algae in the formation of lichens.
He referred to “the living together of two dissimilar organ-
isms, usually in intimate association, and usually to the
benefit of at least one of them.Today, our use of the term
encompasses beneficial, harmful and neutral relationships
that can change over time for any given set of partners.
Despite the importance of interactions, interplay,
codependence and synergy to the concept of symbiosis,
our efforts to study and understand symbioses tend to
emphasize the partners as individuals, rather than as
parts of one unit or system. There are three main reasons
for this. First, there is some logic to defining the parts or
components of the system after all, despite the value of
defining ecotypes, species boundaries do have practical
meaning. Second, there is a strong tendency in modern
Western science towards reductionism and ‘binning’ (for
example, the emphasis on genome assembly in metage-
nomic projects). And third, our methods encourage
emphasis on individuals; for example, in microbiology,
we are taught to ‘isolate’ organisms.
Thinking about symbiosis raises issues concerning the
boundaries of self and the definition of species, and leads
to discussions about, and tension between, holism
egoism (solipsism or individualism). Recent insights into
various symbioses, including human–microorganism
symbioses, reveal that the properties of a given system
cannot be determined or explained by the isolated features
of its component parts. In terms of our number and type
of cells alone, we are more microbial than we are human.
Loss of a sense of self-identity, delusions of self-identity
and experiences of ‘alien control’ are all said to be sug-
gestive of psychopathology
! Small wonder that recent
studies of symbiosis have engendered substantial interest
and attention.
The article by Werren et al. focuses on Wolbachia,
which are alphaproteobacteria in the order Rickettsiales.
Wolbachia are widespread among insects and other
arthropods, in which they act as reproductive parasites
to enhance the production of infected females, as well
as filarial nematodes, in which their effects are ben-
eficial. Wolbachia strains are genetically diverse and
are both maternally inherited and horizontally trans-
mitted within host populations. As suggested by the
oft-quoted verse of British mathematician Augustus
De Morgan
, “Great fleas have little fleas upon their
backs to bite ‘em, and little fleas have lesser fleas, and
so ad infinitum”, humans find themselves parasitized
by filarial nematodes, which themselves harbour bac-
terial endosymbionts of the genus Wolbachia, within
which bacteriophages are found.
Werren et al. review the mechanisms that underlie
the manipulation of hosts by Wolbachia, the genetic
basis for these capabilities, the impact of endosym-
biotic Wolbachia on host evolution and potential
strategies for exploiting these relationships for pest
and disease control. The presence of multiple phage
genes and genes with ankyrin-domain repeats dis-
tinguish parasitic and mutualistic Wolbachia strains.
It has been proposed that Wolbachia ankyrin-repeat
proteins, some of which are embedded in prophages
that are integrated in the Wolbachia genome, mediate
the reproductive effects through interactions with
host proteins. Although integrated copies of the tem-
perate phage WO-B might contribute to cytoplasmic
incompatibility, measurements and modelling of
lytic growth of this phage and resulting lysis of host
Wolbachia suggest that this phage might also repress
cytoplasmic incompatibility by reducing the number
of bacteria
. Wolbachia–insect relationships have been
portrayed as parasitic, but there is some evidence
to suggest that Wolbachia infection of Drosophila
spp. results in enhanced host resistance to fungal
. As a reflection of the intimacy of the
Wolbachia–host relationship, horizontal gene transfer
from the bacterium to the insect is now understood to
be common and widespread.
David A. Relman is Professor
of Microbiology, Immunology
and Medicine at Stanford
University, Infectious
Diseases Section, VA Palo
Alto Health Care System,
154T Building 101, Room
B4-185, 3801 Miranda
Avenue, Palo Alto,
California 94304, USA.
e-mail: relman@stanford.edu
Til death do us part: coming to terms
with symbiotic relationships
Symbiotic interactions of microorganisms are widespread in nature, and support
fundamentally important processes in diverse areas of biology that range from health and
disease to ecology and the environment. Here, David Relman discusses the selection of
articles in this Focus issue, which reflects the exciting advances in our understanding of
intimate partnerships between organisms and their environments.
755 An integrated approach
to classifying neuronal
Michele Migliore and
Gordon M. Shepherd
755 An integrated approach
to classifying neuronal
Michele Migliore and
Gordon M. Shepherd
755 Toll-like receptor
Michele Migliore and
Gordon M. Shepherd
755 The neural basis of
human moral cognition
Jorge Moll, Roland Zahn,
Ricardo de Oliveira-
Souza, Frank Krueger
and Jordan Grafman
opinion The road
to Toll
Jordan Grafman
Page 1
Capabilities of symbionts can expand the physi-
ological repertoire of a host, by allowing it to invade
novel metabolic and ecological niches
. This concept
is particularly well illustrated by marine animals that
inhabit oxic–anoxic boundary zones: their chemoau-
totrophic endosymbionts provide energy and nutrients
that enable host survival under conditions that would
otherwise be inhospitable. Dubilier and colleagues reveal
that chemosynthetic symbioses are ubiquitous and
dominate the biomass in marine environments, such as
deep-sea hydrothermal vents and cold seeps, and are also
common in shallow-water coastal sediments. In these
deep-sea environments, photosynthesis is impossible,
and instead, chemical energy that is derived from the
oxidation of inorganic compounds, such as sulphide, is
used to fix carbon dioxide and synthesize organic com-
pounds, or methane is used as both the energy and the
carbon source. The chemosynthetic symbionts benefit
from the protected niche within the host animal, which
enables access to food substrates.
The diversity of host marine animals that harbour
chemosynthetic symbionts, the large number of clades
of such symbionts and evidence for various independ-
ent associations and convergent co-evolution reveals that
symbiosis has been a successful evolutionary strategy in
the oceans. Chemosynthetic symbionts have been found
in hosts from seven phyla, including ciliates, molluscs,
nematodes, annelids (for example, tube-worms) and
arthropods (for example, shrimp), but according to
Dubilier and colleagues the picture of host and symbi-
ont diversity is woefully incomplete. Some animals are
partnered with multiple symbionts, which could allow
further expansion of host capabilities and benefit the
whole microbial consortium by allowing cross-feeding.
However, as Dubilier et al. point out, complex symbiont
communities present challenges for faithful transmission
to new hosts and avoidance of domination by certain
community members. Some symbionts spend time
apart from their animal hosts: free-living tube-worm
symbiont phylotypes have been found in vent sea-water
and in biofilms
, which raises the possibility of various
alternative lifestyles.
Symbiotic relationships between fungi and plant
roots are among the most ancient and prevalent on
the Earth. Parniske reviews the arbuscular mycorrhiza
(AM), in which fungi of the phylum Glomeromycota
grow along the surface of a plant root, penetrate the root
and form tree-like structures named arbuscules within
cortical cells. A membrane separates the fungal cell from
the plant cell cytoplasm, across which nutrient exchange
occurs. Arbuscules represent the active interface between
the symbiotic partners. In many AM, most of the fungal
hyphal network is present in the soil next to the plant
root. Through this network, water, phosphate, nitrogen
and other nutrients are absorbed and transported to the
plant root system. Interestingly, as with other forms of
symbiosis, including the Wolbachia–insect symbiosis,
the host becomes less susceptible to pathogen-associated
damage after the symbiotic partnership is formed. In
return, the AM fungi obtain carbohydrates from the
plant. This symbiosis has evolved into a dependency:
members of the phylum Glomeromycota only complete
their life cycle in the presence of a living photosynthetic
plant host. It is thought that ancestors of the AM fungi
engaged in similar symbiotic relationships with cyano-
bacteria before the existence of land plants. According to
this theory, the presence of these fungi and their ability
to establish AM may have enabled plants to exploit ter-
restrial habitats.
Mutual recognition and responses between the
symbiont and the host are characteristic of AM, and
suggest co-adaptation and codependence. Plants that
participate in AM symbioses release compounds that
induce pre-symbiotic behaviour in nearby potential
fungal partners. By contrast, AM fungi express and
release factors that induce pre-symbiotic behaviour in
the plant root; preparatory plant responses include the
formation of a subcellular structure known as the pre-
penetration apparatus, which guides subsequent growth
of the invading fungal hyphae. Parniske reviews ongo-
ing efforts to characterize the genetic and biochemical
features of this plant response. Interestingly, the host
seems to control the half-life of the arbuscule and
therefore serves the interests of the plant. Mutations
in an arbuscule-specific phosphate transporter result
in premature degradation of the arbuscule, suggest-
ing that the fate of the arbuscule is tied to its ability to
deliver phosphate. The short arbuscule half-life, rela-
tive to the lifetime of the plant cell, leads to constant
renewal and rewiring of the hyphal network for any
given plant, and competition between potential fungal
partners. As Parniske aptly predicts, the accelerating
pace of development of improved experimental tools
will allow deliberate manipulation of AM symbioses,
which could enhance crop yield and decrease fertilizer
requirements. Such advances are also likely to yield
additional insights into symbiotic mechanisms, the
identification of previously unrecognized symbiotic
partners and opportunities for exploitation.
In addition to the bias and ‘spin’ that each specific
experimental method necessarily imparts to all asso-
ciated measurements, the philosophy and perspective
of the human operator provides a framework from
which experimental strategies are devised and findings
viewed. Ruby examines the experimental ways in which
symbioses are studied, and offers a thoughtful discus-
sion on the complementary value of various models.
Current efforts to understand symbioses reflect a ten-
sion between the reductionist approaches of molecular
biologists and the holistic approaches of ecologists. For
obvious reasons, methods that are well-proven and fea-
sible are most widespread. As Ruby discusses, genetic
approaches in particular have yielded disproportion-
ately large pay-offs in the study of symbioses. But the
applicability of genetic analysis is confined primarily
to the study of individual, cultured members of simple
host–microorganism partnerships. Genetic manipula-
tion can provide valuable information about the neces-
sary and sufficient roles of specific genetic components
of an individual organism, in a context-specific manner.
Could genetic approaches be used to probe the func-
tions of an ecosystem in which community members
VOLUME 6 www.nature.com/reviews/micro
Page 2
are viewed as the individual components in a manner
that is analogous to genes? What might be the experi-
mental approach? Deleting or reducing the numbers of
a specific member of a complex community is currently
difficult or impossible (assuming that the community
cannot be reconstituted from its individual members
in a germ-free host). Traditional antimicrobials are too
broad for specific removal of a member, and lytic phages
provide a possible approach, but are only available for a
small number of cultured species. Nonetheless, targeted
small molecules and re-engineered phages are theoreti-
cal options. Conversely, probiotics or prebiotics might
be viewed as analogous to the genetic approaches of
ectopic gene expression or overexpression. However,
pure populations of all (or even specific) community
members are not available, and therefore we currently
lack reagents of sufficient breadth, depth and specificity
to apply this kind of approach to complex communi-
ties, although in theory these and other approaches are
possible. In the absence of a rigorous genetic approach
for studying the role of individual members in com-
plex symbiotic microbial communities, we must turn
to comparative analysis of large numbers of naturally
occurring variant communities with extensive environ-
mental metadata or simplified models and symbioses.
Ruby reminds us that different models or systems can
provide complementary information.
The specificity of exclusive beneficial symbiont
associations is determined by surface structures,
which are often involved in mediating contact and
physical recognition, as well as by microbial sensing
capabilities and adaptation to specific conditions
of the host, microbial strategies for countering host
defence mechanisms (including the use of type III
secretion systems) and microbial induction of host
responses that create a more suitable niche. These
are the same generic mechanisms and features that
characterize the virulence strategies of microbial
pathogens! Some of the specific features shared by
beneficial and parasitic microorganisms include
structures (such as pili, lipopolysaccharide, type III
secretion apparatuses and cilia), secreted molecules
(such as quorum signals and tracheal cytotoxin) and
regulatory systems (such as two-component sensor-
response regulator systems and AraC-family tran-
scriptional regulators). This might not be surprising,
given that exclusive mutualists and pathogens seek
out and inhabit privileged niches within their hosts,
whereas many skin and mucosal commensals in com-
plex communities are content to ‘hang together’ for
the benefit of community interactions.
The conservation of basic mechanisms and principles
among simple symbioses of microorganisms with hosts
from the whole tree of life and evidence of co-evolution
and co-adaptation of symbiotic partners provide the
background for recent, renewed interest in the more
complex communities that form symbiotic relationships
with vertebrate animals. Rapidly evolving molecular
techniques are available for increasingly deep and effi-
cient census taking and examination of the community-
wide metagenome. Although these vertebrate-associated
communities are in fact less diverse than the communi-
ties that surround these hosts in the external environ-
ment, intriguing features in the patterns of diversity
have been observed, including disproportionate diver-
sification at the level of species and strains, restricted
but conserved representation of phyla, extreme degrees
of unevenness in relative abundance and host specificity.
The factors that are responsible for these features are
the subject of interest and are debated in the Analysis
presented by Ley and colleagues. In particular, Ley et al.
address the nature of the differences between the 16S
ribosomal RNA-based structures of communities found
in humans and other vertebrates compared with those
found in the environment (free living). Their results are
provocative and fundamentally important.
Work published over the past several decades points
to the importance of ancestry, other aspects of history
and lifestyle (especially diet) in determining differ-
ences between the commensals found in individual
humans and in human sub-populations around the
globe. Most of the compelling data focus on patterns
of covariation among specific commensal species,
such as Helicobacter pylori, and their human hosts.
Community-wide comparative phylogenetic analyses
indicate significant inter-human variability, and even
greater variability is observed in different host animal
species, as well as coherence within each host
Diet seems to be a major source of variation among
communities of different host species, in addition to
host individuality and ancestry. Ley et al. point out
that the gut microbiota allowed mammals to secure
herbivorous niches, but that mammals found solutions
to the cellulose digestion problem, including different
strategies for prolonging food transit time to permit
the necessary types of fermentation.
Ley et al. find that the bacterial communities of the
vertebrate gut are distinct in their phylogenetic structure
compared with all other communities, especially free-
living communities from both saline and non-saline
environments, whereas non-gut human-associated com-
munities are intermediate between the two. To a lesser
degree, vertebrate-gut and invertebrate-gut communities
are also distinct. Interestingly, the membership of the
most dominant phyla in the vertebrate gut, Bacteroidetes
and Firmicutes, delineates vertebrate-gut communities
and free-living communities. Thus, it seems that the
uniqueness of the vertebrate-gut microbial community
reflects more than some known physical conditions. It is
tempting to speculate that the adaptive immune system
might be responsible
, but there are some caveats and
alternative explanations. It is possible that some combi-
nation of shared environmental factors of the vertebrate
gut, which are not well measured or recorded and could
be due to selective pressure of the gut microbiota on
the host, explain the distinct patterns of diversity. It is
also possible that structured technical features of this
immense data set create some confounding effects. Yet
the data do confirm previously reported biological and
ecological distinctions. It seems that we are well on our
way towards defining the nature of our ‘extended self’ in
the context of the larger ecosphere.
Page 3
Why focus on symbiosis now? McFall-Ngai points
out the role of new, improved or more widely available
tools in detecting and characterizing microbial diver-
sity. Microbiologists have moved beyond the limited
visualization that is derived from the microscope and
cultivation. We are now able to link sequence-based
phylogenetic information and metabolic activity mea-
surements at the level of the single cell
(FIG. 1). Yet we
are currently constrained by superficial sequence-based
pictures of complex communities, limited abilities to
infer function from sequences or the means to directly
measure community functions. The study of symbioses
has focused primarily on obvious partnerships. Because
experimental capability will always point us in certain
directions, we constantly need to question the complete-
ness of our picture about symbioses and ask questions
in different ways. Can we detect signals or other signs of
a conversation that are not easily attributed to the host
and known partners? Does the population structure of
a host species suggest selective forces that have not been
identified? Do physiological activities in a host bear the
features of symbioses? Ruby and McFall-Ngai encour-
age us to take a holistic view of the biological system
that encompasses a symbiotic partnership, including the
surrounding environment, and carefully explore code-
pendencies and interdependencies.
The papers in this Focus issue highlight the beauty in
biology. We are social creatures and seek to understand
our connections to other living entities. Symbioses are
the ultimate examples of success through collaboration
and the powerful benefits of intimate relationships.
1. de Bary, H. A. Die Erscheinung der Symbiose (Karl J. Trubner,
Strasburg, 1879).
2. Smuts, J. C. Holism and Evolution (MacMillan, London,1926).
3. Phillips, J. Psychopathology and the narrative self. Philos. Psychiatr.
Psychol. 10, 313–328 (2003).
4. De Morgan, A. A Budget of Paradoxes (Longmans, London, 1872).
5. Bordenstein, S. R., Marshall, M. L., Fry, A. J., Kim, U. &
Wernegreen, J. J. The tripartite associations between
bacteriophage, Wolbachia, and arthropods. PLoS Pathog. 2, e43
6. Panteleev, D. et al. The endosymbiotic bacterium Wolbachia
enhances the nonspecific resistance to insect pathogens and alters
behavior of Drosophila melanogaster. Genetika 43, 1277–1280
7. Stewart, F. J., Newton, I. L. & Cavanaugh, C. M. Chemosynthetic
endosymbioses: adaptations to oxic–anoxic interfaces. Trends
Microbiol. 13, 439–448 (2005).
8. Harmer, T. L. et al. Free-living tube worm endosymbionts found at
deep-sea vents. Appl. Environ. Microbiol. 74, 3895–3898 (2008).
9. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora.
Science 308, 1635–1638 (2005).
10. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial
ecology: human gut microbes associated with obesity. Nature 444,
1022–1023 (2006).
11. Dethlefsen, L., McFall-Ngai, M. & Relman, D. A. An ecological and
evolutionary perspective on human–microbe mutualism and
disease. Nature 449, 811–818 (2007).
12. Ley, R. et al. Evolution of mammals and their gut microbes. Science
320, 1647–1651 (2008).
13. McFall-Ngai, M. Adaptive immunity: care for the community. Nature
445, 153 (2007).
14. Behrens, S. et al. Linking microbial phylogeny to metabolic activity
at the single cell level using enhanced element labeling–catalyzed
reporter deposition fluorescence in situ hybridization (EL–FISH) and
NanoSIMS. Appl. Environ. Microbiol. 74, 3143–3150 (2008).
D.A.R. is supported by a National Institutes of Health Director’s Pioneer
Award and a Doris Duke Distinguished Clinical Scientist Award.
David A. Relman’s homepage: http://relman.stanford.edu
Figure 1 | Features of the AnabaenaRhizobium symbiosis. The symbiosis of this cyanobacterium–alphaproteobacte-
rium [Au: particular species?] consortium was revealed at the single-cell level by combining enhanced element
labelling–catalysed reporter deposition fluorescence in situ hybridization (FISH) and stable isotope imaging
(nanometre-scale secondary-ion mass spectrometry)
. This allowed metabolic interactions and molecular phylogeny to
be simultaneously determined. The cells were grown phototrophically in the presence of
C-bicarbonate and
, and
were shown to be
C abundant (a),
C enriched (b),
N enriched (c) and
F enriched (d). Lighter colours indicate
enrichment with the labelled element. The images show that carbon and nitrogen compounds were fixed by the
cyanobacterium and assimilated by Rhizobium epibionts that were attached to a heterocyst. Images courtesy of J.
Pett-Ridge, S. Behrens, T. Lösekann, P. Weber, W.-O. Ng, B. Stevenson, I. Hutcheon and A. Spormann, Lawrence Livermore
National Laboratory, California, USA, Stanford University, California, USA and VA Palo Alto Health Care System, California,
USA. [Au:please state which image came from whom and what institutions each person is from?] [Au:what does the
scale represent in image a?]
VOLUME 6 www.nature.com/reviews/micro
Page 4
  • Source
    • "A metaorganism is a collection of interacting organisms where the sum is not the same as the simple addition of the individual isolated parts (Relman, 2008; Webster, 2014). In fact, the gut, nasal, and lung microbiome all influence human phenotype (Redinbo, 2014). "
    Full-text · Article · Aug 2015 · Frontiers in Microbiology
  • Source
    • "Symbiotic partnerships between microorganisms and their hosts are critical for the health and function of biological systems ranging from individuals to ecosystems [1]. Most frequently, the basis for the symbiosis is the exchange of nutrients between partners. "
    [Show abstract] [Hide abstract] ABSTRACT: Coral reefs have evolved with a crucial symbiosis between photosynthetic dinoflagellates (genus Symbiodinium) and their cnidarian hosts (Scleractinians). Most coral larvae take up Symbiodinium from their environment; however, the earliest steps in this process have been elusive. Here we demonstrate that the disaccharide trehalose may be an important signal from the symbiont to potential larval hosts. Symbiodinium freshly isolated from Fungia scutaria corals constantly released trehalose (but not sucrose, maltose or glucose) into seawater, and released glycerol only in the presence of coral tissue. Spawning Fungia adults increased symbiont number in their immediate area by excreting pellets of Symbiodinium, and when these naturally discharged Symbiodinium were cultured, they also released trehalose. In Y-maze experiments, coral larvae demonstrated chemoattractant and feeding behaviors only towards a chamber with trehalose or glycerol. Concomitantly, coral larvae and adult tissue, but not symbionts, had significant trehalase enzymatic activities, suggesting the capacity to utilize trehalose. Trehalase activity was developmentally regulated in F. scutaria larvae, rising as the time for symbiont uptake occurs. Consistent with the enzymatic assays, gene finding demonstrated the presence of a trehalase enzyme in the genome of a related coral, Acropora digitifera, and a likely trehalase in the transcriptome of F. scutaria. Taken together, these data suggest that adult F. scutaria seed the reef with Symbiodinium during spawning and the exuded Symbiodinium release trehalose into the environment, which acts as a chemoattractant for F. scutaria larvae and as an initiator of feeding behavior- the first stages toward establishing the coral-Symbiodinium relationship. Because trehalose is a fixed carbon compound, this cue would accurately demonstrate to the cnidarian larvae the photosynthetic ability of the potential symbiont in the ambient environment. To our knowledge, this is the first report of a chemical cue attracting the motile coral larvae to the symbiont.
    Full-text · Article · Jan 2015 · PLoS ONE
  • Source
    • "Many of the documented relationships are complicated and understudied, and involve multipartite symbioses. Multipartite symbioses are the beneficial , harmful, and neutral relationships that can change over time among multiple organisms (adapted from Relman, 2008). The nematodes associated with bark beetles can be endoparasites (transported internally) or ectoparasites (transported externally on the body surface or transported in nematangia, specialized pocket-like structures on the jugal wing folds of the bark beetles (Cardoza et al., 2008). "
    [Show abstract] [Hide abstract] ABSTRACT: Symbiotic interactions are prevalent in all bark beetle communities. For many species, the ability to associate with multiple partners enables species to persist through fluctuations in climate, resources, predation, and partner availability. Symbionts, particularly mutualistic species associated with bark beetles, can increase bark beetle fitness by providing nutrition or protection, exhaust or detoxify tree defenses, enhance communication, and promote or discourage other organisms. Alternatively, symbiotic species that are antagonistic to bark beetles can negatively affect bark beetle fitness directly (e.g., pathogens of bark beetles) or indirectly (e.g., competing with mutualistic microbes within trees). Symbionts associated with bark beetles have also been used to better understand the basic field of science such as mutualism theory, evolutionary and ecology adaption (e.g., horizontal gene transfer), and drivers of population dynamics. In general, bark beetle symbionts are known to affect mechanisms of evolution, coadaptation and speciation, tree defenses, chemical communication, population dynamics, range expansion, and pest management. Symbionts can have multiple roles, and interactions can change as species and environments change. Thus, simply categorizing symbionts as mutualistic, antagonistic, commensal etc. can be misleading. The combinations of genomic, behavioral, and ecological research approaches that incorporate symbionts will help us better understand how symbionts affect bark beetles. These interactions and effects will be discussed in more detail in this chapter.
    Full-text · Chapter · Jan 2015
Show more