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Host Biology in Light of the Microbiome: Ten Principles of Holobionts and Hologenomes



Groundbreaking research on the universality and diversity of microorganisms is now challenging the life sciences to upgrade fundamental theories that once seemed untouchable. To fully appreciate the change that the field is now undergoing, one has to place the epochs and foundational principles of Darwin, Mendel, and the modern synthesis in light of the current advances that are enabling a new vision for the central importance of microbiology. Animals and plants are no longer heralded as autonomous entities but rather as biomolecular networks composed of the host plus its associated microbes, i.e., "holobionts." As such, their collective genomes forge a "hologenome," and models of animal and plant biology that do not account for these intergenomic associations are incomplete. Here, we integrate these concepts into historical and contemporary visions of biology and summarize a predictive and refutable framework for their evaluation. Specifically, we present ten principles that clarify and append what these concepts are and are not, explain how they both support and extend existing theory in the life sciences, and discuss their potential ramifications for the multifaceted approaches of zoology and botany. We anticipate that the conceptual and evidence-based foundation provided in this essay will serve as a roadmap for hypothesis-driven, experimentally validated research on holobionts and their hologenomes, thereby catalyzing the continued fusion of biology's subdisciplines. At a time when symbiotic microbes are recognized as fundamental to all aspects of animal and plant biology, the holobiont and hologenome concepts afford a holistic view of biological complexity that is consistent with the generally reductionist approaches of biology.
Host Biology in Light of the Microbiome: Ten
Principles of Holobionts and Hologenomes
Seth R. Bordenstein
*, Kevin R. Theis
1Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America,
2Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee,
United States of America, 3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan,
United States of America
Groundbreaking research on the universality and diversity of microorganisms is now chal-
lenging the life sciences to upgrade fundamental theories that once seemed untouchable.
To fully appreciate the change that the field is now undergoing, one has to place the epochs
and foundational principles of Darwin, Mendel, and the modern synthesis in light of the cur-
rent advances that are enabling a new vision for the central importance of microbiology.
Animals and plants are no longer heralded as autonomous entities but rather as biomolecu-
lar networks composed of the host plus its associated microbes, i.e., "holobionts." As such,
their collective genomes forge a "hologenome," and models of animal and plant biology
that do not account for these intergenomic associations are incomplete. Here, we integrate
these concepts into historical and contemporary visions of biology and summarize a predic-
tive and refutable framework for their evaluation. Specifically, we present ten principles
that clarify and append what these concepts are and are not, explain how they both
support and extend existing theory in the life sciences, and discuss their potential ramifica-
tions for the multifaceted approaches of zoology and botany. We anticipate that the concep-
tual and evidence-based foundation provided in this essay will serve as a roadmap for
hypothesis-driven, experimentally validated research on holobionts and their hologenomes,
thereby catalyzing the continued fusion of biology's subdisciplines. At a time when symbi-
otic microbes are recognized as fundamental to all aspects of animal and plant biology, the
holobiont and hologenome concepts afford a holistic view of biological complexity that is
consistent with the generally reductionist approaches of biology.
The time has come to replace the purely reductionist eyes-downmolecular perspective with
a new and genuinely holistic,eyes-up,view of the living world,one whose primary focus is on
evolution,emergence,and biology's innate complexity.Carl Woese (2004) [1]
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 1/23
Citation: Bordenstein SR, Theis KR (2015) Host
Biology in Light of the Microbiome: Ten Principles of
Holobionts and Hologenomes. PLoS Biol 13(8):
e1002226. doi:10.1371/journal.pbio.1002226
Academic Editor: Matthew K. Waldor, Harvard
Published: August 18, 2015
Copyright: © 2015 Bordenstein, Theis. This is an
open access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
Funding: This publication was made possible by
National Science Foundation (
grants DEB 1046149 and IOS 1456778 to SRB, and
IOS 0920505 to KRT. KRT was supported, in part, by
the BEACON Center for the Study of Evolution in
Action (National Science Foundation Cooperative
Agreement DBI 0939454). The funders had no role in
study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
At the end of the 19th century, the theory of evolution via natural selection was birthed with the
appreciation that individual animals and plants vary in their phenotypes and that competition at
the individual level drives gradual change in the frequencies of these phenotypes [2]. From this
early vantage point, fusing evolution with Mendelian genetics in the early 20th century was a
seamless transition in biology, namely one based on the framework that phenotypes in the
individual animal and plant are encoded by the nuclear genome under the laws of Mendelian
inheritance [35]. In the mid-20th century, the modern synthesis grounded the nucleocentric
foundation of zoology and botany in three areas: (1) the nuclear mutability and recombinogenic
nature of organisms, (2) the sorting of this genetic variation by natural selection, and (3) the
observations that macroevolutionary processes such as the origin of species can be explained in a
manner that aligns with Mendelian genetics and microevolutionary mechanisms [6].
The foundation of the modern synthesis remains as scientifically sound today as when it
was conceived. However, it is critical to recognize that microbiology was largely divorced from
these early epochs in the life sciences. The modern synthesis commenced at a time when the
germ theory of disease dictated the prevailing wisdom on microbes, and the molecular tools
used to understand the microbial world and its influence were inferior to those available now
[711]. The theories of gradual evolution and the modern synthesis were thus forged during
periods of eukaryocentricism and nucleocentrism that did not appreciate the centrality of
microbiology in zoology and botany because of limitations in perspective and technology.
Today, there is an unmistakable transformation happening in the way that life is compre-
hended [1216], and it is as significant for many biologists as the modern synthesis. Animals
and plants are no longer viewed as autonomous entities, but rather as "holobionts" [1721],
composed of the host plus all of its symbiotic microbes (definitions in Box 1). The term "holo-
biont" traces back to Lynn Margulis and refers to symbiotic associations throughout a signifi-
cant portion of an organism's lifetime, with the prefix holo- derived from the Greek word
holos, meaning whole or entire. Amid the flourishing of host microbiome studies, holobiont is
now generally used to mean every macrobe and its numerous microbial associates [19,22], and
the term importantly fills the gap in what to call such assemblages. Symbiotic microbes are fun-
damental to nearly every aspect of host form, function, and fitness, including in traits that once
seemed intangible to microbiology: behavior [2326], sociality [2730], and the origin of spe-
cies [31]. The conviction for a central role of microbiology in the life sciences has been growing
exponentially, and microbial symbiosis is advancing from a subdiscipline to a central branch of
knowledge in the life sciences [14,3235].
This revelation brings forth several newly appreciated facets of the life sciences, including
the testable derivation that the nuclear genome, organelles, and microbiome of holobionts
comprise a hologenome [3537]. The hologenome concept is a holistic view of genetics in
which animals and plants are polygenomic entities. Thus, variation in the hologenome can lead
to variation in phenotypes upon which natural selection or genetic drift can operate. While
there is a rich literature on coevolutionary genomics of binary hostmicrobe interactions, there
have been few systematic attempts to align the true complexity of the total microbiome with
the modern synthesis in a way that integrates these disparate fields [3840].
The object of this essay is to make the holobiont and hologenome concepts widely known.
We clarify and append what they are and are not, explain how they are both consistent with
and extend existing theory in ecology and evolutionary biology, and provide a predictive
framework for evaluating them. Our goal is to provide the main conceptual foundation for
future hypothesis-driven research that unifies perceived divisions among subdisciplines of biol-
ogy (e.g., zoology, botany, and microbiology) and advances the postmodern synthesis that we
are now experiencing [41,42]. We distill this topic with evidence-based reasoning to present
the ten principles of holobionts and hologenomes (summarized in Box 1).
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 2/23
Box 1. The Ten Principles of Holobionts and Their Hologenomes
I. Holobionts and hologenomes are units of biological organization
Complex multicellular eukaryotes are not and have never been autonomous organ-
isms, but rather are biological units organized from numerous microbial symbionts
and their genomes.
Biomolecular associations between host and microbiota are more conceptually simi-
lar to an intergenomic, genotype x genotype interaction than a genotype x environ-
ment interaction.
II. Holobionts and hologenomes are not organ systems, superorganisms, or
As holobionts are complex assemblages of organisms consisting of diverse microbial
genomes, biology should draw a clear distinction between holobionts/hologenomes
and other terms that were not intended to describe hostsymbiont associations.
Organ systems and superorganisms are biological entities comprised of one orga-
nism's genome; metagenome means "after" or "beyond" the genome, does not intrin-
sically imply organismality, and obviates the fundamentals of symbiosis in the
III. The hologenome is a comprehensive gene system
The hologenome consists of the nuclear genome, organelles, and microbiome.
Beneficial, deleterious, and neutral mutations in any of these genomic subunits
underlie hologenomic variation.
IV. The hologenome concept reboots elements of Lamarckian evolution
Although Lamarck never imagined microbes in his theory, applying the tenets to
holobionts rebirths some major aspects of Lamarckism.
The nuclear genome is inherited mainly within a Mendelian framework, but the
microbiome is originally acquired from the environment and may become inherited.
Hostmicrobe associations can forge disequilibria via parental transfer or stable envi-
ronmental transmission.
V. Hologenomic variation integrates all mechanisms of mutation
Every hologenome is a multiple mutant, meaning that there is variation across many
individual genomes spanning the nucleus, organelles, and microbiome.
Base pair mutation, horizontal gene transfer, recombination, gene loss and duplica-
tion, and microbial loss and amplification are all sources of variation.
VI. Hologenomic evolution is most easily understood by equating a gene in the nuclear
genome to a microbe in the microbiome
Evolution for both genes and symbionts is fundamentally a change in population fre-
quency over successive generations, i.e., the fraction of holobionts carrying that par-
ticular nuclear allele or microbe.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 3/23
Covariance of hosts and microbes in a holobiont population (i.e., community genet-
ics) follows a theoretical continuum directly to coinheritance of gene combinations
within a genome (i.e., population genetics).
A grand unified theory of evolutionary and ecological genetics deserves priority
VII. The hologenome concept fits squarely into genetics and accommodates multilevel
selection theory
Multilevel selection theory asserts that selection operates across multiple levels of
genetic variation with phenotypic effects, from genes to hologenomes and beyond.
Holobionts are exclusive to hosts and their associated microbiota; different holo-
bionts, such as a pollinator and a flower, interact with each other under standard eco-
logical principles.
VIII. The hologenome is shaped by selection and neutrality
Natural selection can work to remove deleterious nuclear mutations or microbes
while spreading advantageous nuclear mutations or microbes; in the absence of selec-
tion, the neutral spread of hologenomic variation through populations is an inher-
ently stochastic process.
Mixed ecological models of stochastic and deterministic community assembly likely
reflect natural systems, and partitioning the microbiota into stochastic versus deter-
ministic subunits will be an important future goal of the field.
IX. Hologenomic speciation blends genetics and symbiosis
The Biological Species Concept was never intended to be exclusive of symbiosis,
though history largely divorced the two and created unnecessary controversy.
Antibiotic or axenic experiments in speciation studies must be a routine, if not oblig-
atory, set of experiments in genetic analyses of speciation for an all-inclusive under-
standing of the origin of species.
X. Holobionts and their hologenomes do not change the rules of evolutionary biology
Although the concepts redefine that which constitutes an individual animal or plant,
they are not a fundamental rewriting of Darwin's and Wallace's theory of evolution-
ary biology.
Simply put, if the microbiome is a major, if not dominant, component of the DNA of
a holobiont, then microbiome variation can quite naturally lead to new adaptations
and speciation, just like variation in nuclear genes.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 4/23
I. Holobionts and Hologenomes Are Units of Biological
Hostmicrobial symbioses are familiar to most biologists [14,32], yet detailed examples are
often limited to very defined, often pairwise, associations [14,35,43]. The holobiont and holo-
genome concepts upgrade this conventional vision to encompass the vast ecological and geno-
mic complexity of a host and its total microbiota (see Box 2). These concepts assert that
macrobes are not and have never been autonomous individuals, but rather are organized bio-
logical units, i.e., holobionts, composed of hundreds to thousands of individual organisms
[32,33,35,44]. Host-associated microbes have an overwhelmingly evident influence on the
physiology, anatomy, behavior, reproduction, and fitness of holobionts [14,2325,4549]. The
holobiont and hologenome concepts therefore raise the discussion of individuality [33] and
organismality [50] beyond its historical perspective to a level that challenges and extends cur-
rent thinking. Although there has been widespread discussion and applied success of the eco-
logical theories underlying hostmicrobial interactions [5155], the specific evolutionary
principles governing these multifarious interactions remain fundamentally unexplored.
Box 2. Terminology
Coevolution: reciprocal evolution of interacting species
Commensalism: a relationship benefiting one party while the other is unaffected
Mutualism: a relationship benefiting both parties
Parasitism: a relationship benefiting one party to the others detriment
Symbiosis: two or more species living closely together in a long-term relationship
Macrobe: a eukaryotic host, most being visible by eye
Microbiota: the microbes in or on a host, including bacteria, archaea, viruses, protists,
and fungi
Microbiome: the complete genetic content of the microbiota
Holobiont: a unit of biological organization composed of a host and its microbiota
Hologenome: the complete genetic content of the host genome, its organellesgenomes,
and its microbiome
Microbe flow: the exchange of microbes between holobionts
Phylosymbiosis: microbial community relationships changing in parallel with the host
nuclear phylogeny
Hologenome Concept of Evolution
The hologenome concept of evolution was first explicitly introduced in 1994 during a
symposium lecture by Richard Jefferson [56], and it was independently derived in 2007
by Eugene Rosenberg and Ilana Zilber-Rosenberg [57]. It posits that hosts and their
microbiota are emergent individuals, or holobionts, that exhibit synergistic phenotypes
that are subject to evolutionary forces [3537]. Via fidelity of transmission from parents
to offspring or stable acquisition of the microbiome from the environment, covariance
between the host and microbiota can be established and maintained. Consequently, as
with phenotypes encoded by nuclear genomes, phenotypes encoded by beneficial, delete-
rious, and neutral microbes in the microbiome are subject to selection and drift within
holobiont populations. Genetic variation among hologenomes can arise through changes
to host genomes as well as through changes to the genomes of constituent symbiotic
microbes [3537,58]. The microbiomes, and thus their encoded phenotypes, can change
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 5/23
A default position in modeling host and symbiont associations would be to define them as
genotype-by-environment (G host x E microbiota) interactions. Another simplistic vision is
that the microbiota is a phenotype encoded by the host genome [44,5963]. These tenets are
useful to a degree but merit a reexamination. Ample evidence shows that members of the
microbiota are not subjected unilaterally to the host's intent but instead colonize specific hosts
over other biotic or abiotic habitats [6466]. Thus, microbes are not solely an E that succumbs
to the control of a G host. They are an evolving G themselves, with their own genomes, tran-
scriptomes, metabolomes, etc. If we took this host-centric view to its extreme opposite, then we
end with the equally wrong conclusion that hosts are just an environment for microbes. More-
over, a framework for this biological organization already exists in which the genome and
microbiome forge networks of G x G interactions that can in turn interact with E to potentially
forge multispecific geographic mosaics of coevolution [67,68]. That is, these symbioses are best
viewed as neither G x E nor G x G, but rather G x G x E. The key point here is that the biomo-
lecular associations between host and microbiota are more conceptually similar to an interge-
nomic G x G network or epistasis than any alternative vision that is incapable of dealing with
the nonlinear intricacies of symbioses.
Intergenomic epistasis is when genes of one species interact with specific genes in another.
The interactions, and sometimes intertwining, of genomes and gene products between the host
and microbiota can carry out many functions of a hologenome, such as the synthesis of essen-
tial amino acids [69], chemosynthesis [70], or metabolite production [71]. These symbiotic
combinations can be transmitted across holobiont generations and are critical for the mainte-
nance of mutualisms, homeostasis, and potential coevolutionary outcomes, such as those
exemplified between the nuclear genome and mitochondria [72]. An important and appealing
aspect of intergenomic epistasis is that it unifies, rather than separates, the genetics of popula-
tions and communities [73]. For instance, there is a conceptual continuum between intrage-
nomic (or cytonuclear) interactions and intergenomic interactions between the host genome
and the microbiome. The novelty and future challenge is identifying the number and types of
intergenomic interactions that are ecologically and evolutionarily relevant (Box 3). This will
likely require new theoretical and statistical models, e.g., from complex systems science [74
76], that may ultimately have as much bearing on contemporary and future evolutionary the-
ory as the models underlying the modern synthesis [3,4].
The debatable and testable issue of the hologenome is whether nuclear genes and microbes
are coinherited to a degree that evolution can operate on their interaction. Coinheritance of
hologenomic interactions can occur either by vertical transmission via internal (e.g., transovar-
ial) or external (e.g., breast milk) transfer mechanisms or through stable symbioses acquired
through differences in the relative abundances of specific symbiotic microbes, the modi-
fication of the genomes of existing resident microbes, or the incorporation of new micro-
bial symbionts into holobionts, which can occur even within the reproductive lifetime of
hosts [58]. Importantly, genetic variation in the microbiome vastly exceeds that in the
host genome and accumulates much more rapidly than variation in host genomes.
Therefore, given that genetic variation is the raw material upon which evolution ulti-
mately acts, microbial sources of hologenomic variation are potential targets of evolu-
tion, and, despite its inherent complexity, biologists must consider the incorporation of
the microbiome in the overall study of evolution.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 6/23
Box 3. Long-Term Inquiries of the Hologenome
Hologenomic homeostasis
Although microbiota are host specific [7784], they are often highly diverse. The same
can be said of nuclear genetic variation across the genome. Thus, an important area of
scholarship will be to determine the homeostatic mechanisms within hologenomes that
maintain such diverse but specific hostmicrobe assemblies. On the surface, the chal-
lenge for selection on holobiont traits seems extraordinary given the multitude of
microbes that can potentially colonize hosts. It is presumably accomplished through the
hosts immune system and through competitive exclusion and antimicrobial production
by members of the microbiota itself [14,35,80,8587]. This area of inquiry, which is
approachable from many disciplines, is among the primary frontiers for biologists to
Hologenomic breadth
It is important that we increase the comparative breadth and depth of study systems in
hostmicrobial evolution. Much of the novelty of the hologenome concept lies in its
emphasis on the integrative roles of hosts and their diverse microbiota in holobiont fit-
ness. Well-defined hostmicrobial systems, in which one or two microbial partners
exhibit great effect on their hosts, are tremendously valuable in elucidating the proximate
aspects of symbiosis given their general tractability and ease of manipulation. However,
if the hologenome concept, or any other allied theory, is robust, it must be evaluated
using systems in which hosts are populated by complex microbial communities as well.
While continuing to capitalize on well-defined systems, we should additionally encour-
age studies assessing the routes and fidelity of transgenerational hostmicrobial associa-
tion, the strength of functional integration, and the fitness consequences of
comprehensive microbiome variation in complex hostmicrobial systems. This will
require concomitant advances in multi-omics analytical techniques and complex systems
modeling, thereby catalyzing transdisciplinary discoveries in the process.
Population and community genetics
To determine if evolutionary changes at the hologenomic level are indeed concordant
with evolutionary changes at the nuclear level, there are a handful of critical questions
that must be answered across a broad swath of animal and plant clades. How stable is the
interspecific covariance, or correlation, between a host and its microbiota and their inter-
acting genes? How consistent is microbial transmission from one holobiont generation
to the next? Is genetic disequilibria between host and microbial genes strong enough for
evolution to drive covariance and changes in their frequencies over multiple holobiont
generations? How much intergenomic epistasis occurs in the hologenome such that one
nuclear allele's effect on a trait depends on the state of another microbial allele? Although
these inquiries are formidable, they are unquestionably within the realm of population
and community genetics approaches.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 7/23
faithfully from the environment. We discuss these crucial transmission mechanisms further in
principle IV.
II. Holobionts and Hologenomes Are Not Organ Systems,
Superorganisms, or Metagenomes
There appears to be a considerable number of misplaced characterizations and colloquialisms
used to refer to host-microbiota symbioses, and these misnomers can potentially act as
impasses to new advances. In this section, we adapt and append the lucid clarifications previ-
ously noted in The Hologenome Concept [35]. First, neither the holobiont nor the microbiota
should be labeled as an organ system or organ, despite frequent uses in the popular media and
scientific literature [8890]. An organ or organ system is strictly composed of cells from the
same genome that perform one or more specific functions. In contrast, the microbiota is a mul-
tispecies consortia of cells with many genomes that can contribute to multiple functions
throughout the body. Second, the holobiont is not a superorganism. This term is exclusively
used in the context of an assembly of multiple individuals from the same species, such as in col-
ony-forming ants, wasps, bees, and termites [91,92]. The holobiont is instead composed of
multiple domains of life, as well as viruses. Finally, the term metagenome is not equivalent to
hologenome. Metagenome refers to the sum of genetic information from an environmental
sample and was first used in this context to describe the collective genomes of soil microbes
[93]. Meta means afteror beyondin Greek. Equating an environmental metagenome to a
host's hologenome obviates the fundamentals of symbiosis in the holobiont. Consider the
thought exercise of removing the bacterial metagenome from soil and hosts. In nature, soil
would persist, but the host would not. While we understand that metagenomics will not be
restrained by any one definition, we and others also recognize the salience of clear definitions
in this nascent field, particularly ones that distinguish the metagenome "beyond" the soil from
the hologenome that encompasses the "whole" collection of genomes in a holobiont. To sum-
marize, biology can and should draw a clear distinction between the hologenome and other
terms that were never intended to describe host-symbiont associations, including organ, super-
organism, and metagenome.
III. The Hologenome Is a Comprehensive Gene System
The geneticist Sewall Wright stated that "selection, whether in mortality, mating or fecundity,
applies to the organism as a whole and thus to the effects of the entire gene system rather than
to single genes" [94]. In other words, selection operates on phenotypes encoded by the orga-
nism's underlying gene system. In this light, the hologenome is the entire gene system of the
holobiont, including elements of the nuclear genome, organelles, and microbiome that increase
fitness, decrease fitness, or do not affect fitness at all. Within these genomic subunits, muta-
tions are constantly arising at their own finite rates. In the nuclear genome, selection fixes
favorable variants and purges the deleterious ones, or "selfish" genes can spread to enhance
their own fitness. In the microbiome, selection favors the spread of beneficial microbes
involved in nutrition, defense, or reproduction [20], while pathogenic microbes are either
purged by holobiont selection or the pathogens deploy adaptations such as reproductive distor-
tions to enhance their selfish transmission to the next generation [95,96]. Moreover, neutral
mutations in the nuclear genome can drift to fixation or extinction across generations, as do
microbes without any fitness consequences. Thus, nuclear genes with adaptive, deleterious,
and neutral mutations that change their frequencies in a holobiont population are generally
analogous to beneficial, parasitic, or neutral microbes that also change their frequencies in a
holobiont population. How these entities change their frequencies can of course vary with
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 8/23
transmission mode, and we address similarities and differences below. Also, classifying
microbes at just one end of the symbiotic spectrum pigeonholes the reality that microbial
symbioses can be pleiotropic or context-dependent. These varied evolutionary forces can suffi-
ciently explain why animal and plant holobionts harbor species-specific microbial communi-
ties that are segregated into their own limited supply of hologenomic variability [31,35].
If hologenomic variation underscores fitness differences, then manipulating the total micro-
biota will alter host fitness, and therefore germ-free, gnotobiotic, and transbiotic (i.e., popu-
lated by an atypical microbiota) hosts will exhibit reduced fitness compared to wild-type and
conventionalized hosts. Such predictions need assessment among a broad phylogenetic range
of hosts, but ample evidence already exists. For example, in hemipteran insects, germ-free and
interspecific gut microbiota cause a decrease in survivorship and delayed development in com-
parison to control or conventionalized species [97,98], and mice with human gut microbiota
have a global immunodeficiency including less T cell proliferation and increased susceptibility
to enteric infection [99]. Moreover, interspecific hybridizations can lead to a breakdown in
hologenomic interactions within species [100,101].
IV. The Hologenome Concept Reboots Elements of Lamarckian
The nuclear genome is inherited mainly within a Mendelian framework, and the microbiome
is presumed to be mostly acquired from the environment or inherited uniparentally [102106].
Whether these different transmission modes can be unified into a coherent evolutionary theory
depends in part on whether dynamics between host and symbiont genes in the hologenome
(e.g., intergenomic epistasis and coinheritance) are similar to dynamics between genes in the
same nuclear genome [107]. In considering how genome-microbiome disequilibria, i.e., statis-
tical associations of covariance, among hologenomes could arise, let's begin with the simplistic
assumption that hologenomic change commences with Lamarck's fundamental evolutionary
theory [58], generally defined as inheritance of acquired characteristics. Although evolution
has had a long and tenuous history with Lamarckism [108,109], it is time to integrate it to a
degree alongside Darwinism in light of modern advancements. Consider the cases of mito-
chondria and insect endosymbionts as textbook examples of bacteria that were once acquired
from the environment during an organism's lifetime but now are vertically inherited over gen-
erations. It follows that the principal tenets of Lamarckism are operational in the origins of inti-
mate symbioses: holobionts can gain symbiotic traits through environmental acquisition of
microbes, and holobionts can potentially pass these traits on to the next generation via vertical
transmission. Although Lamarck never imagined microbes in his theory, applying the tenets to
holobionts rebirths Lamarckism, as some have duly noted [35,58,110].
Once new host-microbe associations are established, they can be maintained in disequilibria
via vertical or stable environmental transmission [35,111]. Persuasive evidence is thoroughly
reviewed elsewhere [35,105,106]. The more generations for which hologenomic disequilibrium
is maintained, and the more significant the variantsfitness effects, the more likely it is that
selection will operate on them to drive changes in their frequencies. While some microbes are
vertically transmitted and thus fit seamlessly into current population genetic theory, other
microbes are generally not assumed to be vertically transmitted sensu strictu from one genera-
tion to the next, though we need to delve much deeper into these areas. Some fraction of the
microbiota may also be acquired in a stable manner from the environment each generation,
while the other fraction may be more permissive across holobiont generations. It is also impor-
tant to note that vertically transmitted microbes do not have to remain present through a holo-
biont's lifetime nor comprise a major fraction of the microbiota to play out their evolutionary
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 9/23
role. For instance, they may come and go across a lifetime or body site to be vertically transmit-
ted and may also shape critical microbial successions that occur during development. Lastly,
although the relationships between hosts and microbial symbionts could be fragile when there
is deviation from vertical transmission [112], such concerns are no more or less valid than
those for gene-gene interactions within a nuclear genome that can be broken up by recombina-
tion [107]. A critical point is that covariance of genes within and between genomes is funda-
mentally similar, and associations can be reinforced by population structuring and symbiont-
host epistasis.
If portions of the microbiome are transmitted with fidelity across holobiont generations or
stably acquired from the environment, we expect at least three types of evolutionary outcomes.
First, offspringsmicrobiota and/or microbiomes should be more similar to those of the
respective organs of their parents at a similar age than to those of other unrelated adults in the
population. Second, for inherited microbes, experimentally tagged (e.g., genetically labeled
[113,114]) microbes in adult organs should appear in the respective organs of their offspring at
a similar age more often than their offspringspeers. Third, host immune systems, morphologi-
cal structures, and/or behavioral repertoires should include mechanisms to promote the effec-
tive transmission of beneficial microbes from parents to offspring. Some illustrative model
systems are already well developed [115117]. Broadly evaluating immunological and behav-
ioral mechanisms for transmission of microbial partners across holobiont generations should
be a future research priority [23,118].
V. Hologenomic Variation Integrates All Mechanisms of Mutation
Every hologenome is a multiple mutant, meaning that there is variation across many individual
genomes spanning the nucleus, organelles, and microbiome. Without this variation, there can
of course be no evolutionary change in a population of holobionts. Random nucleotide changes
are the most obvious source of variation in the hologenome, followed by recombination within
and between chromosomes, horizontal gene transfer within and between holobionts, and
duplications/losses of gene regions. These changes can occur in any portion of the hologenome,
so there is potential for immense genetic diversity across the entire gene network.
Features of the microbiome such as fluctuations in microbial abundances within holobionts
are also sources of variation [35]. Indeed, they are akin to gene duplication events driving
changes in a nuclear gene's abundance. For instance, the same microbial lineage that occurs at
different relative abundances in two otherwise genetically identical holobionts could have dif-
ferent functional consequences that selection can act upon. The most obvious illustration is
when a microbe operates as a commensal when rare but as a pathogen when relatively abun-
dant [119122]. Here, the fitness of the holobiont can change dramatically. Moreover, since no
two holobionts develop in exactly duplicate environments, there can be continuous establish-
ment and evolution of holobiont-specific microbes at different relative abundances that may
drive evolutionary change.
Any analysis of holobionts and their hologenomes must also account for the multiple gener-
ations that microbes experience within the host's single generation. These differences in gener-
ation time are not fatal to the concepts, but they likely affect evolutionary outcomes of the
symbiosis. For example, the propensity for symbiosis to drive molecular complexity is now a
foundational premise [123], such as in obligate symbionts (with their own generation times)
supplementing the missing nutrients in the inadequate diets of thousands of holobiont species
spanning cicadas, bedbugs, and aphids [124]. In cicadas, the case is so extreme that genomic
and cellular complexity has increased even in the absence of new symbionts via symbiotic het-
eroplasmy [125]. Notably, even nuclear genomes of mammalian species including humans,
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 10 / 23
nonhuman primates, rodents, and elephants increase in complexity via microbial symbiosis
and independent gene transfer events from virus-derived elements [126]. Similarly in Drosoph-
ila melanogaster, viral sequences are endogenized adjacent to retrotransposon DNA, and when
transcribed, the RNA is altered by the RNA interference (RNAi) machinery and used as part of
the immune system to combat lethal viral infections [127].
VI. Hologenomic Evolution Is Most Easily Understood by Equating
a Gene in the Nuclear Genome to a Microbe in the Microbiome
Is the hologenome concept refutable? We believe it is and suggest the implementation of the
following litmus test: are evolutionary changes at the hologenomic level fundamentally in con-
flict with evolutionary changes at the nuclear gene level? Or to put it more simply, how is the
evolution of a nuclear gene any different than the evolution of a microbial symbiont in a holo-
biont population? While the strength of selection, levels of genetic variation, and transmission
strategies differ between nuclear genes and microbes, they also vary among different types of
genes in the same nuclear genome. The important point is that evolution for both genes and
symbionts is fundamentally a change in frequency over successive generations, i.e., the fraction
of holobionts carrying that particular nuclear allele or microbe. Therefore, there is no intellec-
tual disparity in contemplating the spread of a nuclear gene as akin to the spread of a microbe
through a holobiont population. Hologenomic evolution occurs when one whole animal or
plant, i.e., holobiont, leaves a different number of reproducing progeny than another, thereby
changing the frequencies of their associated genes in the next generation.
Covariance of hosts and microbes (i.e., community genetics) in a holobiont population is
important to this discussion as it follows a theoretical continuum directly to coinheritance of
gene combinations within a genome (i.e., population genetics) [73]. The parameter Θis useful
here as it is the degree of coinheritance of polygenic or hologenomic combinations. When Θis
low because of recombination of nuclear genes or random horizontal transmission between
hosts and microbes, there is little heritability and therefore selection will have little effect on the
combinations. When Θis high because of linkage disequilibria in the same genome or covari-
ance of hosts and microbes, then evolution will operate on the combinations in a manner simi-
lar to as if they were single genes. Intermediate levels of Θare likely to reflect natural systems
and the limits of inference.
Historically, models of evolution have not properly accounted for genetically complex
traits, even in the nuclear genome, because multiple genetic signals underlying phenotypes are
more diffuse [128]. Yet, high-throughput sequencing techniques have enabled genome-wide
association studies that map many small-effect alleles associated with phenotypic variations.
Similarly in the microbial sciences, it is becoming increasingly appreciated that animal and
plant holobionts are multispecies modules in which polygenic and complex systems theories
of phenotypic variation are needed to identify signals of hologenomic functions and evolution-
ary events. These questions and ideas are an important priority for future research and
emphasize the theoretical and genetic continuum between polygenic traits in the nuclear
genome and hostmicrobe interactions in the hologenome [107]. Thus, holistic theoretical and
experimental models deserve priority attention in which the genes and organisms underlying
hologenomic traits vary in their inheritance mode, heritability for the traits, and linkage dise-
quilibria. Moreover, a hologenomic framework may lead to resolving part of the missing herita-
bility problem for complex traits that are attributable to both the nuclear genome and the
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 11 / 23
VII. The Hologenome Concept Fits Squarely into Genetics and
Accommodates Multilevel Selection Theory
Multilevel selection theory asserts that selection operates across multiple levels of genetic varia-
tion with phenotypic effects [129], i.e., genes, chromosomes, genomes, cytonuclear interac-
tions, groups, symbionts, communities, species, etc. Evolution as a change in allelic frequencies
undoubtedly applies as all these entities have mutations that could lead to phenotypic variation.
Under a framework in which evolutionary individuality includes hologenomic networks, fit-
ness differences can arise not only from nuclear or cytoplasmic mutations, but also from host
microbe associations. Therefore, both evolutionary and ecosystem adaptive change are relevant
to the study of fitness. Indeed, the proposal of an "eco-evolutionary" framework, the interplay
between evolutionary and ecological dynamics [130134], is worthy of serious attention as
biology evolves to handle the combinatorial nature of hologenomic units of evolution.
A limitation of scaling the so-called "individual" unit of evolution to a holobiont is that biolo-
gists may ask: where does the multiorganismal assembly of the holobiont end? Does it proceed ad
infinitum? Interactions between symbiotic microbes and their hosts make sense, but should inter-
acting holobionts themselves be considered part of the same inclusive holobiont? For instance, do
the genomes of an insect pollinator and flower constitute a hologenome? The answer here is not
complex. Holobionts and their hologenomes are exclusive to the hosts and their associated micro-
biota. Different holobionts, such as the aforementioned pollinator and flower, clearly interact, but
these interactions are not new to biology, as they form the basis for all past and present ecological
investigations [135,136]. They are simply holobionts themselves interacting with each other.
VIII. The Hologenome Is Shaped by Selection and Neutrality
Natural selection acts on holobiont phenotypes encoded by any potential source of variation in
the hologenome. As previously introduced in principle III, selection can work to remove dele-
terious nuclear mutations or microbes while spreading advantageous nuclear mutations or
microbes. In the absence of selection or when variants are selectively equivalent, the neutral
spread of hologenomic variation through populations is an inherently stochastic process. For
instance, many microbes could replace each other over holobiont generations because of
redundant functions [137]. This may explain why animals generally have an evident core
microbiota at higher taxonomic levels, i.e., phylum, but not at lower levels, i.e., species [85,138
140]. Neutral evolution in the nuclear genome can also occur when nuclear allelic variants with
the same function replace each other. It is crucial to remember that neutrality does not neces-
sarily mean that variants are functionless. Functional constraints and therefore negative selec-
tion are consistent with the neutral theory. Thus, both natural selection and neutral evolution
can be seen as part of the spectrum of evolutionary possibilities operating on the hologenome.
Beyond this evolutionary framework, various ecological theories of community assembly
are also relevant for determining whether the microbiome is constructed stochastically or
deterministically [52,141143]. Neutral theories of ecology emphasize the role of chance in
community assembly because ecological drift and random dispersal can affect which microbial
species inhabit a holobiont. If microbial community structure and dynamics are primarily
stochastic, then community composition should not differ from expectations based on random
community assembly models [142,143]. In contrast, if the host-associated microbiota is
deterministically assembled, i.e., by host-microbiota interactions, then its composition will
consistently deviate from neutral expectations. Mixed models of stochastic and deterministic
community assembly likely reflect natural systems, and partitioning the microbiota into sto-
chastic versus deterministic subunits will be an important future goal of the field.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 12 / 23
What experiments can detect non-neutral dynamics in the hologenome? Consider the follow-
ing scenario involving a genus of closely related holobiont species reared in an unbiased manner.
As horizontal transmission is the presumed main mode of acquisition for the microbiota
[35,106], the microbial community is not a priori expected to change in parallel with the host
nuclear phylogeny unless hologenomic interactions generate specificity and codivergence
between the genome and microbiomea process that we previously termed phylosymbiosis
[100]. Phylosymbiosis does not assume that microbial communities are stable or vertically trans-
mitted from generation to generation. Instead, phylosymbiosis predicts that for each generation,
intraspecific microbial communities are more similar to each other than to interspecific microbial
communities, and the levels of genetic divergence between hosts will associate with the relative
differences between their microbial communities, yielding phylosymbiotic concordance. Thus,
given a genus of closely related animal or plant species, the host and microbiota can either assem-
ble (1) randomly by stochastic processes without concordant relationships or (2) phylosymbioti-
cally by deterministic processes in which the relationships of the microbiota are concordant with
ancestry. At present, evidence for phylosymbiosis under diet-controlled regimes exists only in
Nasonia [144]andHydra [145], but the pattern also occurs in wild populations of sponges [146],
ants [147], and apes [148,149]. Testing null models of population genetics and ecology for the
hologenome will require the application of current and new statistical tests to distinguish selec-
tion from neutrality at both evolutionary and ecological scales.
IX. Hologenomic Speciation Blends Genetics and Symbiosis
The Biological Species Concept [150] importantly offers a research program to explain the ori-
gin of speciesnamely, the evolution of barriers to interbreeding, i.e., reproductive isolation.
In the absence of reproductive isolation and unlimited interbreeding between holobionts,
complete gene flow and "microbe flow," a term we introduce here to denote the exchange of
microbes between holobionts, can act as cohesive forces merging holobiont populations back
into a cohesive group. In contrast, isolating mechanisms such as ecological isolation, mate dis-
crimination, and hybrid incompatibilities may serve as traits that drive holobiont populations
into incipient species with unique sets of hologenomic associations [151154].
Despite the century-long paradigm of studying speciation genes in nuclear genomes of
model systems, the Biological Species Concept was never intended to be exclusive of speciation
symbionts [31,155]. Indeed, Theodosius Dobzhansky's graduate student Lee Ehrman pio-
neered studies of symbiosis to explain Haldane's rule in Drosophila [156]. Today, there are
numerous holobiont systems wherein speciation microbes have been identified [31]. In fact,
the number is similar in scope to the quantity of known speciation genes, and we ponder how
many genetically mapped traits involved in intrinsic isolation could be "cured" if the micro-
biome was removed. Antibiotic or axenic experiments in speciation studies must be a routine,
if not obligatory, set of experiments in genetic analyses of speciation. The simple ability to rear
closely related animal species and their hybrids free of bacteria and then to inoculate bacteria
back into axenic animals permits a gain-and-loss investigation of whether microorganisms
underlie any isolating barrier between holobiont species. The study of hologenomic speciation
is no longer optionalit is a necessary frontier that must be traversed for an all-inclusive
understanding of the origin of species (Box 4).
X. Holobionts and Their Hologenomes Do Not Change the Rules of
Evolutionary Biology
It is possible that preconceptions about how evolution works might cause some to think that
the hologenome concept changes the way they understand evolutionary biology. However,
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 13 / 23
Box 4. Hologenomic Speciation
Animal and plant species do not arise exclusively from divergence in their nuclear
genomes [31]. Instead, symbiotic and nuclear genetic components can cause isolation
barriers that influence the evolution of new animal and plant species. We argue that a
combinatorial nature of hologenomic speciation is a far more accurate vision of specia-
tion than has been traditionally recognized. Just as a speciation geneticist might inquire
how many genes cause reproductive isolation and identify their functions [157,158], a
speciation microbiologist would inquire how many host-associated microbes cause
reproductive isolation and determine what kinds of microbes they are [31]. By simulta-
neously pursuing both sets of the questions rather than one or the other as is usually
done, speciation biologists can achieve a unified theory of the Biological Species Concept
that fuses symbiosis and Mendelian genetics. For instance, in the case of mushroom-
feeding Drosophila flies or Nasonia parasitoid wasps, both symbiotic and nuclear genetic
components combine to cause nearly complete reproductive isolation between young
species [100,159,160]. All that matters is that the hologenomic components, the collec-
tion of host, organelle, and microbial DNA, function in isolation barriers.
Pioneering work on symbiont-induced speciation traces back to Lee Ehrman and her
studies of infectious hybrid sterility between subspecies of D.paulistorum [161]. The bac-
terial infections in the testes were later identified as beneficial Wolbachia within the sub-
species that functionally breakdown in hybrids [162], similar to how adaptive nuclear
genes within species can also breakdown in hybrids. Another salient example is the evo-
lution of Wolbachia-induced F
hybrid inviability in the incipient stages of speciation
between closely related Nasonia species [160,163]. Symbiont-induced, behavioral barri-
ers to reproduction occur as well. For instance, variation in the gut microbiota, and con-
sequently host odor profiles, causes premating isolation between strains of D.
melanogaster [152].
Speciation genetic experiments are classically designed to rule in nuclear genes by
mapping traits to chromosomal regions, but they fail to assess microbes as causes of
reproductive isolation. As a result, the significance of microbial-induced isolation has
undoubtedly been underassessed. We propose that microbe-free experiments be univer-
sally implemented in speciation studies to upgrade this narrow approach. By way of illus-
tration, one of the best-studied genes involved in Drosophila adaptive evolution and
hybrid inviability, Nup96 [164,165], encodes a component of the nuclear pore complex
that is hijacked by viruses to breach the nucleus [166]. Thus, mapping speciation genes
to nuclear chromosomes is not evidence against hologenomic speciation sensu strictu, as
some have previously noted. Rather, speciation genes in the nucleus may be half of the
story as they often interact with the microbiota to cause reproductive isolation. This pre-
cedent is evident in Nasonia in which quantitative trait loci that associate with F
lethality are contingent on the presence of the Nasonia gut microbiota [100].
The large and integral role of immune genes on reproductive isolation in both animals
and plants has been previously termed the "Large Immune Effect[31]. The immune sys-
tem rapidly evolves to handle the resident microbiota of the holobiont, namely a finite
subset of host-associated microbes spanning mutualists, pathogens, and commensals.
For instance, molecular population genetic studies demonstrate in Drosophila, humans,
and chimps that defense and immunity genes evolve more rapidly and are under more
positive selection than the rest of the genome [167169]. Immunity genes can also be
preferentially misexpressed (i.e., either an increase or decrease in levels of expression
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 14 / 23
there is no fundamental rewriting of Darwin's and Wallace's theory of evolutionary biology
involved in this concept. Like single nucleotide mutations, acquisition of new symbionts births
raw genetic variation that evolution can operate on. If one looks at the host-associated micro-
biome as a major, if not dominant, component of the DNA of an animal or plant, then trans-
missible changes in the microbiome can quite naturally lead to new adaptations and speciation
just like changes in nuclear genes. We adhere to this general view and invite the community to
consider an expansive but not revolutionary extension of evolutionary genetics in light of the
heritable [60,78] and inherited microbiome [103,105]. In the perennial debate about whether
evolutionary biology needs a rethink [42], it has already been noted that "this expansion of evo-
lutionary biology does not denigrate Darwin in the least but rather emphasizes the fertility of
his ideas" [41].
At a time when symbiotic microbes are recognized as fundamental to nearly all aspects of ani-
mal and plant biology, the holobiont and hologenome concepts afford holistic, eyes-up views
of the multicellular eukaryotic world that are consistent with the generally reductionist
approaches of evolutionary biology. Rather than transforming evolutionary thought, the holo-
genome concept develops it in a substantive and timely way. From a specific standpoint, the
holobiont and hologenome concepts redefine that which constitutes an individual animal or
plant by asserting that hosts and their symbiotic microbes are complex units of biological orga-
nization upon which ecology and evolution can act. From a general standpoint, the concepts
assert that macrobe evolution has been driven by both population and community genetics
and that symbiotic microbes and nuclear genes hold equivalent significance in the origin of
new holobiont species. Like all good scientific theories, the concepts are subject to refutation,
and in this essay, we have explained how they can be empirically and experimentally falsified.
compared to the parental expression) in some hybrids, suggesting that the genes subject
to high rates of positive selection within species are also the ones likely to be aberrantly
expressed in hybrids. For example, in the hybridization of D.melanogaster and D.simu-
lans, we previously calculated that 93% of the immune genes were differentially
expressed relative to the nonhybrid controls, compared with 57% of the nonimmune
genes [31,170]. Hybrid autoimmunity is a frequent occurrence in plants as well
[171,172]. Immune gene breakdowns in hybrids are likely windows into speciation by
symbiosis and the hologenomic complexities maintaining hostmicrobe homeostasis.
Indeed, in a recent study of the house mouse hybrid zone, hybrids displayed numerous
differences in their microbiota, increased gut pathology, and altered immune gene
expression [173]. Cases of accelerated rates of immune system evolution and positive
selection within species coupled with aberrant immune gene function and gut microbiota
in postmating reproductive isolation are verifications for hologenomic speciation. More-
over, the microbiota itself is now recognized as essential in the training and function of
the holobiont immune system [47], including the remarkable possibility that mucus-
associated bacteriophages operate as part of the adaptive and innate antimicrobial
immune system [174]. Finally, the study of microorganisms associated with disease
agents is poised to greatly impact our knowledge and therapeutic treatments of infectious
diseases [175]. Collectively, these efforts and views should lead to deeper insights into
hostmicrobial relationships and provide exciting new opportunities for the study of the
origin of animal and plant species.
PLOS Biology | DOI:10.1371/journal.pbio.1002226 August 18, 2015 15 / 23
We anticipate that the conceptual foundation provided in this essay will serve as a roadmap for
hypothesis-driven, experimentally validated research on holobionts and their hologenomes.
We thank colleagues Robert Brucker, Tony Capra, Tal Dagan, Nolwenn Dheilly, Devin Drown,
Jonathan Klassen, Georgiana May, Edward Van Opstal, Nick Parrish, Maulik Patel, and Kat-
rine Whiteson for their critical reading and feedback on this manuscript. We also deeply appre-
ciate the feedback of the external reviewers, including three transparent reviewers who
exemplify progress in the peer review system. Together, our colleagues made us think in diverse
ways that reflect the genuine breadth of this topic. Any opinions, findings, and conclusions or
recommendations expressed in this material are those of the author(s) and do not necessarily
reflect the views of the National Science Foundation.
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... It is widely accepted that higher organisms like plants and animals harbour complex microbial communities, including (but not limited to) bacteria, viruses and fungi [1,2]. Organisms are no longer viewed individually, but as "holobionts", referring to the sum of an organism and its full community of microbial associates [3][4][5]. The microorganismal part of the holobiont (also called microbiome) is known to play a role in the extended phenotype of macroorganisms and can affect host physiology, phenotype and fitness [2,5,6]. ...
... Organisms are no longer viewed individually, but as "holobionts", referring to the sum of an organism and its full community of microbial associates [3][4][5]. The microorganismal part of the holobiont (also called microbiome) is known to play a role in the extended phenotype of macroorganisms and can affect host physiology, phenotype and fitness [2,5,6]. These interactions between microorganisms and their host range from mutualistic to pathogenic and parasitic [7]. ...
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Microorganisms living in and on macroorganisms may produce microbial volatile compounds (mVOCs) that characterise organismal odours. The mVOCs might thereby provide a reliable cue to carnivorous enemies in locating their host or prey. Parasitism by parasitoid wasps might alter the microbiome of their caterpillar host, affecting organismal odours and interactions with insects of higher trophic levels such as hyperparasitoids. Hyperparasitoids parasitise larvae or pupae of parasitoids, which are often concealed or inconspicuous. Odours of parasitised caterpillars aid them to locate their host, but the origin of these odours and its relationship to the caterpillar microbiome are unknown. Here, we analysed the odours and microbiome of the large cabbage white caterpillar Pieris brassicae in relation to parasitism by its endoparasitoid Cotesia glomerata. We identified how bacterial presence in and on the caterpillars is correlated with caterpillar odours and tested the attractiveness of parasitised and unparasitised caterpillars to the hyperparasitoid Baryscapus galactopus. We manipulated the presence of the external microbiome and the transient internal microbiome of caterpillars to identify the microbial origin of odours. We found that parasitism by C. glomerata led to the production of five characteristic volatile products and significantly affected the internal and external microbiome of the caterpillar, which were both found to have a significant correlation with caterpillar odours. The preference of the hyperparasitoid was correlated with the presence of the external microbiome. Likely, the changes in external microbiome and body odour after parasitism were driven by the resident internal microbiome of caterpillars, where the bacterium Wolbachia sp. was only present after parasitism. Micro-injection of Wolbachia in unparasitised caterpillars increased hyperparasitoid attraction to the caterpillars compared to untreated caterpillars, while no differences were found compared to parasitised caterpillars. In conclusion, our results indicate that host-parasite interactions can affect multi-trophic interactions and hyperparasitoid olfaction through alterations of the microbiome.
... Consequently, hosts and their associated microbes are considered as a functional unit in evolution, the metaorganism, in which the effects mediated by the microbiota are integrated into the host phenotype [4,5]. Genetic and thus phenotypic variations in the metaorganism can result from both changes in the host genome and changes in the microbiota such as acquisition of new microbes or changes in relative species abundance [2, 6,7]. As a consequence, the microbiota may influence the distribution of host phenotypes within a population and thus the evolutionary trajectory of the host [6,8]. ...
The microbiota shapes host biology in numerous ways. One example is protection against pathogens, which is likely critical for host fitness in consideration of the ubiquity of pathogens. The host itself can affect abundance of microbiota or pathogens, which has usually been characterised in separate studies. To date, however, it is unclear how the host influences the interaction with both simultaneously and how this triangular interaction determines fitness of the host-microbe assemblage, the so-called metaorganism. To address this current knowledge gap, we focused on a triangular model interaction, consisting of the nematode Caenorhabditis elegans, its immune-protective symbiont Pseudomonas lurida MYb11, and its pathogen Bacillus thuringiensis Bt679. We combined the two microbes with C. elegans mutants with altered immunity and/or microbial colonisation, and found that (i) under pathogen stress, immunocompetence has a larger influence on metaorganism fitness than colonisation with the protective microbe, (ii) in almost all cases, MYb11 still improves fitness, and (iii) disruption of p38 MAPK signalling, which contributes centrally to immunity against Bt679, completely reverses the protective effect of MYb11, which further reduces nematode survival and fitness upon infection with Bt679. Our study highlights the complex interplay between host genetics, protective microbe, and pathogen in shaping metaorganism biology.
... The taxonomic profiles of vertebrate microbiota often cluster by host [1], and in rare cases, the phylogeny of host and the phylogeny of microbial symbionts appeared congruent [2]. This phenomenon has been referred to as phylosymbiosis [3] and was interpreted by some as evidence for the existence of a "hologenome, " meaning that a subset of the microbial community, as well as the microbial genes, show stable transmission over evolutionary times and strict inheritance [4]. Stable transmission has recently been supported by findings from Suzuki et al. [5], who found that dozens of bacterial lineages showed evidence of co-diversification with human populations. ...
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Background Gut microbes play crucial roles in the development and health of their animal hosts. However, the evolutionary relationships of gut microbes with vertebrate hosts, and the consequences that arise for the ecology and lifestyle of the microbes are still insufficiently understood. Specifically, the mechanisms by which strain-level diversity evolved, the degree by which lineages remain stably associated with hosts, and how their evolutionary history influences their ecological performance remain a critical gap in our understanding of vertebrate-microbe symbiosis. Results This study presents the characterization of an extended collection of strains of Limosilactobacillus reuteri and closely related species from a wide variety of hosts by phylogenomic and comparative genomic analyses combined with colonization experiments in mice to gain insight into the long-term evolutionary relationship of a bacterial symbiont with vertebrates. The phylogenetic analysis of L. reuteri revealed early-branching lineages that primarily consist of isolates from rodents (four lineages) and birds (one lineage), while lineages dominated by strains from herbivores, humans, pigs, and primates arose more recently and were less host specific. Strains from rodent lineages, despite their phylogenetic divergence, showed tight clustering in gene-content-based analyses. These L. reuteri strains but not those ones from non-rodent lineages efficiently colonize the forestomach epithelium of germ-free mice. The findings support a long-term evolutionary relationships of L. reuteri lineages with rodents and a stable host switch to birds. Associations of L. reuteri with other host species are likely more dynamic and transient. Interestingly, human isolates of L. reuteri cluster phylogenetically closely with strains from domesticated animals, such as chickens and herbivores, suggesting zoonotic transmissions. Conclusions Overall, this study demonstrates that the evolutionary relationship of a vertebrate gut symbiont can be stable in particular hosts over time scales that allow major adaptations and specialization, but also emphasizes the diversity of symbiont lifestyles even within a single bacterial species. For L. reuteri, symbiont lifestyles ranged from autochthonous, likely based on vertical transmission and stably aligned to rodents and birds over evolutionary time, to allochthonous possibly reliant on zoonotic transmission in humans. Such information contributes to our ability to use these microbes in microbial-based therapeutics.
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Microbiome science has highlighted human and microbial interdependency, offering a radical epistemic shift from the individualistic view of the human body and self. Research has accordingly offered to see humans as ‘homo-microbis’ – complex biomolecular networks composed of humans and their associated microbes. While social scientists have begun to address microbiome science, the proliferation and commodification of the homo-microbial episteme have largely been overlooked. Based on an ethnographic account of a research project that offered microbiome- based personalised nutrition and the successful start-up that emerged from it, this article examines the emergence, proliferation, and commodification of the homo-microbial body. We show that this episteme necessarily depends on opaque machine learning algorithms; that the microbiome is paradoxically seen as a data-driven individuating marker; and that homo-microbis is, in fact, also a homo-algorithmicus – a being that can only access its non-human sub-parts by blindly following opaque algorithmic recommendations in an app.
In the ecosystem, the plant microbiome is often in association with other microorganisms like bacteria, actinobacteria, and fungi that carry on different roles for the ecosystem. The functional microbiome of the rhizosphere has been studied widely for improvement and enhancement of crop productivity which directly supports a farmer first and later the economy of any country. The integrated functions of bacteria, in the development of synergies with fungal partners, have several advantages. In most of these, many are required to be revised and targeting them according to farmers’ needs to propagate conventional agriculture to less environment-impacting types of agriculture. Thus, focusing on it is important to re-look at the constraints of developing biofertilizers using multiple microorganisms. This review addresses the development of need-based and microbial consortia for farmers and the economy.KeywordsMicrobial consortiaRhizobacteriaRhizosphereEcosystemFarmers
The world population is supported by food availability that depends on cultivation. Agriculture, however, comports environmental threats related with global warming and nature contamination. Therefore, more friendly techniques that are less damaging for the environment without resignation of yield have gained attention. Among them, bioinoculants containing microbial species (bacteria and fungi) emerge in the farming market as possible contributors. This review revises the scientific basis of such products as biofertilizers, biostimulators, stress regulators, biopesticides, and bioremediation agents. More than 40 years of research suggests that bioinoculants’ efficiency relies on root growth promotion that enhances soil exploration and root capability for superior nutrient and water uptake, and such growth promotion is mostly dependent (directly and/or indirectly) on production of plant growth regulators (phytohormones) by microorganisms. Notwithstanding, in keeping yield, bioinoculants are not enough by themselves, and they should be combined with other technologies, namely, plants genetically designed for more efficient use of resources, direct sowing, moderate and specifically oriented fertilization, green soil coverage, and crop rotation.KeywordsBioformulationsPGPBPlant growth-promoting bacteriaPlant hormonesRoot efficiencySustainable agriculture
Climate change globally endangers certain marine species, but at the same time, such changes may promote species that can tolerate and adapt to varying environmental conditions. Such acclimatization can be accompanied or possibly even be enabled by a host’s microbiome; however, few studies have so far directly addressed this process. Here we show that acute, individual rises in seawater temperature and salinity to sub-lethal levels diminished host fitness of the benthic Aurelia aurita polyp, demonstrated by up to 34 % reduced survival rate, shrinking of the animals, and almost halted asexual reproduction. Changes in the fitness of the polyps to environmental stressors coincided with microbiome changes, mainly within the phyla Proteobacteria and Bacteroidota. The absence of bacteria amplified these effects, pointing to the crucial importance of a balanced microbiota to cope with a changing environment. In a future ocean scenario, mimicked by a combined but milder rise of temperature and salinity, the fitness of polyps was severely less impaired, together with condition-specific changes in the microbiome composition. Our results show that the effects on host fitness correlate with the strength of environmental stress, while salt-conveyed thermotolerance might be involved. Further, a specific, balanced microbiome of A. aurita polyps is essential for the host’s acclimatization. Microbiomes may provide a means for acclimatization, and microbiome flexibility can be a fundamental strategy for marine animals to adapt to future ocean scenarios and maintain biodiversity and ecosystem functioning.
The study of the interactions between the neuroendocrine and immune systems is a highly interdisciplinary research endeavor, in which the boundaries between the systems being studied become blurred. We address a common scientific perspective in dealing with intertwined complex systems, namely the conceptual approach in science that treats each system (e.g., nervous, immune, endocrine systems) as separate units or “building blocks” with unique functions that correspond to specific structures. While there are merits to this way of decomposing complex systems, there are several reasons why such an approach is limited when trying to recompose a physiological system that is engaged in intricate co-functioning and that is the result of co-development, and co-evolution, not just between these systems, but with the gut microbiota as well. Our suggestion is to take an alternative ecological evolutionary developmental approach to the neuro-endocrine-immune-microbiota system (NEIMS) as a whole, which can serve as complementary to the predominant building block perspective.
Significant part of planet’s land is covered by arid deserts, and these ecoregions are driven and dominated with microbial dwellers. Microbial residents of desert land are known to interact with plants and boost their health through their plant growth-promoting abilities and can withstand climatic stresses imposed by arid habitats. Groups of such beneficial soil microbes are being called as plant growth-promoting microorganisms (PGPM) that are capable of alleviating plant immunity and growth through indirect means via inducing plant defense against phytopathogens or directly promote growth by nutrient solubilization, by assimilation, by modulating phytohormones, and by secreting specific solutes and enzymes. Explorations of microbial communities from extreme arid ecoregions across the globe have revealed abundance of Proteobacteria, Actinobacteria, and Bacteroidetes like bacterial communities and fungal phyla like Basidiomycota and Ascomycota. Several members of these groups, more specifically Bacillus sp., are known for wide diversity of plant growth promotion mechanisms and reported from hot as well as cold arid deserts. Exploration of such dryland microbial communities and their potentials aiding plant health against arid atrocities may open up opportunities to draw endless unexploited desert reservoir for agricultural sustainability. This chapter provides insight about microbial diversity in arid deserts of globe and highlights their plant promotion potentials.
Recent studies have highlighted associations between diseases and host microbiota. It is yet extremely challenging -especially under natural conditions- to clarify whether the host microbiota promotes future infections, or whether changes in host microbiota result from infections. Nonetheless, deciphering between these two processes is essential for highlighting the role of microbes in disease progression. We longitudinally surveyed, in the wild, the microbiota of individual fish hosts (Leuciscus burdigalensis) both before and after infection by a crustacean ectoparasite (Tracheliastes polycolpus). We found a striking association between parasite infection and the host microbiota composition restricted to the fins the parasite anchored. We clearly demonstrated that infections by the parasite induced a shift in (and did not result from) the host fin microbiota. Fin microbiota further got similar to that of the adult stage, and the free-living infective stage of the parasite during infection with a predominance of the Burkholderiaceae bacteria family. This suggests that Burkholderiaceae bacteria is involved in a co-infection process and possibly facilitate T. polycolpus infection. We reveal novel mechanistic insights for understanding the role of the microbiota in host-parasite interactions, which has implications for predicting the progression of diseases in natural host populations.
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Reinforcement refers to the evolution of increased mating discrimination against heterospecific individuals in zones of geographic overlap and can be considered a final stage in the speciation process. One the factors that may affect reinforcement is the degree to which hybrid matings result in the permanent loss of genes from a species' gene pool. Matings between females of Drosophila subquinaria and males of D. recens result in high levels of offspring mortality, due to interspecific cytoplasmic incompatibility caused by Wolbachia infection of D. recens. Such hybrid inviability is not manifested in matings between D. recens females and D. subquinaria males. Here we ask whether the asymmetrical hybrid inviability is associated with a corresponding asymmetry in the level of reinforcement. The geographic ranges of D. recens and D. subquinaria were found to overlap across a broad belt of boreal forest in central Canada. Females of D. subquinaria from the zone of sympatry exhibit much stronger levels of discrimination against males of D. recens than do females from allopatric populations. In contrast, such reproductive character displacement is not evident in D. recens, consistent with the expected effects of unidirectional cytoplasmic incompatibility. Furthermore, there is substantial behavioral isolation within D. subquinaria, because females from populations sympatric with D. recens discriminate against allopatric conspecific males, whereas females from populations allopatric with D. recens show no discrimination against any conspecific males. Patterns of general genetic differentiation among populations are not consistent with patterns of behavioral discrimination, which suggests that the behavioral isolation within D. subquinaria results from selection against mating with Wolbachia-infected D. recens. Interspecific cytoplasmic incompatibility may contribute not only to post-mating isolation, an effect already widely recognized, but also to reinforcement, particularly in the uninfected species. The resulting reproductive character displacement not only increases behavioral isolation from the Wolbachia-infected species, but may also lead to behavioral isolation between populations of the uninfected species. Given the widespread occurrence of Wolbachia among insects, it thus appears that there are multiple ways by which these endosymbionts may directly and indirectly contribute to reproductive isolation and speciation.
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This chapter describes the quantum leaps of technological advances in genomics, proteomics and metabolomics. The current state of the art is outlined, and their informational and translational value is then assessed. The omics have produced two major outputs: knowledge bases, and clinical/diagnostic translations and applications. The omics sciences form the analytical basis for an integrated, systematic and quantitative understanding of how a living system functions. The transcriptome, the entire repertoire of transcripts in a species, represents a key link between information encoded in the DNA and the phenotype. Transcriptomic studies have improved the understanding of the complex interaction between genetic and environmental factors, such as lifestyle and nutrition and have enabled the assessment of nutritional interventions at global gene expression level. The omics revolution is a stunning example of how high-throughput technologies and large-scale informatics have transformed life science.
Omics, including genomics, proteomics, and metabolomics, enable us to explain symbioses in terms of the underlying molecules and their interactions. The central task is to transform molecular catalogs of genes, metabolites, etc., into a dynamic understanding of symbiosis function. We review four exemplars of omics studies that achieve this goal, through defined biological questions relating to metabolic integration and regulation of animal-microbial symbioses, the genetic autonomy of bacterial symbionts, and symbiotic protection of animal hosts from pathogens. As omic datasets become increasingly complex, computationally sophisticated downstream analyses are essential to reveal interactions not evident from visual inspection of the data. We discuss two approaches, phylogenomics and transcriptional clustering, that can divide the primary output of omics studies—long lists of factors—into manageable subsets, and we describe how they have been applied to analyze large datasets and generate testable hypotheses.
The theory of evolution by natural selection is, perhaps, the crowning intellectual achievement of the biological sciences. There is, however, considerable debate about which entity or entities are selected and what it is that fits them for that role. In this chapter I aim to clarify what is at issue in these debates by identifying several distinct, though often confused, concerns and then identifying how the debates on what constitute the units of selection depend to a significant degree on which of these different questions a thinker regards as central. Chief among these distinctions are replicators versus interactors as well as who benefits from a process of evolution by selection, that is, who benefits in the long run from a selection process and who gets the benefit of possessing adaptations that result from a selection process. Because Richard Dawkins is the primary source of several of the confusions addressed in this essay, I treat his work at some length.For more than twenty-five years, certain participants in the “units of selection” debates have argued that more than one issue is at stake. Richard Dawkins (1978, 1982a), for example, introduced “replicator” and “vehicle” to stand for different roles in the evolutionary process. He proceeded to argue that the units of selection debates should not be about vehicles, as they had formerly, but about replicators. David Hull (1980) in his influential article “Individuality and Selection” suggested that Dawkins’s “replicator” subsumes two quite distinct functional roles and broke them up into “replicator” and “interactor.” Robert Brandon (1982), arguing that the force of Hull’s distinction had been underappreciated, analyzed the units of selection controversies further, claiming that the question about interactors should more accurately be called the “levels of selection” debate to distinguish it from the dispute about replicators, which he allowed to keep the “units of debate” title.