1Red Sea Research Center (RSRC), Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science
and Technology (KAUST), Thuwal, Saudi Arabia. 2Department of Biology, University of Konstanz, Konstanz, Germany. 3Aquatic Research Facility,
Environmental Sustainability Research Centre, University of Derby, Derby, UK. 4Computational Bioscience Research Center (CBRC), Division of
Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
5Department of Global Health and Social Medicine, Center for Bioethics, Harvard Medical School, Boston, MA, USA. 6Wyss Institute for Biologically
Inspired Engineering, Harvard University, Boston, MA, USA. 7Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens
Lyngby, Denmark. 8Department of Biology, University of Massachusetts Boston, Boston, MA, USA. 9Smithsonian Tropical Research Institute, Panama City,
Panama. 10APC Microbiome Ireland, School of Microbiology, and Department of Medicine, University College Cork, Cork, Ireland. 11Helmholtz Institute
for Functional Marine Biodiversity (HIFMB), Oldenburg, Germany. 12RD3 Marine Symbioses, GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel,
Germany. 13Department of Microbiology, Oregon State University, Corvallis, OR, USA. 14Lawson Health Research Institute, University of Western Ontario,
London, Ontario, Canada. 15Department of Biology and Marine Biology, University of North Carolina Wilmington, Wilmington, NC, USA. 16Institute for
Bioengineering and Biosciences, Instituto Superior Técnico, University of Lisbon, Lisbon, Portugal. 17Scripps Institution of Oceanography, University of
California San Diego, San Diego, CA, USA. 18Weill Cornell Medicine, New York, NY, USA. 19Department of Biology, Eastern Washington University, Cheney,
WA, USA. 20Centre for Marine Science and Innovation and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney,
Australia. 21Institute of Environmental Biotechnology, Graz University of Technology, Graz, Austria. 22University of Postdam and Leibniz Institute for
Agricultural Engineering and Bioeconomy (ATB), Potsdam, Germany. ✉e-mail: firstname.lastname@example.org
Five of the nine proposed planetary boundaries, which represent
the limits within which humans can safely inhabit the Earth1,
have now been breached due to human activities: climate
change, biosphere integrity loss, land-system change, plastic and
chemical pollution, and altered biogeochemical cycles2. We are now
firmly entrenched within a sixth mass extinction event3, with loss in
corals, bats, bees and amphibians being the most prominent exam-
ples of anthropogenically driven biodiversity loss4–6 (Supplementary
Fig. 1). Currently, widespread extinction events impair the resil-
ience, function and stability of ecosystems, which impacts our
existence7–9, conceptually referred to as ‘One Health’ (that is, the
interconnection between people, animals and the environment)5,6.
In the face of such alarming challenges, recent advances in
research have indicated the potential of microbiome-based inter-
ventions, such as probiotics to protect wildlife and mitigate environ-
mental impacts, and microbiome transplants to restore ecosystems
and improve their resilience10–21. We explore synergies between
different disciplines, synthesize basic microbiome engineering
and symbiosis concepts, and identify critical challenges and safety
issues. Importantly, we provide guidelines for designing and imple-
menting microbiome-based strategies to mitigate biodiversity
decline using existing examples. We argue that the consequences
of biodiversity loss are so serious that the risk of inaction must be
weighed against the risk of taking a less-than-perfect action or even
the risk of making things worse. This argument implies that regula-
tory and safety guidelines must be practical, flexible and stipulated
using a case-by-case approach, considering the current state of each
host and ecosystem as well as scientific insights. In this regard, we
discuss crucial ethical considerations, risks, costs and benefits, and
opportunities across multiple fields of microbiome management to
synthesize an evidence-based framework to accelerate the practi-
cal use of emergent approaches. Finally, we draw parallels to other
Harnessing the microbiome to prevent global
Raquel S. Peixoto 1 ✉ , Christian R. Voolstra 1,2, Michael Sweet 3, Carlos M. Duarte 1,4,
Susana Carvalho1, Helena Villela 1, Jeantine E. Lunshof 5,6, Lone Gram 7, Douglas C. Woodhams8,9,
Jens Walter 10, Anna Roik 11, Ute Hentschel 12, Rebecca Vega Thurber13, Brendan Daisley 14,
Blake Ushijima15, Daniele Daffonchio 1, Rodrigo Costa 16, Tina Keller-Costa 16, Jeff S. Bowman 17,
Alexandre S. Rosado 1, Gregor Reid 14, Christopher E. Mason 18, Jenifer B. Walke19,
Torsten Thomas 20 and Gabriele Berg21,22
Global biodiversity loss and mass extinction of species are two of the most critical environmental issues the world is cur-
rently facing, resulting in the disruption of various ecosystems central to environmental functions and human health.
Microbiome-targeted interventions, such as probiotics and microbiome transplants, are emerging as potential options to
reverse deterioration of biodiversity and increase the resilience of wildlife and ecosystems. However, the implementation of
these interventions is urgently needed. We summarize the current concepts, bottlenecks and ethical aspects encompassing
the careful and responsible management of ecosystem resources using the microbiome (termed microbiome stewardship) to
rehabilitate organisms and ecosystem functions. We propose a real-world application framework to guide environmental and
wildlife probiotic applications. This framework details steps that must be taken in the upscaling process while weighing risks
against the high toll of inaction. In doing so, we draw parallels with other aspects of contemporary science moving swiftly in the
face of urgent global challenges.
NATURE MICROBIOLOGY | www.nature.com/naturemicrobiology
PersPective NaTure MIcroBIoloGy
fields of applied science moving swiftly in the face of other current
and urgent global challenges.
Biodiversity loss in the Anthropocene
One of the primary hallmarks of the Anthropocene is the progres-
sive elimination of species across a wide taxonomic range—from
plants to insects, amphibians, birds and mammals22,23. In contrast,
relatively little is known about the decline in microbial diversity
and its potential consequences24. Symbiotic relationships between
eukaryotic hosts and microbes constituting the holobiont or
meta-organism25,26 are key for organism health and support critical
ecosystem functions in all habitats on Earth27. In a healthy organism,
host–microbe interactions are sufficiently balanced, with certain
microbiome members often buffering against biological or environ-
mental disturbances to maintain homoeostasis and function (Fig. 1).
Projecting back, microbial symbionts were drivers of plant terres-
trialization in early Palaeozoic land ecosystems28, and co-evolution
with their hosts resulted in specific and unique host–microbe
interactions and microbial assemblages on Earth29. Consequently,
the loss of multicellular, eukaryotic hosts documented by massive
extinction events in the past and today is in all likelihood accompa-
nied by the currently undocumented loss of microbial genetic and
metabolic diversity30. Recent studies have described a microbiome
signature of the Anthropocene, which is characterized by a shift
towards global homogenization, diversity loss, r-strategist (that is,
fast-growing) microbes and often multiresistant pathogens24,31,32.
We posit that such shifts, particularly in host–microbiome asso-
ciations, are often followed by dysbiosis (that is, the disruption of
microbial networks and functions that impact symbiotic relation-
ships within a holobiont)33 and facilitate disease. Dysbiosis is also
associated with severe chronic diseases and long-term biotic stress
that are well-documented for humans34,35 and crops36,37 but remain
understudied in wildlife and natural vegetation.
The treatment and management of microbial disruptions have
traditionally focused on administering antimicrobials38, with little
consideration for the maintenance of the beneficial constituents
With microbiome stewardship
Healthy microbiome ⟶ Maintenance of biodiversity⟶
Disease prevention ⟶
Promotion of ecosystem conservation and services
Disturbed ecosystems ⟶ Biodiversity loss ⟶
Disease outbreaks ⟶
Increased risk of new pandemics
Without microbiome stewardship
Commensal/beneﬁcial microbes Pathogens and secondary invaders
Animal and environment health
Microbiome engineering/microbial inoculation
Fig. 1 | Microbiome stewardship as a potential tool to mitigate anthropogenic impacts. Anthropogenic impacts can disturb healthy microbiomes, causing
dysbiosis characterized by loss of diversity, evenness and homoeostasis, and increased prevalence of r-strategy microbes, hypermutation and antimicrobial
resistance. This can result in disturbed ecosystems, the outbreak of pests and pathogens and, thus, increased risk of disease. Microbiome stewardship
can exploit the microbiome given that these microbial communities are key members of the holobiont, connect all ecosystem entities, respond rapidly to
manipulation with immediate effects and are easier to manipulate than macro-organisms. The use of probiotics or synbiotics is one approach to promote
ecosystem functioning and overall one health, avoiding biodiversity loss, pandemics and other impacts while retaining ecosystem services.
NATURE MICROBIOLOGY | www.nature.com/naturemicrobiology
of the microbiome itself. We adopt the term ‘microbiome steward-
ship’ to underscore that organismal and ecosystem health can be
more effectively managed and maintained by monitoring and suit-
ably manipulating the microbiome. Accordingly, the term encom-
passes the sum of all approaches, methodologies and technologies
to understand and, consequently, manipulate microbiome func-
tion, with stewardship emphasizing the advocacy and support for
Understanding and manipulating microbiome function is a
daunting task, given the metabolic and physiological flexibility of
microbes to adapt in response to change39. Additionally, our under-
standing of how to retain or restore a healthy microbiome is often
limited40, in large part by available technologies and the lack of basic
understanding of the ecological mechanisms that govern microbi-
ome assembly, growth and evolution39,41.
Microbiome members that are important for holobiont func-
tioning could be harnessed to rescue threatened host species or eco-
systems. Competitive microbial interactions and the host immune
response are the proposed mechanisms for enriching community
members with antagonistic properties against pathogens. Similarly,
microbial relief of holobiont stress has been proposed to rescue
hosts subjected to environmental effects11–17,21,42–44. Mechanistically,
this involves beneficial microbes that can improve the uptake of
nutrients, vitamins and minerals, mitigate toxic compounds, con-
trol pathogens, and promote growth and fitness, among other
favourable roles45. This concept is similar to the pollution-induced
tolerance concept introduced by Blanck and Wängberg46 in ecotox-
icology or the biological control of pathogens widely explored in
Microbe-mediated disease control is becoming more commonly
employed, with microbiome-targeted interventions undergoing
development. These efforts have focused on humans and plants,
with aquaculture species also receiving increasing attention48–50. In
Box 1, we present a detailed summary of the state-of-the-art micro-
biome stewardship approaches for some of these hosts and the
strategies applied to the tailored design of probiotics across holo-
bionts. This tendency towards defined and tailored treatment has
existed for many areas (for example, precision farming and person-
alized medicine)51,52. While some of these strategies work well53,54,
many others have failed or demonstrated inconsistent results55,56.
These approaches are not necessarily new or exclusive to a specific
host50,57–59, and efforts to manipulate the human microbiome date
back over a hundred years60. The recent elevated interest in this
concept is encouraging and includes a focus on wildlife and natural
In general, microbiomes can be managed either by directly
applying (1) defined microbes and mixtures/consortia of strains
with beneficial properties (probiotics), (2) microbiota transplants,
(3) microbiota-active metabolites or (4) mixtures of probiotics and
prebiotics (synbiotics), or even indirectly by changing environmen-
tal conditions to drive shifts in the microbiome structure and func-
tion, turning a dysbiotic holobiont into a healthy one51. Although
the definition of a ‘healthy’ microbiome is still being characterized
and debated, on the basis of the available data, we propose a ‘micro-
biome stewardship’ concept that focuses on the use of probiotics.
These approaches and the associated outcomes should be measured
against the available alternative treatments and potential associated
risks (Fig. 1).
Designing probiotics for microbiome stewardship
Designing probiotic products comprises four steps: discovery,
screening and evaluation, formulation and application. This process
benefits from an ecological and evolutionary understanding of the
target ecosystem and the disrupted factors (with a particular focus
on function). This strategy has been used to some extent for micro-
biome stewardship of the human gut microbiome as a treatment for
Clostridioides difficile infection61. Disruption of the gut microbiome
by antibiotics can lead to C. difficile infection due to reduced micro-
bial competition and habitable niches. Microbiome restoration has
been performed with faecal microbiota transplantation (FMT),
which can re-establish colonization resistance and thus alleviate dis-
ease62. This paradigm of transplanting complex communities from
healthy donors with intact communities to health-compromised
recipients with disrupted communities could apply to other organ-
isms and ecosystems.
Specific beneficial microbes or defined mixtures/consortia of
strains could also be used to promote the health of a host or ecosys-
tem11,13,14. Probiotic strains for such applications can be discovered
from various sources, but ecology-based selection strategies that
consider the origin and evolutionary history of strains are suggested
to ensure adaptation and functionality. For example, microbes that
exhibit inverse associations with pathologies are promising can-
didates for developing probiotics or defined consortia that can be
explored for therapies63.
Probiotic candidates must undergo extensive screening to evalu-
ate their efficacy and mode of action (MOA) following enrichment
and isolation. The effectiveness of a multifaceted screening approach
to obtain the ‘best’ microorganisms from natural bioresources has
been demonstrated64. Microbial transplants from resilient wild
plants, mosses and lichens were used and their colonization on crop
roots and leaves were tracked to re-isolate promising probiotic can-
didates64. Moreover, a comprehensive set of assays was developed to
determine the capability of isolates to protect against different sources
of stress and MOA studies were also performed64. The inclusion of
multi-omics technologies in the screening process is particularly
valuable to assess the full potential of candidate strains57, including
their MOA65 and potential off-target or side effects51. Consortia that
combine microbes with different MOAs (that is, ‘helper strains’) and
metabolic boosters (that is, compounds that can accelerate/trigger
the production of specific metabolites) have also been shown to have
higher efficiency than single-strain inoculations51.
Once data on their activity, genetic profile and interactions with
other microbes or the host has been assembled, promising can-
didates or consortia can be chosen for a formulation process. In
some cases, stabilizing additives are used to provide long shelf life.
Subsequent large-scale production and registration are the remain-
ing important hurdles for probiotic development. While the focus
of the probiotic design is often the efficacy of the strains, other
important aspects, such as safety and risk assessment, knowledge
translation and ethics, must be considered during the early stages
Risk and safety considerations of microbiome stewardship
Risk assessment is an important requirement that is currently
among the greatest bottlenecks when registering a novel probiotic:
they are costly, time-consuming and often inefficient in considering
the specific features of each bioproduct66.
The regulation of bioproducts for microbial management var-
ies between countries and areas of application, and are not compat-
ible with each other. For example, in the United States, the Food
and Drug Administration developed a safety evaluation framework
that may assign microbial products the ‘Generally Recognized as
Safe’ status before being marketed (https://www.fda.gov/home).
However, the European Union Food Safety Authority uses a dif-
ferent framework based on a list of microbial species that may be
considered safe depending on their taxonomic affiliation, existing
scientific knowledge, pathogenicity and virulence, and safety for
the environment. However, several microbial species still require
full safety assessment and the number of included species is lim-
ited. Thus, most environmental probiotic candidates require a full
safety assessment as they are not included in this list. This is fur-
ther complicated by the fact that microbial products rely on living
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PersPective NaTure MIcroBIoloGy
Box 1 | Examples of commonly studied hosts receiving probiotics
Probiotics for humans date back to 1907, when Lactobacilli
were suggested to increase longevity60. Towards the end of the
twentieth century, the concept of probiotics emerged91 and
was applied to intestinal and urogenital health92. Interest in
manipulating microbes and their metabolic readouts, including
probiotics, prebiotics (that is, substrates for benecial microbes),
synbiotics (microbes and growth stimulants) and postbiotics
(microbial metabolites)93–96, as well as FMTs, has since increased
considerably. Examples of successful microbiome manipulation
in humans includes FMT for Clostridioides dicile infection and
the use of probiotics to prevent and treat necrotizing enterocolitis
Benecial microorganisms represent one of the fastest-growing
sectors in agronomy, with a compound annual growth rate of 15%
to 18%. Various plant probiotic formulations are currently in use
and are categorized according to mode of action: biopesticides
(direct activity toward pests and pathogens, which are segmented
by the target into bioherbicides, bioinsecticides and biofungicides),
biofertilizers (nutrient provision for plants) and biostimulants
(direct support of plant growth). e majority of products comprise
strains native to plants, namely Azospirillum, Bacillus, Beauveria,
Coniothyrium, Pseudomonas, Trichoderma and Rhizobium65. New
products will probably be needed to overcome the challenges of
climate change, weed and insect infestations, poor soil quality,
postharvest spoilage and the growing human population. Another
emerging approach is the restoration or protection of extinct or
endangered native vegetation and specic wild plants through
native mycorrhizal transplants99.
Chemotherapeutic agents, particularly antibiotics, have been
among the primary treatments used in aquaculture disease
management100–102, contributing to the emergence of antibiotic-
resistant bacteria100. Restrictions on their use have been implemented
in some countries to halt the dissemination of these bacteria and
to reduce the negative eects of residual antibiotics in aquaculture
products103. Potential alternatives to prevent disease outbreaks
include vaccines and probiotics (Gram-negative or Gram-positive
bacteria, yeasts, bacteriophages or unicellular algae)50,58,59,104–106.
Currently, a lactic acid bacterium-based product (Bactocell, a feed
formulation prepared from the Gram-positive species Pediococcus
acidilactici)107 is on the market, and work on the commercial
production of a Gram-negative Alphaproteobacteria from the
Roseobacter group, particularly the species Phaeobacter inhibens,
is underway50. However, the exact mechanisms by which such
aquaculture probiotics work are unknown, which has led to new
initiatives that base the selection of strains on the mode of action.
Bees are critical pollinators for a wide range of agricultural
processes that form global food supplies, but their population
has undergone a catastrophic decline over the past decade108. Bee
microbiome composition can be a useful indicator of the overall
colony health status, and these microbial communities can confer
colonization resistance against parasites, inhibit entomopathogenic
tissue invasion and improve nutrient assimilation from the
diet109. To improve resistance to infection during active seasons,
beekeepers frequently employ antimicrobials as a prophylactic
measure to suppress opportunistic bacterial and fungal pathogens.
Recently, strains of Lactobacillus spp. have demonstrated the
capacity to attenuate negative eects associated with antibiotic
use by stabilizing core microbiota dynamics and preventing the
overgrowth of opportunistic pathogens17. Several studies on bees
or other model insects have demonstrated the strain-specic
benets of Lactobacillus, Apilactobacillis and Pediococcus spp. for
increasing host survival against single or combinatorial stressors
of infection and pesticide exposure20,21,110,111. Together with a high
safety prole, this suggests that probiotic lactobacilli could oer a
cost-eective and convenient solution to mitigate two of the major
factors responsible for bee population decline.
Coral reefs have been increasingly challenged by the rate and
severity of global change and the inability of their foundational
species, reef-building coral, to cope with detrimental eects112–114.
Microbiome-based interventions are promising because they
could act on short timescales115,116. Desired benecial roles of
coral microbiome members have recently been proposed and
summarized117,118, together with an experimental framework
to identify coral probiotic strains and to reveal mechanisms of
action11,13,117,118. Several approaches of microbiome stewardship
aiming to improve coral resistance to external stressors or
bioremediation (for example, through elimination of the
pollution eects of oil spills) have already been successfully
proven in laboratory trials with dierent types of coral and
bacterial species (for example, Pseudoalteromonas sp., Cobetia
sp., Halomonas sp., Bacillus sp. and Brachybacterium sp.)10–14.
Despite the challenges of applying microbes to surfaces beneath
the saltwater ocean, coral microbiomes have been manipulated
ex situ through the introduction of probiotic strains by incubation,
topical application11,13,14,119,120 or direct feeding121. Microbiome
transplantation using resistant donor corals from the wild has also
demonstrated thermal protective eects on coral populations10,
such as increased growth120 and reduced stress responses under
heat (including mortality evasion following thermal stress
bleaching)11,13,119, oil exposure12,14 and pathogen challenges11,116, all of
which are accompanied by microbiome restructuring. Given their
associations with a complex microbiome39,122, corals may represent
a particularly good system to prove the capacity of microbiome
stewardship to reverse organismal and ecosystem decline.
Amphibians perform essential roles in food webs and provide
ecosystem services, but global population declines and extinctions
include over 500 species123,124. In particular, the invasive chytrid
fungi Batrachochytrium dendrobatidis and B. salamandrivorans
are emerging pathogens of urgent concern. Work in Panama has
indicated signs of recovery for several amphibian species seriously
aected by chytridiomycosis43. is work demonstrated that, while
pathogen virulence did not change, mucosal skin defences were
higher aer disease emergence43. is example of resilience may
provide strategies for overcoming environmental disturbance.
e use of probiotic bacteria, including16 Janthinobacterium
lividum44, Serratia spp.42, Pseudomonas reactans125, Bacillus sp. and
cocultures125,126, Stenotrophomonas sp. and others16,127, for amphibian
disease mitigation has been investigated. Skin microbiome
transplants from disease-resistant to disease-susceptible hosts
represents another research avenue128,129. Microbes that function
via volatile organic compounds are increasingly studied in
white-nose syndrome in bats130 and are being translated to snake
fungal disease131 and amphibian chytridiomycosis systems132.
NATURE MICROBIOLOGY | www.nature.com/naturemicrobiology
organisms that themselves have complex and ever-changing physi-
ologies. Although multi-omics technologies often allow us to
obtain detailed insight into the potential safety of probiotics for
environmental applications, the current lack of a consensus and
globally recognized framework for safety assessment still consti-
tutes a major bottleneck in their development.
We believe that an extensive network of collaboration between
research, industry and regulators is required to resolve these issues.
Integrating microbiome-based concepts, as well as improving and
adapting assays to evaluate the effects of new candidate probiotics
on living systems offer novel possibilities for efficient risk assess-
ment51,66. A more flexible, science-based system is needed to evalu-
ate risks associated with the use of specific probiotics, where each
situation will be evaluated through a case-by-case assessment, as
detailed in Fig. 2. Whole-genome sequencing can contribute to
understanding a candidate’s mode of (inter)action in detail and
detecting genes encoding bioactive metabolites, virulence and anti-
microbial resistance. Detecting genes of interest is especially criti-
cal if present on mobile genetic elements. However, basing the risk
assessment only on genomic traits or inferred functions is probably
insufficient due to other crucial factors (for example, epigenetic pat-
terns). Therefore, assessments should be supplemented with addi-
tional investigations and methods.
Combining ecological, genomic, transcriptomic and physiologi-
cal data is of scientific value and should be included as much as
possible for research on probiotic candidates. However, stipulating
clear criteria for which features require investigation for a given pro-
biotic application is challenging, and consideration must be given
to the primary outcome. We suggest that knowledge-based assess-
ments on a case-by-case basis using experimental data on microbe
behaviour are necessary for environmental microbiome stewardship
to counterbalance all aspects discussed above. Notably, such broadly
defined individual assessments could represent an even longer pro-
cess that is difficult to regulate. By comparison, a clear and universal
framework that includes a fair, flexible and straightforward road-
map to follow would be more beneficial. This flexible framework
should include experimental evaluations of the risks and benefits of
using probiotics. In addition, the inherent risks and costs associated
with inaction must be considered, as they create the opportunity to
select, test and validate potentially innovative and efficient probiot-
ics for environmental applications that current legislations would
Lessons learned from global challenges
We should assess when rapid action is critical and would jus-
tify potential and calculated risks, as described in Fig. 2. The
knowledge-based assessments of risk outlined above could ben-
efit from an integrative analysis of the use of probiotics for differ-
ent hosts, delivery methods and quick bench-to-host pathways.
The rapid development of multiple vaccines against SARS-CoV-2
is an example of science moving swiftly in response to a medical
emergency. Global efforts bridging stakeholders, scientists, and the
public and private sectors greatly accelerated these developments,
as well as adaptations in legislation, licensing and authorization
systems (rapid emergency use authorization), and risk assessment
systems, moving from long-term passive/active to real-time safety
surveillance. In this emergent framework, rare adverse effects from
vaccines were deemed acceptable considering the risk–benefit con-
siderations to immunize most of the human adult population67,68.
As another example, while FMTs have been described for
many years, they have not yet been proven safe beyond doubt and
adverse effects, although rare, have been reported. Despite this,
they are now regularly applied to treat human disease69,70. For
C. difficile infections, the gain of curing71 most patients (up to
90%) facing life-threatening diseases must be carefully weighed
against the risk of rare but serious adverse outcomes, as reported
when one patient died as a result of multidrug-resistant pathogens
being transplanted72. In these cases, additional precautions, such
as implementing multidrug-resistant strain screening or reassess-
ing microbiota components in donor stool, must be immediately
developed to avoid such unacceptable risks. A further illustration of
microbiome stewardship for the greater good is manipulation of the
bacterial symbiont Wolbachia in insect vectors for human disease
control (for example, to prevent the spread of dengue, yellow fever
or malaria by mosquitoes or other insects)73,74. Despite the need for
improvements, all these examples had known and unknown risks at
the time of application, but their benefits outweighed the concerns,
and inaction would have left a heavy toll in terms of human mortal-
ity and morbidity.
Ethical considerations and the inherent risk of inaction
Recent climate-related events, including extremely high tempera-
tures in the Arctic and Antarctic regions75, devastating fires in the
Amazon Rainforest, Australia and North America76–78, and the
massive loss of coral reefs23 underscore the fact that the duty of
environmental stewardship is not an abstract ideal but a concrete
imperative for humankind. The stewardship of biodiversity is a col-
lective duty as the planet’s ecosystems are strongly interdependent
and the integrity of each of these systems is a necessary condition
for sustaining life. Therefore, the highest priorities are to restore and
conserve threatened ecosystems.
Some may consider microbiome management ethically challeng-
ing given the potential effects on other ecosystem members being
modified or on the downstream food chain. For example, would
using probiotic strains on honey bees result in irreversible altera-
tions to flowering plant microbiota, or would the application of
microbes to restore coral reefs affect the fish food chain and, ulti-
mately, humans? Could environmental damage be triggered by such
Such ecosystem interventions imply major challenges for assess-
ing risks and benefits, with substantial implications for decision
making, responsibility, accountability and governance. One poten-
tial risk is the loss of native diversity (for example, if a single pro-
biotic strain takes over an inherent function). This is minimized by
niche opportunity and environmental traits that shape microbial
diversity (that is, probiotics establishment is rare and seems to be
controlled by the host13 or by the availability of nutrients and con-
ditions79 that triggered impact mitigation). However, this potential
drawback should not be ignored and must be evaluated on the basis
of the available alternatives.
It is also important to consider that, in some cases, not using
probiotic applications may still result in losing native diversity and
permit the spread of pathogens, causing major environmental dam-
age. Engineering the environment to support a ‘healthy’ microbi-
ome is an alternative approach to administering selected probiotics.
This might include using prebiotics or beneficial bacteria isolated
from the target environment, cultivated at scale and re-introduced
into the system. These approaches might lower the risk of losing
native diversity compared with administering genetically modified
or exogenous strains41. Another potentially innovative approach
would be to use bacteriophages to replace antibiotics and target spe-
cific, non-beneficial, microbes80,81.
One critical question that remains is who should decide on the
initiation of field trials to test probiotics for environmental appli-
cations? For instance, the local or regional communities should be
fully informed and involved during the early stages of an interven-
tion, especially if an application remains local (for example, due to
species-specific constraints). However, any alterations could ulti-
mately spread globally to all members of that host species, creat-
ing an ethical conundrum: who makes the initial decision and can
thus be held responsible? How can ecosystem interventions be justi-
fied? How can balanced information be provided? These complex
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PersPective NaTure MIcroBIoloGy
ethical questions must be part of a global debate with all relevant
stakeholders. Decisions must be based on broad scientific assess-
ments (for example, peer-reviewed data, scientific networks and
so on) and community consultations aligned with international
regulations agreed upon in a binding manner, ideally with control
instances established (for example, in the form of independent sci-
entific entities that inform governments).
Ethical justifications for novel interventions have a stronger case
if the intervention is a last resort, underscoring the ethical impera-
tive to avoid these desperate situations. In addition, we should
consider whether traditional interventions or alternative treat-
ments, such as antibiotics, fertilizers, pesticides and other poten-
tially harmful agents, may be more hazardous than probiotics.
An evidence-based framework for microbiome stewardship
We argue that clear ethical considerations and environmental
safety management are necessary to advance research on probiotics
applied to the environment and their primary host target. We pro-
pose an evidence-based framework (Fig. 2) for implementing envi-
ronmental and wildlife probiotics (live microbes administered to
2. Perform a risk:benefit ratio and an
effort:benefit ration calculation
Are alternative treatments available,
effective or more appropriate?
Is the risk of inaction higher than the risk of
taking a less-than-perfect action?
should be applied.
•Discovery and exploitation
of new bioresources and
•Deep investigation on their
mode of action/interaction,
and application strategies
Once the MDMM is
defined, it would be
indicated to evaluate how
such MDMM compares to
natural concentrations of
the same microorganisms
Are benefits potentially
greater than risks?
common and locally
3. Selection of microbes to ensure
4. Define an effective concentration:
What is the MDMM required?
5. Assess effects of MDMM on target
and non-target organisms/environments
(in pilot experiments)
6. Risk definition through a combination
of consequences, improvements and
their corresponding likelihood
(based on 2, 3, 4 and 5)
7. Determine economic, environmental
and cultural/societal benefits of
8. Application of
experimental or well-
Registration and depository (microbiome bank)
Regulatory aspects of our proposed framework must be addressed by scientists and stakeholders through a case-by-case approach,
and the criteria for its application in damaged ecosystems cannot be guided by the same concerns as those applied for pristine areas.
Fig. 2 | Proposed evidence-based framework for microbiome stewardship. The science-based flexible framework includes clear ethical and environmental
safety management considerations for developing and implementing probiotics for applications to the environment in a case-by-case approach. The proposed
steps could be followed sequentially or in combination and include the specific aspects that need to be considered for the selection and application of
probiotics for wildlife. We highlight that risk assessment is the first step, that it should also weigh the risk of inaction against the need for rapid action and
that the selection of probiotics should follow a science-informed exclusion of potential pathogens. The framework also suggests an overall survey on the
application regime and potential side effects, as well as parallel research to improve our knowledge on the mechanisms driving host–microbiome interactions.
NATURE MICROBIOLOGY | www.nature.com/naturemicrobiology
species living in the wild) using elements discussed above, with
steps that could be followed sequentially or in combination.
First, a detailed initial assessment of the problem must be
undertaken similar to environmental impact assessments, ideally
including the ecological and evolutionary understanding of the
foundational species or ecosystem functions that can help eluci-
date the mechanistic basis of the environmental disruption. This
assessment should include an examination of existing alternative
treatments and the resulting risk–benefit and effort–benefit ratios.
For example, if the problem is sewage outflow, well-studied alterna-
tives, such as wastewater treatment plants using membranes, floc-
culants and activated sludge, could be assessed82–85. Likewise, the
widespread application of amoxicillin (a potent, broad-spectrum
antibiotic) to control the rapidly spreading stony coral tissue loss
disease in the Caribbean86,87 could be compared with the harm it can
cause versus the outcome of using probiotics.
Second, selecting probiotic strains on the basis of specific traits or
functions is crucial to optimize the chance of success and minimize
the risks. Any microbial species or strain known to be potentially
pathogenic should be automatically excluded unless a convincing
argument can be made to consider it. Native, commonly found
and abundant commensal species should be preferentially selected
unless a compelling case can be made to apply a non-native spe-
cies. Strain properties should be assessed on the basis of what they
are expected to achieve in the target environment. For example, the
expected result could be to displace specific pathogens, function as
keystone species to establish a base for the recovery of communities,
improve host functions (development, immune system and so on)
or remove pollutants from a habitat or holobiont system. The inter-
action of a probiotic organism with existing indigenous species and
the surroundings should also be considered.
Third, an effective dosage of the probiotic should be used to
achieve the desired effect or outcome with minimal degree of
microbiome manipulation (MDMM). Whether this should exceed
the native abundance of the beneficial microorganisms that exist
when the host site is ‘healthy’ remains to be determined.
Fourth, the probiotic delivery system must be determined.
Considerations include shelf life, storage and handling, dispersion
when applied to water or other surfaces, time to reach metabolic
activities essential for success, target uptake, carrier dissolution or
degradation, and the broader effects on other organisms in this
niche, plus assessing the overall function of the environment. For
example, applying probiotics to a honeybee hive to improve resis-
tance against pathogens should not result in lower pollination rates
or damage to certain flowering plants.
Fifth, how an MDMM affects different life stages, non-target
organisms and environments should be assessed. This assessment
could be performed in vitro, accounting for spatial and temporal
dilution, using model organisms or, when possible, as pilot experi-
ments in natural ecosystems88,89. On the basis of the data, risks are
defined through a combination of measured consequences and the
likelihood of occurrence. Consequences must be defined in the con-
text of economic, environmental, cultural and societal values41. In
any case, a definitive, closely monitored pilot study is mandatory
before full-scale environmental application. Finally, if the benefits
of the target organism are greater than the risks to non-target organ-
isms or the environment, then the application of probiotics should
be recommended for full in-field assessment. Both scientists and
stakeholders must address regulatory aspects, use a case-by-case
approach with the proposed framework and acknowledge that the
criteria for application in damaged ecosystems cannot be guided by
the same concerns as those applied for pristine areas.
Conclusions and future perspectives
Despite the need for well-exercised caution, there is an increasing
understanding that time is of the essence. Microbiome stewardship
is dependent on specific traits, abiotic conditions and goals (for
example, whether specific pathogens or beneficial microbes must
be eliminated or promoted, respectively). Its scope includes (1) tar-
geted disruption of specific microbes and their metabolic activity,
(2) supplementing the host or ecosystem with native or non-native
microbes, (3) changing the microbiome by manipulating substrates
and (4) reducing host exposure to factors such as antimicrobial
toxins or pollutants. Ensuring a sound scientific basis for overseeing
these investigations forms an important part of microbiome stew-
ardship, but this takes time, resources and willpower. Unfortunately,
time is running out, which is why commitments must be made now,
while robust investigation on macro and (especially) micro biodi-
versity losses, as well as ecosystem function and mechanism, should
also be prioritized and supported by targeted funding opportunities.
Numerous challenges are shared across different hosts and envi-
ronments. In many cases, the current technology is not safer than
a microbiome modulation per se, for example when the current
treatment is antibiotics, which comes with potential risk of failure
or multidrug-resistance spread. We argue that the administration of
strain-specific microbes, risk-assessed by the best means possible
and scientifically characterized, is a safe option with potentially pro-
In conclusion, we emphasize that it is imperative to address the
nature and extent of the consequences of continued inaction. Many
examples exist where we have failed to treat diseases with a chemi-
cal approach and have consequently caused major environmental
disruption. The proposed use of beneficial microbes as an alterna-
tive is currently hindered by the lack of appropriate risk assessment
or ethical frameworks that consider the dynamics of the expected
benefits, current alternatives and unknown risks. We suggest joint
microbiome stewardship involving existing scientific networks (for
example, the beneficial microorganisms for marine organisms net-
work) for the rapid exchange of protocols, results, strategies and
resources, together with microbiota repositories (inspired by micro-
biota vaults90), which could catalyse the rapid development of probi-
otic applications to the environment. Carefully crafted production
and safety policies in a system that stipulates speed without bureau-
cratic bottlenecks would provide companies with a clear framework
to develop products that meet regulatory standards. Pilot-scale
experiments could be proposed to provide baseline evidence before
full-scale field tests. With sufficient data in place, legislators could
work with researchers and companies to plan more widespread
applications. Ultimately, we need to be able to reflect on our actions
and know that we did not miss an opportunity to save our environ-
ment and the species critical to our survival.
Received: 21 June 2021; Accepted: 14 June 2022;
Published: xx xx xxxx
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R.S.P. acknowledges funding from King Abdullah University of Science and Technology
(grants FCC/1/1973-51-01 and BAS/1/1095-01-01). C.R.V. acknowledges funding
from the German Research Foundation (DFG) (grants 433042944 and 458901010).
J.W. acknowledges support from the Science Foundation Ireland (SFI) through an SFI
Professorship (19/RP/6853) and a Centre award (APC/SFI/12/RC/2273_P2) to the APC
Microbiome Ireland. L.G. acknowledges funding from the Danish National Research
Foundation (DNRF137). Funding for this work came from NSF grant no. 1924501 to
R.V.T. J.S.B was supported by a Simons Foundation Early Career Investigator in Marine
Microbial Ecology and Evolution award and the US National Science Foundation
(NSF-OPP 1821911 and 1846837). R.C. and T.K.-C. acknowledge structural funding to
iBB (grants UIDB/04565/2020 and UIDP/04565/2020) from the Portuguese Foundation
for Science and Technology (FCT). R.C. acknowledges further funding from FCT and
the European Regional Development Fund (ERDF) (grants PTDC/BIA-MIC/31996/2017
and ALG-01-0145-FEDER-031966). T.T. acknowledges support from the Betty and
Gordon Moore Foundation. G.R. was funded by the Natural Sciences and Engineering
Research Council of Canada (NSERC). B.D. acknowledges support from an NSERC
Postdoctoral Fellowship (PDF-558010-2021) and the Ontario Ministry of Agriculture,
Food and Rural Affairs (ND2017-3164). A.R. was funded by the Helmholtz Institute
for Functional Marine Biodiversity at the University of Oldenburg, Niedersachsen,
Germany and acknowledges the travel award/young investigator award from the CRC
1182 (DFG). U.H. acknowledges support from the DFG-CRC 1182 TPB01. A.S.R.
acknowledges funding from King Abdullah University of Science and Technology (grant
The original discussion about the risk of inaction was initiated as part of a round table
of the Beneficial Microorganisms for Corals (BMMO) network organized/developed
by R.S.P., M.S., U.H., G.B, L.G, R.C and T.K.-C. at the 15th Symposium on Bacterial
Genetics and Ecology (BAGECO). R.S.P, C.R.V and G.B. prepared the original draft.
All authors heavily contributed with additional writing, ideas, edits and approval of the
The authors declare no competing interests.
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41564-022-01173-1.
Correspondence should be addressed to Raquel S. Peixoto.
Peer review information Nature Microbiology thanks Maria Gloria Dominguez-Bello,
David Relman and Angela Sessitsch for their contribution to the peer review of this work.
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