Microbiome stewardship in rapidly declining ecosystems: The high risk of inaction

New microbiome-based interventions, such as the use of probiotics, are beginning to be identified as key to reverse deterioration and protect wildlife. There is an urgent need for moving from devising to safely testing and implementing these approaches.
Microbiome stewardship in rapidly declining ecosystems: The high risk of inaction
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Key ecosystems are at the brink of ecological collapse, driving enormous biodiversity losses and mass extinctions, disrupting the planet’s ‘one health’ and our livelihoods. Even if rapid action is taken to mitigate some of the main causes of these impacts, such as the reduction of CO2 emissions, the conditions to reverse current impacts must be provided. Healthy organisms and ecosystems rely on healthy microbiomes and their contribution to nutrient cycling, vitamin production, carbon fixation, mitigation of toxic compounds, and biological control of pathogens, among other functions (Peixoto et al., 2021a, b). Anthropogenic impacts can disturb these healthy microbiomes, causing, for example, dysbiosis (i.e., the breakdown of the symbiotic relationships between the host and their associated microbiome), and the consequent outbreak of pests and pathogens. In addition to being targets for dysbiotic processes, microbes are also key members of the holobiont. They connect all ecosystem components, respond rapidly to manipulation with immediate effects, and are easier to manipulate than macro-organisms. Microbes, therefore, represent an incredible opportunity for proper management aimed at the restoration of a healthy status. This has been perfectly clear to me since the very beginning of my career when I developed my MSc and PhD theses on plant and soil microbiology, a field in which probiotics have been explored and exploited for decades (*kudos to my great mentors and collaborators Leda Mendonca-Hagler, Lucy Seldin, Alexandre Soares Rosado, and Kornelia Smalla for introducing me to this fantastic micro-biotech world). Probiotics have also been applied in humans and aquaculture, and I have personally noticed their beneficial effects to my wellbeing. We are all familiar with the concept of taking probiotics, or yogurt, before or whilst taking antibiotics, in an attempt to minimize the impacts on the gut microbiome. Microbiome manipulation has received widespread attention, for example through the use of fecal transplants in human patients suffering from Clostridioides difficile associated disease (CDAD) to restore or improve gut function (D’Amato et al., 2020). Recently, the same concept was applied to wildlife, such as reef-building corals, bats, bees, and amphibians (Daisley et al., 2020; Hoyt et al., 2019; Rosado et al., 2019; Woodhams et al., 2018). The use of probiotics (i.e., the introduction of bacteria beneficial to an organism’s health) has emerged as a viable and promising tool to improve wildlife health and resilience. The adaptation and expansion of such models from humans, plants, and aquaculture to other organisms is, in my opinion, a straightforward natural development that uses parallels between different hosts/holobionts. When successful, probiotics “reboot” dysbiotic microbiomes to restore key symbiotic relationships between hosts and their associated microbes, which also reverses post-stress disorders to, ultimately, prevent mortality (Santoro et al., 2021).

However, despite the promising results obtained in lab experiments that have used probiotics to protect and wildlife, only a few field trials have been developed. This is largely due to the lack of a clear framework to guide researchers on a safe, but realistic, path from pilot experiments to large-scale application. The lack of a clear roadmap also hampers the scientific development of these tools, since it creates various regulation barriers that are not necessarily aligned with the most recent science (and needs). In addition, no ethical discussions are available to provide guidelines and rules to accelerate the transition from devising to applying environmental probiotics. Researchers provide the knowledge but cannot (or do not know how to) translate it into real world application. Yet, probiotics are now conventionally applied in agroecosystems, demonstrating that successful applications in open environments are possible with controlled risks.

An open and inclusive discussion on this topic, promoted and fostered by the Beneficial Microorganisms for Marine Organisms (BMMO) network, in a roundtable at the 15th BAGECO, in Lisbon, highlighted the need for a clear roadmap that could speed up the research of new probiotics and their test/application to different systems. We have also noticed a lack of consensus regarding basic concepts and ethical requirements that made us dive into a deep reflection about the risks associated with both action and inaction, as well as the necessary risk assessment steps necessary to ensure a responsible development in the field. We also detected the need to include these considerations into a systematic and standardized framework, that could summarize our hard work going to every single aspect associated with probiotic application to wildlife and therefore facilitate the decisions made by our colleagues and stakeholders. Finally, we included a key aspect to this discussion, which is the fact that microbiome stewardship and probiotic applications that have been proposed are targeting organisms living in ecosystems that are no longer pristine (i.e., where microbiomes have already been changed, usually to a dysbiotic/pathobiotic one (Sweet et al., 2017). In this sense, the discussion regarding whether the use of probiotics could impact the organisms and/or ecosystems should also take into consideration the changes that have already been triggered by anthropogenic factors, as well as whether probiotics could reverse it.

The original roundtable discussion was followed by the inclusion of specific leading experts from crosscutting areas of probiotic research, ranging from microbial ecology, microbiome manipulation, environmental management (agri- and aquaculture, humans, and wildlife) to bioethics. As a result, a thorough, yet flexible, framework for the advancement of the use and study of probiotics was built. As a side note, I found the experience to be extremely productive; we brainstormed all aspects of microbiome stewardship to the core, including every detail and controversial aspect of the topic, dissecting our own doubts and concerns, to the point of a convergent, solid, and unified message. The process of turning well-founded, and eventually contradictory, opinions into common ground was probably the highlight of this experience, at least for me. Everyone’s voices were heard and everyone’s concerns were taken into consideration. This is probably the reason we had such a great (and long) time preparing our perspective, and also the reason I feel so proud of the final result.

Our flexible, science-based framework outlines how microbiome stewardship can be applied to reverse deterioration and improve the resilience of wildlife and ecosystems, from the laboratory bench through to pilot studies and large-scale application (i.e., from a concept to a real-world solution, as for example the solutions being currently tested, on a pilot/small scale, at the KAUST/RSRC Coral Probiotics Village). We address ethical considerations, the risks and benefits, and the high toll of inaction, concluding that the criteria for the framework development and application in damaged ecosystems cannot be guided by the same concerns as those applied for pristine areas. A pragmatic regulatory environment-adapted roadmap for specific applications and domains is required, in particular considering how rapidly ecosystems (and organisms’ health) can deteriorate. Our science-based framework therefore integrates transversal knowledge and accelerated steps in light of the lessons learned from other fields. We identify the necessary safety checks in the upscaling process, weighing comprehensive and strict risk assessment against the risks of inaction. Our goal is that our Perspective piece catalyzes research, regulation, and real-world application of probiotics for wildlife, taking all the risks into consideration while following the safest path to minimize biodiversity loss.

 

References

Daisley, B. A. et al. Novel probiotic approach to counter Paenibacillus larvae infection in honey bees. ISME J. 14, 476–491 (2020).

D’Amato et al., Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients. Microbiome, 8, 140 (2020).

Hoyt, J. R. et al. Field trial of a probiotic bacteria to protect bats from white-nose syndrome. Sci. Rep. 9, 9158 (2019).

Peixoto, R. S., Harkins, D. M. & Nelson, K. E. Advances in microbiome research for animal health. Annu. Rev. Anim. Biosci. 9, 289–311 (2021).

Peixoto, R. S. et al. Coral probiotics: Premise, promise, prospects. Annu. Rev. Anim. Biosci. 9, 265–288 (2021).

Rosado, P. M. et al. Marine probiotics: increasing coral resistance to bleaching through microbiome manipulation. ISME J. 13, 921–936 (2019).

Santoro, E. P. et al. Coral microbiome manipulation elicits metabolic and genetic restructuring to mitigate heat stress and evade mortality. Sci. Adv. 7, (2021).

Sweet, M., Bulling, M. On the Importance of the Microbiome and Pathobiome in Coral Health and Disease. Frontiers in Marine Science, 2017.

Woodhams, D. C. et al. Batrachochytrium: Biology and management of amphibian chytridiomycosis.  in: eLS. John Wiley & Sons, Ltd: Chichester. 1–18 (2018).