Citation: McFall-Ngai M (2024) Symbiosis takes a front and center role in biology. PLoS Biol 22(4): e3002571. https://doi.org/10.1371/journal.pbio.3002571

Academic Editor: Nancy A. Moran, University of Texas Austin, UNITED STATES

Published: April 5, 2024

Copyright: © 2024 Margaret McFall-Ngai. 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 credited.

Funding: Work in the McFall-Ngai lab is supported by the National Institutes of Health (R37 AI50661, R01-GM135254 and by grants from the Gordon and Betty Moore Foundation (GBMF 9328 and GBMF 12342). The funders had no role in design of the Perspective, decision to publish, or preparation of the manuscript.

Competing interests: The author has declared that no competing interests exist.

Three major revolutions have occurred in biology over the last 150+ years: in the 19th century, the development of the theory of evolution by natural selection; in the 20th century, the discovery of DNA as the genetic material of all life forms; and in the 21st century, the recognition of the primacy of the microbial world. This most recent revolution was a result of the integration of the first 2. It began in the 1970s with Carl Woese’s work [1], in which he used nucleic acid sequences to determine the evolutionary relationships between microbes; however, at that time, the technology was slow and expensive. Advances in nucleic acid chemistry around 2006 (i.e., “next-generation sequencing”), rendered these determinations rapid and inexpensive, thereby democratizing the process. This breakthrough catalyzed the development of a new perspective on microbiology, revealing a world we could not have known. Efforts such as the NIH Human Microbiome Project (2007 to 2016), the Tara Oceans Project (2009 to 2013), and the Earth Microbiome Project (2010 to present) have demonstrated that the vast majority of the biosphere’s diversity has been, over evolutionary time and up to the present day, strongly dominated by microbes. Those life forms that we can see with the naked eye occur as a patina on this unseen tapestry of vast physiological and ecological range and impact.

One major change that has resulted from this revolution is the recognition of the widespread occurrence of animal and plant symbioses with microorganisms. The scholarly books of AE Douglas, Symbiotic Interactions (1994) and The Symbiotic Habit (2010), which were written before and after the onset of the “revolution,” respectively, illustrate this point. It had been thought that maintaining a lifelong relationship with a specific set of microbes was largely restricted to invertebrate and plant species. The emerging capability to identify microbial species has demonstrated that symbiosis among these taxa is even more pervasive than had been appreciated; however, the most striking change in our understanding has been with the vertebrates. The current data show that acquisition, development, and maintenance of a taxon-specific microbial consortium along mucosal surfaces of most vertebrate organ systems is a shared, derived character of all jawed vertebrates, not only of ungulates. These symbiotic communities interact both directly with host tissues and indirectly through the import of metabolic products of the microbiota into the host’s metabolome (i.e., the small molecules in the blood and tissues) [2]. Through these influences, these microbial consortia profoundly influence the form and function of the healthy individual host animal and, when dysfunctional, are often the root cause of disease.

Consider, for example, our concepts of the animal immune system. While invertebrates have only the components of an innate immune system, the possession of both an innate and an adaptive immune system is a shared, derived character of all vertebrate species. Immunologists had long believed the principal selection pressure on both these systems was to keep the onslaught of pathogens at bay. Specifically, immunity operated as a strong mechanism, often with a memory, for reacting to adverse interactions with the microbial world; the many microbes that were believed to have no effect on the host (i.e., “commensals”) were simply ignored. With an increase in research on the human microbiome, the view of the vertebrate immune system has reversed [3]; it is now perceived as a mechanism that manages the large, complex “ecosystem” of beneficial microbes that, while composed of human-associated guilds, are unique, like fingerprints, to each individual [4]. In fact, the realization that a person’s microbiome provides a recognizable signature is driving its application in forensic sciences [5]. Thus, to operate effectively, the vertebrate immune system must be permissive and flexible, maintaining a highly complex set of microbes in balance while detecting and attacking pathogens. Vertebrates arose early in animal evolution and only represent 3% of its diversity; therefore, the coordination of an innate immune system with an adaptive immune system is not only a unique strategy, but also a rather rare one among successful animal species.

The immune system of invertebrates, which comprise the other 97% of animal species, is not as well understood as that of vertebrates. All metazoans, from anemones and flatworms to insects, urchins and clams, share with the vertebrates an innate immune system that exhibits many biochemical, molecular, and physiological similarities (i.e., innate immunity is conserved across the evolution of animals). However, innate immunity had also been assumed to have no memory [6] and to be nonspecific:

New data are calling these assumptions into question for vertebrates [6] as well as invertebrates; for example, in both these animal groups, elements of the innate immune system (e.g., antimicrobial peptides, microbe-associated molecular patterns) participate in shaping the symbiotic microbiota [7]. However, studies of the mutualistic symbioses between microbes and invertebrates have demonstrated that the actions of the innate immune system are very different from those in vertebrates. While often living in environments with dense microbial assemblages, such as the soil or oceans, many invertebrates can recruit and maintain stable and invariant associations with a very limited number of microbes. For example, in the squid–vibrio system on which my lab works, the male host harbors a single, specific, vibrio species [8]. Within a few hours after hatching from the egg into the surrounding seawater, which contains about a million nonspecific bacteria per milliliter, the juvenile squid harvests its specific microbial symbiont, which represents <0.1% of the bacterioplankton. The host squid retains its dynamic vibrio populations over its lifetime, and confocal analyses of living animals has demonstrated that all other tissues, both within the mantle cavity and on the surfaces, remain free of living microbes of other phylotypes. This behavior of specific host–symbiont recognition occurs with fidelity each generation, approximately 4 generations a year, and has done so for tens of millions of years. We know that the innate immune system controls some of this process. How much is controlled by other, unknown activities that involve a type of recognition memory remains to be determined. However, the processes that control colonization and persistence in this association cannot possibly be viewed as nonspecific.

More recently, emerging studies (e.g., [9,10]) of several other associations have discovered similar patterns of a limited, predictable set of stable symbiont species living with an invertebrate host. However, it should be noted that exceptions to this general strategy have been documented. For example, termites, cockroaches, and sponges have highly diverse microbiota that can consist of hundreds of species. At the other end of the spectrum, it is likely that some animals do not harbor a persistent microbiome [11]; nevertheless, they still may have essential interactions with specific microbes at certain periods in their ontogeny (e.g., [12]). Finally, controversy still exists surrounding the actual nature of certain symbioses, such as those of corals [13,14], concerning whether or not the microbiomes of these invertebrate species are highly diverse.