An Ecological Framework To Understand Gut Microbiota Modulation By Probiotics

Due to the biological importance of the dense microbial communities that reside in the digestive tract of humans and animals (the gut microbiota), there is an enormous interest in their modulation to improve health. One attempt to do so is through the oral administration of live microorganisms, an approach that has been used, in one form or another, for more than a century.

Probiotics are now taken by millions and are often advertised as an approach to modulate the microbiota through a seeding with beneficial microorganisms, and many scientists agree. However, to what extent this is possible, and the mechanisms by which such alterations would occur, remain questionable. Most probiotics, although able to survive gastrointestinal passage, show virtually no persistence and little effect on the composition of the resident microbiota.

In a recent review published in Current Opinion in Biotechnology, a team of scientists from the Universities of Alberta and California, Davis argues that due to the highly interactive and co-evolved nature of the gut microbiota, a successful modulation through probiotics can only succeed when basic ecological and evolutionary criteria are considered. By applying concepts from invasion and community ecology, the authors propose a holistic ecological framework to understand the success and ecological impact of live microbes when introduced into the digestive tract.

Invasion ecology conceptualizes biological invasions as a multifaceted process that requires the incoming organism to first be introduced into the new habitat in an active form and in sufficient numbers, overcome the immediate habitat filters, gain access to resources that allow growth under the often competitive conditions, and, if the resident community is to be changed, attain sufficient metabolic activity at a local site to engage in interactions that influences the abundance of functionality of the resident community. The outcome of each of these steps, and the factors that influence them are strictly governed by ecological principles, and more specifically by the characteristics of the potential colonist (C), host-related factors (H), and microbiome-related mechanisms (M).

Characteristics of the potential colonist (C) include a sufficient dose and frequency of application, and the microbes need to be metabolically active and possess functional traits to overcome both the habitat filters and compete with the resident community while avoiding predators. Microbes are more likely to possess such traits if they share an evolutionary relationship with the gastrointestinal environment of a particular host. These requirements are not met by most commercial probiotics, which are often selected by more practical criteria, such as safety, ability to grow under industrial conditions, and shelf life survival. As a consequence, most probiotic products do not contain species that are real members of the human gut microbiota.

The authors’ research demonstrated that if a species that belongs to the human core microbiome is given as a probiotic (in this case Bifidobacterium longum subsp. Longum), it can be stably established in a subset of humans for at least 6 months. Such adapted microbes are compatible with the Host related mechanisms (H) that select microbes that are most fitted, e.g. through the provision of resources in the form of secreted glycans (including mucus and milk glycans). Together with substrates provided through the host’s diet, such substrates constitute key components that provide niche opportunities for which the incoming microbes.

Competition for such resources determines species coexistence and thus the success of colonization. The outcome of invasion is, therefore, not solely determined by the characteristics of the incoming microbes but also those of the microbial community in a particular host, which can differ vastly among individuals. Such Microbiome related mechanisms (M) often relate to the diversity and stability of the communities, as these attributes render the ecosystem more resilient to invasions.

In addition, the chance of invasion increases if the invader is functionally distinct from the species present in the recipient community, thereby avoiding competition for resources. This seemed to apply in the experiments mentioned above with the probiotic Bifidobacterium longum subsp. longum, as the microbiome of subjects permissive to colonization had a significantly lower abundance of the species B. longum as well as genes involved in carbohydrate utilization. Clearly, other M-related mechanisms, such as antagonism (e.g. through bacteriocins), mutualism (facilitation), and predation (bacteriophages and protozoa) are also likely to be important, some of which are discussed in the review.

One take-home message from the review is that for incoming microbes to really have an impact on the resident microbiota, C, H, and M have to be accommodating if not favorable for colonists to occupy niches long enough to engage in competitive, antagonistic, or symbiotic interactions with other community members that would impact their abundance or functional role in the ecosystem. The scientific literature is often prone to unrealistic expectations on what can actually be achieved with current probiotic products, claiming that non-adapted probiotic strains with marginal persistence can induce substantial and sometimes even long-term changes to the gut microbiota. However, such dramatic shifts are unlikely due to the homeostatic nature of the gastrointestinal ecosystem, and mechanisms by which they would occur have not yet been identified. In fact, well-controlled studies on probiotics that control for confounders have shown that non-adapted strains have no impact on microbiome composition.

Well adapted autochthonous microbes (either single organism, mixtures, or FMTs) can be introduced into the gut, but only if niches are available or if the introduced strains have sufficient fitness to compete with resident species. Would such a highly adapted strain be antagonistic or mutualistic towards resident members in the ecosystem, specific alterations within the overall community could be the result, but empirical evidence for such effects is for the most part missing. From an ecological perspective, it will probably prove difficult to reconfigure communities that are not severely perturbed, as this would require the replacement of keystone species, which could potentially be achieved through the removal of the community members through subtractive strategies, such as antibiotics or bacteriophages.

The holistic ecological framework can aid in the interpretation of the effects of the currently used microbiome-modulating strategies, and further advance the field by providing a basis for the development of novel or improved products and strategies. Factors that support biological invasions, such as evolutionary history, genotypic diversity, adaptability of microbes, and their metabolic activity, have been hardly considered for probiotic strains. In contrast, probiotic strains have often become adapted to artificial conditions (which might lead to evolutionary “trade-offs” and, thus, reduced fitness in the gut) and are often administered, for practical reasons, in a metabolically inactive form (e.g. freeze-dried).

The central importance of resources provides a rationale to provide growth substrates in parallel, which is essentially the idea of the symbiotic concept that combines probiotics with prebiotics. An ecological perspective is further necessary to predict the impact and consequences of strategies, which will differ between humans due to the highly individualized configuration of the microbiome, setting the basis for personalizing strategies.

Last but not least, microbiome-modulating strategies constitute a challenge for regulatory agencies, as they represent a novel paradigm in drug development, requiring a regulatory framework that considers the unique biological and ecological characteristics of gut microbiomes. A dialogue between regulators and researchers will be necessary to develop such frameworks, and these discussions will have to be informed by an understanding of the ecological effects of microbiome-modulating therapies, which can only be understood using a framework grounded on ecological theory.

These findings are described in the article entitled To engraft or not to engraft: An Ecological Framework for Gut Microbiome Modulation with Live Microbes, recently published in the journal Current Opinion in BiotechnologyThis work was conducted by Jens Walter from the University of AlbertaMaría X Maldonado-Gómez from the University of California, Davis, and Inés Martínez from the University of Alberta and Sacco System.