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Synthetic ecology of the human gut microbiota

In this Review, we provide an overview of the current synthetic ecology strategies that can be used towards a more comprehensive understanding of the human gut ecosystem.

The human gut microbiota is a complex and dynamic microbial community that is integral to the maintenance of health1,2 and the regulation of the host immune system3,4. Recent breakthroughs in culture-independent, high-throughput profiling have enabled the rapid, large-scale quantification of the composition of the gut microbial community in health and disease.

Alterations of the gut microbiota (that is, dysbiosis) have been linked to many diseases and conditions, such as obesity5,6,7,8 and diabetes mellitus9,10,11,12. As a result, modulating the gut microbiota has been viewed as a potential source of novel therapeutics for treating diseases that are associated with dysbiosis13,14.

Nonetheless, the clinical translation of microbiota-based therapies has been slow, with one of the main obstacles being lack of a mechanistic understanding of the metabolic and ecological interactions between microorganisms and with the host.

Although a relatively complete atlas of the taxa that make up the human gut microbiota has been compiled in the past 10 years, much more limited progress has been made in elucidating the wiring of the human gut ecosystem — that is, the distinct characteristics of individual community members and the complex web of interactions among them2,8.

Sequencing data alone have been shown to be inadequate to fully predict microbial phenotypes and functions in a community. For example, a recent study revealed that 75% of metabolic models of gut bacterial species, based on genomics and literature information on growth requirements alone, failed to predict the growth of the same bacterial species in different media15.

Analyses pairing complementary ‘omics’ data (that is, metatranscriptomics, metaproteomics and metabolomics) with shotgun data arguably have more predictive power and are able to assess active species, pathways and genes in an ecosystem. However, it is not yet possible to (fully) assess the complex ecological interactions using ‘omics’ data alone16.

Here, we argue that a synthetic ecology approach — that is, the study of complex microbial systems using synthetic communities — could form the solution to this problem.

Synthetic microbial communities are systems of known and reduced complexity that are amenable to experimental intervention and modelling, enabling a systems-level understanding17,18,19.

From a bottom-up ecological perspective (going from components to communities), synthetic communities are a way to study how microbial community structure emerges (for example, through competition and cooperation) and to identify the conditions necessary to generate specific interaction patterns (for example, cross-feeding, syntrophy and auxotrophy).

From a top-down ecological perspective (starting with the system), they can answer questions about the overall function and the resistance and resilience of microbial systems18. The study of synthetic microbial communities requires (i) controlled in vitro environments, (ii) biologically relevant bacterial strains and (iii) mathematical models of the ecological interactions to simulate and test.

Work on creating human gut-specific, controlled in vitro environments, isolating intestinal bacterial strains and mathematically modelling gut bacterial communities is currently under way. Still, the use of a synthetic-ecology approach is still relatively new for the gut microbiota field. It was once thought that as few as ~20% of the human gut microorganisms were culturable20, indicating that the design of synthetic gut microbial communities would always be limited.

Now, however, new methods such as culturomics21 are overturning this paradigm and have inspired a culturing renaissance21,22,23,24 (Fig. 1). Furthermore, recent efforts to sequence the genomes of these cultured gut microorganisms21,24 (see also the Human Microbiome Project)25 and to assemble complete or nearly complete metagenome-assembled genomes (MAGs) from shotgun metagenomes26,27,28 are improving our ability to identify bacterial taxa of interest, down to the strain level.

he combination of these advances allows us to begin designing meaningful, synthetic gut microbial communities and study those communities in vitro.

In summary, the human gut is a complex ecosystem for which modulation strategies can be envisaged, but a mechanistic understanding is needed of the intricate interactions that drive its ecology. Given the vast array of metabolic activities and multiple points of interaction of the gut microbiota with the human host, the opportunities for health-promoting interventions are bountiful.

The key steps towards the development of a functional model of the colon ecosystem that can be used for the design of therapeutic solutions appear all to be in place, but they have yet to be aligned and combined. Synthetic ecology holds promise as the road to a renaissance in human microbiota-based therapeutics for health and well-being.

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Posted on: February 4 2020

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Crohns & Colitis