Researchers construct most complex, complete synthetic microbiome

The gut microbiome, the collection of hundreds of bacterial species that live in the human digestive system, influences neural development, response to cancer immunotherapies, and other aspects of health. But these communities are complex and without systematic ways to study the constituents, the exact cells and molecules linked with certain diseases remain a mystery.

Researchers have built the most complex and well-defined synthetic microbiome, creating a community of over 100 bacterial species that was successfully transplanted into mice. The ability to add, remove, and edit individual species will allow scientists to better understand the links between the microbiome and health, and eventually develop first-in-class microbiome therapies.

Many key microbiome studies have been done using fecal transplants, which introduce the entire, natural microbiome from one organism to another. While scientists routinely silence a gene or remove a protein from a specific cell or even an entire mouse, there is no such set of tools to remove or modify one species among the hundreds in a given fecal sample.

Each cell in the microbiome occupies a specific functional niche, performing reactions that break down and build up molecules. To build a microbiome, the team had to ensure that the final mixture was not only stable, maintaining a balance without any single species overpowering the rest, but also functional, performing all the actions of a complete, natural microbiome. Selecting species to include in their synthetic community was also difficult given the natural variation across individuals; two people selected at random share less than half of their microbial genes.

They selected over 100 bacterial strains that were present in at least 20% of the HMP individuals. Adding a few species needed for some subsequent studies brought them to 104 species, which they grew in individual stocks and then mixed into one combined culture to make what they call human community one, or hCom1.

Though satisfied that the strains could coexist in the lab, the true test was whether their new colony would take root in the gut. They introduced hCom1 to mice that are carefully designed to have no bacteria present. hCom1 was remarkably stable, with 98% of the constituent species colonizing the gut of these germ-free mice, and the relative abundance levels of each species remaining constant over two months.

To make their colony more complete, the researchers wanted to make sure that all vital microbiome functions would be performed by one or more species. They relied on a theory called colonization resistance, which explains that any bacterium, when introduced into an existing colony, will only survive if it can fill a niche not already occupied.

By introducing a complete microbiome, in the form of a human fecal sample, to their colony and tracking any new species that took up residence, they could build a more complete community.

To demonstrate the utility of their synthetic microbiome, the scientists took hCom2-colonized mice and challenged them with a sample of E. coli. These mice, like those that were colonized with a natural microbiome, resisted infection. (Prior studies have shown that a healthy natural microbiome leads to protection).

This method of building a microbiome from the ground up will make engineered microbiome-based therapies possible in the future.

Alice G. Cheng et al, Design, construction, and in vivo augmentation of a complex gut microbiome, Cell (2022). DOI: 10.1016/j.cell.2022.08.003