Researchers just built a synthetic human gut microbiome. Now they can test it like never before

Researchers at Stanford University have built from scratch the most complex and well-defined synthetic microbiome that will help us better understand the connections between the microbiome and human health, a university press release said last week.

The microbiome is a community of microorganisms that are found to cohabit in a given environment. The human gut has its own set of microorganisms that are markedly different from those on the skin. Over the years, the study of the human gut microbiome has attracted interest after researchers have found it to play a role in neural development as well as response to immunotherapies when treating cancer.

However, the collective nature of the microbiome makes it difficult to study the role of individual organisms and molecules in certain diseases. Our understanding of the individual components of the microbiome is so limited that even medical interventions involve the complete transfer of fecal matter from one organism to another. So, Stanford researchers Michael Fischbach and his team set about to develop their own synthetic microbiome in a bid to better understand the components.

Assembling the synthetic microbiome

To construct their own synthetic microbiome, the researchers individually grew the constituent organisms of the human gut and then mixed them together. While doing so, they needed to ensure that the resultant mix was not just stable but also balanced, where no species overpowered the rest.

The researchers also had to ensure that the microbiome was functional and would perform the functions of a naturally occurring one. This is rather tricky since the microbiomes of two individuals selected at random are less than 50 percent similar. So, the researchers turned to the Human Microbiome Project (HMP), a public project undertaken to sequence gut microbiomes of 300 adults.

They started their work with 100 bacterial species that were found in at least 20 percent of the HMP participants and added some more species based on the subsequent study. The tally of 104 organisms was grown individually and then combined to make up the first iteration of the microbiome, dubbed human community one, or hCom1.

Improvements and testing of the microbiome

After testing their synthetic microbiome in the lab, the researchers set out for the real challenge of knowing if it would survive in the gut. They inserted hCom1 into the gut of specially bred mice that have no gut microbiome. The researchers found that 98 percent of the species in hCom1 colonized the mice gut and co-existed in the desired composition for a period of over two months.

To strengthen the microbiome, the researchers then introduced human fecal samples into the mix. The theory of colonization resistance suggests that newly introduced species would be added to the colony only if they could fill a niche function that was currently not being done.

There was also a risk that the microorganisms in the fecal sample would decimate the hCom1. However, the community held together against the fecal sample and even assimilated up to 20 new bacterial species into their mix.

The researchers then added these organisms to the original mix of their synthetic microbiome after removing the organisms that did not grow in the mice gut. The resultant mix of organisms consisted of 119 species that managed to hold ground against other fecal sample introductions. This was called hCom2.

The research team also tested the hCom2-colonized mice against an E.coli infection, which they resisted. Since the team knows the exact species in their microbiome mix, they can selectively remove some organisms and iterate the process until they figure out which bacteria are critical for preventing infection. The same approach can also be used to find out what makes immunotherapies work.

The research findings were published in the journal Cell.

Abstract

Efforts to model the human gut microbiome in mice have led to important insights into the mechanisms of host-microbe interactions. However, the model communities studied to date have been defined or complex, but not both, limiting their utility. Here, we construct and characterize in vitro a defined community of 104 bacterial species composed of the most common taxa from the human gut microbiota (hCom1). We then used an iterative experimental process to fill open niches: germ-free mice were colonized with hCom1 and then challenged with a human fecal sample. We identified new species that engrafted following fecal challenge and added them to hCom1, yielding hCom2. In gnotobiotic mice, hCom2 exhibited increased stability to fecal challenge and robust colonization resistance against pathogenic Escherichia coli. Mice colonized by either hCom2 or a human fecal community are phenotypically similar, suggesting that this consortium will enable a mechanistic interrogation of species and genes on microbiome-associated phenotypes.