A team of researchers at Stanford University has built the first synthetic microbiome model built entirely from scratch, containing over 100 different bacterial species. It is hoped that this work will revolutionize the study of the gut microbiota by providing scientists with a consistent working model for future experiments.

There are trillions of microorganisms living in our gut. Perhaps one of the most important discoveries in medicine in recent decades is how deeply these microbes affect our general health. From influencing the effectiveness of the medicines we consume to regulating our immune system, the gut microbiome plays a powerful role in all aspects of our health.

It’s also surprisingly complex. No two people have exactly the same gut microbiota composition. Researchers frequently look at how certain bacteria affect metabolic mechanisms, but translating these findings into actual clinical treatments in humans has been difficult.

Michael Fischbach, The lead author of the new study says that the foundation of the study is the recognition that science needs some objective model of the gut microbiome, and that research will help determine what specific interventions lead to beneficial health outcomes. Fischbach says there are two specific motivating factors underpinning this research over five years.

“Initially, I was intrigued by experiments in which a (complete and undefined) fecal sample was transplanted into human→mouse and the associated phenotype emerges (e.g. response to anti-PD1). , it is difficult to know which strains/genes are involved.” he explained on twitter“Second, we are interested in the chemistry of the microbiome, with an emphasis on mechanisms. We colonize mice with defined but incomplete communities[to test molecular mechanisms].” They have become unsatisfied with experiments that transform them, and they often fail to reproduce normal physiology.”

So the first step was to look at the large body of previous studies of the human microbiome to develop a candidate list of the most common bacteria found in most people. The research team identified 104 bacterial species and named this first microbiome iteration hCom1.

After growing each bacterial species individually and mixing them all up, the researchers introduced hCom1 into germ-free mice. A germ-free mouse is an animal that has evolved to have no natural microbiome. Incredibly, hCom1 was a stable microbial ecosystem when transplanted into mice. Some bacterial species became more prevalent than others, but the 100 or so species showed a relatively stable balance and the animals were found to be metabolically normal.

The next step was to fill in any bacterial gaps that might have been missing in the original microbial composition. To do this, the researchers fed hCom1 mice human fecal samples. Based on a theory called colonization resistance, researchers hypothesized that unfilled bacterial niches in hCom1 would be filled by these new invaders.

But Fischbach points out that not everyone thought this part of the experiment would work. Some thought that human fecal samples would completely overtake this artificial bacterial community collected by researchers.

“The hCom1 bacterial species lived together for only a few weeks,” Fischbach explained. “Here we have a community that has lived together for 10 years. Some people thought it would destroy our colony.”

The challenge was successful. For the most part, the bacterial communities assembled by researchers survived the fight against the human microbiome.

Approximately 20 new bacterial species were found to successfully colonize hCom1, killing a small number of previously selected bacteria. Ultimately, researchers cataloged 119 strains of bacteria, naming this second-generation microbiome hCom2. We found that this hCom2 microbiome community functions as effectively as the general microbial composition of mice.

“hCom2-colonized mice appear immunologically normal, have similar microbiome-derived metabolites, Escherichia coli,” Fischbach said“Despite improvements to be made, we believe hCom2 (in its current form) is a good model system for the microbiome.”

What should I do then? Fischbach and his team want to make his model of the microbiome available to as many researchers as possible. They believe that the true impact of this study will come from the work of other scientists, allowing for the first time a consistent microbiome model for research to build.

Further down the line, researchers envision a future where patients receive transplants of engineered bacterial communities. Working towards this, Fischbach is director of the recently founded Stanford Microbiome Therapy Initiative (MITI). This initiative will improve the microbiome model.

A new study was published in cell.

Source: Stanford University