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As scientists gain new insights into the human microbiome and how it influences our health, microbiology labs may gain new diagnostic biomarkers

In a study that took more than five years to complete, researchers from Stanford University have successfully created the first synthetic microbiome model from scratch. The goal of the study was to create a baseline microbiome model so that future studies will have a better understanding of which clinical laboratory tests and medical interventions could be useful for treating specific ailments and improving patient care.

To create their synthetic human microbiome, the Stanford researchers combined 119 species of bacteria, The New York Times reported, adding that “the new synthetic microbiome can even withstand aggressive pathogens and cause mice to develop a healthy immune system, as a full microbiome does.”

According to the National Institute of Health (NIH), the human gut contains trillions of microbes, and no two people share the exact same microbiome composition. This complex community of microbial cells influences human physiology, metabolism, nutrition and immune function, and performs a critical role in overall health.

The Stanford scientists believe researchers now have a common microbiome foundation for future microbial studies.

They published their findings in the journal Cell in an article titled, “Design, Construction, and In Vivo Augmentation of a Complex Gut Microbiome.”

“We were looking for the Noah’s Ark of bacteria species in the human gut, trying to find the ones that were almost always there in any individual,” said Michael Fischbach, PhD, Associate Professor in the Departments of Bioengineering and Microbiology and Immunology at Stanford University. Future microbial studies that use Stanford’s synthetic human microbiome may develop improved clinical laboratory tests and microbiome therapies. (Photo copyright: Stanford University.)

Creating the ‘Human Community One’ Microbiome

The researchers began their study by examining the gut bacteria makeup of adults involved in the Human Microbiome Project (HMP), an NIH initiative created to sequence the full microbial genomes of more than 300 adults.

The scientists then selected bacterial strains that were present in at least 20% of the HMP individuals. They focused on 104 bacterial species that they grew in individual stocks, and then mixed them into one combined culture to create what they named “Human Community One” (hCom1).

The researchers had to ensure that the final mixture had the stability to maintain a balance where no single species overpowered the rest and could perform all the actions of a natural microbiome. 

After being satisfied that the bacterial strains could coexist in a lab situation, the scientists set out to determine if their community would colonize in the gut. To do this, they introduced hCom1 to germ-free mice that are designed to have no natural microbiome.

When transplanted into the mice, the researchers discovered hCom1 was an extremely stable ecosystem, with 98% of the species taking root in the guts of the mice, and the levels of each bacterial species remaining constant over a two-month period. 

“We colonized germ-free mice with hCom1 and found that it was stable over time. Its species span six orders of magnitude of relative abundance: from ~10% to less than one in 1,000,000,” Michael Fischbach, PhD, Associate Professor in the Departments of Bioengineering and Microbiology and Immunology at Stanford University and one of the authors of the study, explained on Twitter

Based on a theory called colonization resistance, the team then introduced a human fecal sample to hCom1 to ensure that all vital microbiome functions would be performed by one or more species. Colonization resistance is the phenomenon where the normal gut microbiome protects itself against invasion by new and often harmful microorganisms. This theory hypothesizes that any bacterium introduced into an existing colony will only survive if it can fill a niche that is not already occupied. 

Creating a Second New Microbiome

Some researchers involved in the project were skeptical that introducing human fecal matter to hCom1 would work. They believed it would overtake the synthetic microbiome model.

“The bacterial species in hCom1 had lived together for only a few weeks,” Fischbach explained in a Stanford press release. “Here we were introducing a community that had coexisted for a decade. Some people thought they would decimate our colony.”

However, the scientists found that hCom1 thrived with only about 10% of the cells in the final community originating from the fecal transplant. A few of the original bacterial species died off and approximately 20 new bacterial species were able to successfully colonize hCom1. They ultimately catalogued 119 bacterial strains present in the colony after the transplant and dubbed the new microbiome “Human Community Two” (hCom2).

To further prove the functionality of their synthetic microbiome, the team then introduced an Escherichia coli (E. coli) sample to mice colonized with hCom2 and found that they were able to resist infection.

“Mice colonized by hCom2 look normal immunologically, have similar microbiome-derived metabolites, and exert colonization resistance against E. coli,” said Fischbach on Twitter, “There are improvements to make, but we think hCom2 (in its current form) is a good model system of the microbiome.”

Future Microbial Studies

The Stanford team hopes its synthetic microbiome model will allow researchers around the world to have a common foundation for future studies and provide them with the ability to create engineered microbiome-based therapies.

“We built this consortium for the broader research community,” said Fischbach in the press release. “We want to get this into as many hands as possible to have an impact on the field.”

While direct links to new clinical laboratory tests and microbiome therapies have not yet been established, research like the Stanford study demonstrates the increasing value of the human microbiome as a source of diagnostic information that can guide decisions on better ways to treat patients.

—JP Schlingman

Related Information:

Stanford Researchers Construct Most Complex, Complete Synthetic Microbiome

Design, Construction, and In Vivo Augmentation of a Complex Gut Microbiome

Stanford Scientists Build First Synthetic Human Microbiome from Scratch

Role of the Gut Microbiota in Health and Chronic Gastrointestinal Disease: Understanding a Hidden Metabolic Organ

Researchers Find Health of Human Microbiome Greatly Influenced by Foods We Eat

Dey Laboratory Research Finds Bile Acids Affect Gut Motility and the Human Microbiome, Insights That May Lead to New Clinical Laboratory Tests