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Our bodies harbor hundreds or thousands of microbial species, but no one knows exactly how many there are. This is just one of the many mysteries of the so-called human microbiome.
Our internal ecosystem defends itself against pathogens, helps digest food, and can even influence behavior, but researchers haven’t yet figured out exactly what microbes do or how. Many studies indicate that many species must work together to perform each microbiome task.
To better understand how microbes affect our health, scientists have created for the first time a synthetic human microbiome, combining 119 species of bacteria naturally found in the human body. When the researchers gave the mixture to mice that didn’t have their own microbiome, the bacterial strains took hold and remained stable even when the scientists introduced other microbes.
The new synthetic microbiome is even able to resist aggressive pathogens and encourage the mice to develop a healthy immune system like a full microbiome does. The results were published September 6 in the journal Cell.
If we better understand the microbiome, there would be ways to treat many diseases more effectively. Doctors can already use the microbiome to treat intestinal infections caused by Clostridium difficile bacteria, some of which are fatal. All you have to do is transplant the feces of a healthy donor and the infection usually clears up.
“It works amazingly well,” said Alice Cheng, a gastroenterologist at Stanford University who led the new study.
Now, Cheng and his colleagues can use the new synthetic microbiome to learn the function of each microbe, insights that should help doctors fight other diseases. For example, scientists could mix 118 of the 119 species in the lab and then see how the altered microbiome affects the health of the mice.
Before the 21st century, most of what was known about the human microbiome came from the few species that researchers could grow in a petri dish. In the early 2000s, scientists made a breakthrough by extracting DNA from human saliva, feces, and skin samples. Using these genetic sequences, they created a catalog of species that live in our bodies.
The list was very long and many species were new to microbiologists. Also, most species live inside some people but not others, which is more confusing. There is no single human microbiome.
Several researchers turned to mice to learn more about some of these unknown organisms. They raised germ-free animals in sterile cages and then inserted broth made from human feces into their intestines. The microbes from this fecal transplant then began to replicate in the animals.
Some researchers have taken on this challenge, giving germ-free mice a single species of microbe to observe its effects; However, such experiments have their own limitations, as many microbes do not do well without ecological partners to help them.
Scientists have tried giving germ-free mice specific combinations of microbes, but even in the most successful attempts, transplanted mice have shown the presence of fewer than 20 species, not the hundreds living in humans. These miniature microbiomes result in an underdeveloped immune system and metabolism in mice. “You end up with a mouse that doesn’t work,” said Lora Hooper, an immunologist at the University of Texas Southwestern Medical Center, who was not involved in the new study.
In 2017, Cheng and his Stanford colleague Michael Fischbach had lengthy discussions about how to overcome the shortcomings of previous studies. “We had to build an ecosystem from scratch,” Fischbach said.
They knew that growing a variety of microbes in the lab would be difficult, and it was entirely possible that a mouse would have its ecosystem failing. “At the time, we couldn’t count on it working,” says Fischbach.
First, Cheng and his colleagues compiled a list of 166 species found in a significant percentage of humans. When they contacted labs and companies, they got 104.
Cheng found that the 104 species created a stable ecosystem in the mice. Not only did the microbes persist in the animals, but the structure of the ecosystem did not change. Some microbes soon became and remained plentiful; others were rare but never disappeared; and the same ecosystem kept reappearing in different mice.
“It’s amazing how more than a hundred strains from the human gut form a stable and resilient community,” said Kiran Patil, a biologist at the University of Cambridge who was not involved in the study. “It’s like a 100 piece jigsaw puzzle that looks daunting but then all you have to do is mix and shake the pieces and voila! The riddle will solve itself.”
Next, Cheng and his colleagues put their microbiome to the test: they transplanted feces from human volunteers into the mice. Would the animals’ synthetic microbiome have the resistance needed to withstand the onslaught?
This is how it happened: Only seven of the original species disappeared. Some of the new species found holes in the ecosystem and became a stable part of the microbiome.
“I lay down on a sofa and stared at the skylight,” Cheng said. “At that point I was like, ‘I can’t believe it worked.’”
With this second experiment, Cheng and his colleagues fine-tuned their microbiome. They selected the 22 most successful newcomer species and added them to their microbial zoo, bringing the total to 119 species.
This new microbiome, which they have dubbed hCom2, is even more resilient than the first version. When the scientists gave the hCom2 mice a stool transplant, none of the newly arrived microbiomes could establish themselves in the animals.
The researchers also tested how well the mice might respond to a potentially deadly strain of E. coli. In previous experiments, scientists have found that this strain can explode in the guts of mice with a small 12-species microbiome.
Cheng and his colleagues dosed their hCom2 mice with E. coli and found that they resisted the invaders just as well as mice given a whole human stool sample.
The hCom2 microbiome also had the same impact on its hosts as a whole microbiome. The mice produced healthy digestive fluids in the gut and developed a complete immune system not found in germ-free mice.
Cheng and his colleagues have already started experiments in which they leave certain microbes out of the cocktail to better understand how your microbiome works. They also make their microbe bank available to other researchers who want to carry out their own experiments.
When asked if he intends to use the synthetic microbiome for his own research, Hooper replied succinctly, “Of course I do.”