Our bodies are home to hundreds or thousands of species of microbes, but no one knows for sure how many there are. This is just one of the many mysteries of the so-called human microbiome.
Our internal ecosystem defends us from pathogens, helps digest food, and can even influence behavior. But scientists haven’t yet figured out what each microbe does or how. Various studies indicate that many species have to work together to perform each of the microbiome’s tasks.
To better understand how microbes affect our health, scientists have for the first time created a synthetic human microbiome, combining 119 species of bacteria found naturally in the human body. When the researchers gave this mixture to mice that did not have a microbiome of their own, the bacterial strains took up residence and remained stable, even when the scientists introduced other microbes.
The new synthetic microbiome can even ward off aggressive pathogens and cause mice to develop a healthy immune system, just like a complete microbiome does. The results were published on September 6 in the scientific journal Cell.
A better understanding of the microbiome could allow us to have a powerful tool to treat a number of diseases. Doctors can now use the microbiome to treat intestinal infections with the bacteria Clostridium difficile, which are potentially deadly. They just have to transplant stool from a healthy donor and the infection usually clears up.
“It works surprisingly well,” said Dr. Alice Cheng, a gastroenterologist at Stanford University who led the new study.
Cheng and his colleagues can now use the new synthetic microbiome to learn the role of individual microbes, knowledge that could help doctors treat other disorders. For example, scientists could mix a cocktail of 118 of the 119 species in the lab and then see how the modified microbiome affects the health of the mice.
“This is something that has been sorely needed for a long time,” said Dr. Gary Wu, a gastroenterologist at the University of Pennsylvania School of Medicine, who was not involved in the research.
Each of us harbors 30 billion microbes, roughly the same number as our cells. But because bacteria are much smaller, they only make up a few pounds of our weight.
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. With those genetic sequences in hand, they created a catalog of the species that live in our bodies.
The list was surprisingly long, and many species were new to microbiologists. Also, most species live in some people but not in others. There is no single human microbiome.
Synthetic microbiome: trials that show promise
Several researchers turned to mice to become familiar with some of these unknown organisms. They raised germ-free animals in sterile cages and then introduced broth made from human feces into their intestines. The microbes from that fecal transplant began to reproduce in the animals.
These experiments have given some promising results. For example, in some experiments, germ-free mice given microbiomes from obese people gained more weight than mice transplanted with microbiomes from people of average weight.
But it is more difficult to determine why these changes occur. There is no way to manipulate the microbiome of a stool sample on a species-by-species basis. “It’s completely mixed and cannot be changed,” says Cheng.
Some researchers have addressed this challenge by giving germ-free mice a single species of microbe and observing its effect. But those experiments have limits, as many microbes don’t function properly without ecological partners to help them.
Scientists have tested giving germ-free mice combinations of microbes. But so far, even the best efforts have left transplanted mice with fewer than 20 species, not the hundreds that live in humans. These miniature microbiomes leave mice with underdeveloped immune systems and metabolisms. “You have 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.
Building an ecosystem from scratch
In 2017, Cheng and his Stanford colleague Michael Fischbach had lengthy conversations about how to overcome the shortcomings of previous studies. “We needed to build an ecosystem from scratch,” said Fischbach.
They knew that it would be difficult to grow a wide variety of microbes in the laboratory. And it was entirely possible that, once in a mouse, the ecosystem would fail. “At the time, we couldn’t expect this to work,” Fischbach said.
First, Cheng and his colleagues compiled a list of 166 species that have been found in a significant percentage of people. When they contacted laboratories and companies, they managed to get hold of 104 of them.
Each microbe came with its own instructions for staying alive. To Fischbach’s surprise, Cheng figured out how to meet each of his stringent requirements for producing colonies in the lab.
Cheng mixed all 104 species and introduced them into germ-free mice. He then gave the microbes time to settle…or die. To see how this makeshift microbiome fared, he had to collect the mice droppings and work with his colleagues to sequence all the DNA they contained.
Cheng found that all 104 species created a stable ecosystem in mice. Not only did the microbes persist in the animals, but also the structure of the ecosystem did not change. Some microbes quickly became abundant and stayed that way. Others became few in number but never disappeared. And the same ecosystem emerged over and over again in different mice.
“It’s amazing how more than a hundred strains from the human gut form a stable and resistant community,” said Kiran Patil, a biologist at the University of Cambridge who was not involved in the study. “It’s like a 100-piece puzzle that looks intimidating, but then you just have to mix and shake the pieces, and voila! The puzzle solves itself.”
Next, Cheng and his colleagues put the microbiome to the test: They gave mice transplants of feces from human volunteers. Would the synthetic microbiome of animals be tough enough to withstand the onslaught?
It was. Only seven of the original species disappeared. Some of the new species found empty places in the ecosystem and became a stable part of the microbiome.
“I threw myself on a couch and stared at the skylight,” Cheng said. “I was overcome with the feeling of ‘I can’t believe it worked'”.
From that 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 for a total of 119 species.
This new microbiome, which they have called hCom2, is even more resistant than the first version. When the scientists gave the hCom2 mice a stool transplant, none of the newly arrived species were able to establish themselves in the animals.
The researchers also tested how well the mice could cope with a strain of Escherichia coli potentially lethal. In previous experiments, scientists had found that strain can burst in the gut of mice that have a miniature 12-species microbiome.
Cheng and his colleagues gave their hCom2 mice a dose of E. coli and found that they resisted the invaders just as well as mice that had received a complete human stool sample.
The hCom2 microbiome also had the same kind of influence on its hosts as an entire microbiome. The mice produced healthy levels of digestive fluids in the gut and developed full immune systems not found in germ-free mice.
The mystery of microbiomes
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 are also offering their microbe bank to other researchers who want to run their own experiments.
When asked if he intended to use the synthetic microbiome for his own research, Hooper succinctly replied, “Of course.”
He hopes to use hCom2 mice to understand How the microbiome influences obesity. It is clear that part of the answer lies in how microbes help the intestine to absorb fatty lipids from food. But studies in mice haven’t shed much light on which microbes help and which get in the way.
“It’s taken us a long time to get to the answer to that question,” he said. “So this kind of experimental system will allow us to move forward.”
The New York Times. Special
Translation: Elisa Carnelli