Experts in the microbiome research field gathered during a recent event hosted by The Jackson Laboratory to discuss the trillions of microorganisms including bacteria, viruses, and fungi that live within us, and how they contribute to health and disease.
, deputy director of and professor and director of clinical diagnostic research, discussed how disruptions of the microbiome are linked with human diseases including autoimmune diseases, inflammatory disorders, and obesity with Professor Professor Weinstock holds the Evnin Family Chair and serves as director of microbial genomics at the Laboratory.
“The microbiome is simply all the microorganisms that have colonized your body,” said Weinstock. “You have a huge concentration of bacteria in your gastro-intestinal tract. It's like a big bioreactor and you have to picture that those enormous numbers of bacteria that are there are all performing their own separate kinds of metabolism.”
He said fungi also colonize our bodies, and there is an even larger number of viruses that we carry. “Even though we're healthy, we're actually all infected,” he said. “Just like we have all those bacteria, we have all those viruses too and the viruses are having some kind of dialogue with our immune system.”
Adams added that there are about 20,000 genes in the human genome, and millions of different genes in all the bacteria that are in the gut: “So that is a tremendous amount of functional capacity that is augmented by the bacteria that are in our systems.”
The search for the “fountain of youth” bacteria
Weinstock emphasized that our microbiome impacts our health throughout the entire course of our lives. “The microbiome is playing as much a part in your development as your own host cells are and that continues through your life,” he said.
Infants have a lot of organisms that are just colonizing for the first time, and while many of those organisms can be pathogens, they often do not create the same problems in babies that they do in adults due to their immune systems not being fully developed yet. “A lot of the times the problems you have with infections are the result of your response to it,” he explained, citing COVID-19 as an example of our host response to a virus.
The microbes colonizing infants’ guts are setting the threshold for being able to distinguish between good beneficial bacteria that are going to be with them for their whole lives, and pathogenic bacteria that are going to cause problems.
“As you grow, you acquire this complex microbial community that is the one that most of us have that is common between all of us,” he said.
He explained that our microbes affect everything from preventing pathogens from infecting us to creating neurotransmitters. “In fact, 50% of the serotonin in your body (an important neurotransmitter) comes from microbes,” he said. “There’s a gut-skin axis, a gut-mouth axis, a gut-liver axis. There’s lot of communications between your different organs and the microbes in your guts.”
As we age, our microbiomes change, and there are some bacteria that are more prevalent in elderly people than in young people, and vice versa. “We would all love to find those bacteria that are important for young people, and give them to older people to reverse aging,” said Weinstock. “That's the fountain of youth bacteria.” He said chronic inflammation, healthy aging, and frailty could all have to do with the constellation of microbes in our bodies.
Weinstock said we are just at the beginning of trying to understand how to manipulate our microbiome. “You can manipulate those microbes by changing your diet, by taking probiotics, by antibiotic treatment. There's evidence that exercise can change your microbiome,” he said. He also discussed using phage (viruses that infect bacteria) therapy, which could help target a particular species of bacteria.
Genetic approaches to the microbiome
Weinstock explained that the mouse is the “go-to system” for studying the microbiome, because we can control their environments and they provide ample opportunity for studying the genetic variation that takes place among humans.
“When we do personalized medicine, we are thinking not only about the human genome, but now more and more about the microbiome. What part of the microbiome is going to influence that person's response to a treatment, or account for that person's particular characteristics?” said Weinstock.
One way to understand this variance better is by using inbred strains of mice, in which an experiment has many mice that have exactly the same genes and variance. Some of those genetic variants cause one microbe to be higher or lower in abundance.
“JAX has not only a collection of inbred strains, but they also have a very well defined way of introducing variation, called diversity outbred mice,” said Weinstock. “In this case, you can mimic a human population by putting in a known amount of variation, and now you can study a cohort that's similar to humans, in that you can see what the variation does.”
Applying microbiome research to diabetes
Weinstock described how the Laboratory, in collaboration with Alan Attie, Ph.D. and Mark Keller, Ph.D., from the University of Wisconsin-Madison, is using diversity outbred mice, as well as characterized inbred mice, in order to study the effects of genetic diversity on diabetes at an unprecedented scale, by generating multiple types of data from different parts of the mouse.
One experiment, called “the three bears” in an affectionate reference to the fabled Goldilocks tale, examines how one strain of mouse gains weight and gets diabetes very rapidly, while another is immune to its high-fat diet and does not gain any weight, and a third is in between the two.
“We study the microbiome in each of those three, and look for correlations, look for what organisms are more abundant, or less abundant in that mouse strain that gets diabetes rapidly, and what are the ones that are differentiated in the mouse strain, that can eat high fat diet without it affecting it at all,” said Weinstock. “As we dig deeper and deeper, we can see which particular microbes (of the millions of strains of microbes that are in a mouse) are the ones that are really differentiated between those animals.”
The researchers have found biochemical pathways that are associated with these particular bacteria that differentiate the overweight mouse from the lean mouse. “And lo and behold, when you look in the diabetes literature for humans, these are biochemical pathways that have some association with humans propensity to get diabetes too,” he said.
Weinstock says we now have many different avenues to pursue with this new knowledge.
“If we can identify a pathway that’s bad for a particular person because a certain microbe is overabundant, maybe we can figure out how to knock down that microbe and reverse that person's condition,” said Weinstock. “We are right at the very edge of being able to make those kinds of suggestions and treatments.”