The origins of human microbiota research

Anand Jagatia 0:04

There are trillions of microbes living on us and in us; a thriving ecosystem of bacteria, viruses, archaea, and fungi. Collectively, these microscopic organisms form the human microbiota. And it appears to play a key role in many aspects of our health.

Researchers now have evidence that the microbiota aids our digestion and nutrition and shapes our immune system. But it's also been linked with certain inflammatory diseases, with cancer, and it may even play a role in brain development. But how do we get to this point?

David Relman 0:38

This all began with the means to see microbes; it was the invention of the microscope. And the first data sets were on the shape of these cells and their movement.

Anand Jagatia 0:53

This is David Relman, Professor of Medicine and of Microbiology and Immunology at Stanford University in the US.

David Relman 1:00

The next major technological breakthrough was the advent of culture. And what culture allowed scientists and others to do was to create enough of this microscopic life to see it in its bulk form, but also to measure its bulk properties, meaning, what are the biochemical reactions that it performs.

The third big breakthrough was the technology that allowed us to sequence the small molecules of life, and those molecules included DNA, but also eventually RNA. As these technologies became cheaper, easier, and more sensitive, and accurate, over the last 20 years, it became possible to sequence proteins and infer the structure of metabolites.

Looking at these different kinds of molecules, we could say, not just who these cells are, and to whom they're related, but what they're doing, what they're making, what their functions might be. And so the net sum of all of these effector molecules that microbes are making, and using to talk to each other become, then, the basis for the functioning of a true community.

Anand Jagatia 2:14

Thanks to these technologies, scientists were able to move from looking at a handful of microbial strains in a petri dish, to studying the complex relationships and interactions within communities. This was the start of microbiota research as we know it, which really got going in the late 1990s. So what were some of those first key experiments?

David Relman 2:34

I would point to a paper by Joel Dore in 1999, where he and his colleagues in Paris amplified sequences from human faecal samples and sequenced them, and then used those sequences to infer the nature and relationships of the organisms that were in this faecal sample. In the same year, we did work in my laboratory, looking at some scrapings from human teeth (they were actually my own teeth). But from the same samples, we also asked the clinical microbiology lab here at Stanford to grow everything they could. And we compared what it was that we could see from culture, and what it was that we could see from molecular technologies. The bottom line was that the sequencing approach revealed far more, and was an order of magnitude more sensitive, and informative.

Anand Jagatia 3:32

Since those early experiments, we've continued to learn much about the microbiota, sometimes referred to as the microbiome, and its impact on human health. Several key strands of research have emerged.

David Relman 3:43

Perhaps the first of these would be the recognition that the microbiome turns out to be one of the major defences against invasion or infection by external pathogens. These are organisms like salmonella, that can normally infect a healthy person, but only when present in very large numbers.

And that was work that that began in the 19…, late 1950s and early 1960s, when it was found that antibiotics when used to treat an animal render the animal much more susceptible to these invasive pathogens, and today has been worked out in much more detail so that we understand mechanisms.

Anand Jagatia 4:27

Researchers have also become much more aware of how the microbiota relates to nutrition, and it's links with obesity or malnutrition. They're also interested in the role that microbial populations play in chronic diseases like inflammatory bowel disease, and how the microbiota helps shape our immune system.

David Relman 4:46

That's work that was again, recognised early on, when germ-free animals were found to have deficient and defective immune systems, but became much better understood as germ-free animals could be reliably recolonized, and their immune system studied in a great deal of detail.

Anand Jagatia 5:09

Across all of these strands, and the many more that have emerged since, researchers have tried to link aspects of human health to the composition of the microbiota. But they quickly discovered that there's no one healthy microbial makeup. We're all unique. David, things that understanding why this variation exists is key.

David Relman 5:28

What are all the environmental factors? What are all the other host factors that that cause differences in a microbiome? And can we understand those to the point of making predictions or designing interventions that could change our microbiome? And and for this, I would point to the work of multinational population based studies of thousands of individuals and their and their microbiome, to understand what is it that can account for differences between people? And what are these lifestyle factors that might be most important, and how do we rank them and and think about those that we might be able to influence?

Anand Jagatia 6:08

These kinds of population-scale studies, including the Human Microbiome Project, the Flemish gut flora project, and the American gut project have identified and genetically sequence the microbial populations of thousands or tens of thousands of people. It's a long way from the early experiments that characterised the species on David's teeth. So given how far research has come, where does David think it's headed in the future?

David Relman 6:32

If we accept that the microbiome is fundamentally important for health, then the future will be very much about how can we ensure that our microbiome continues to function properly? And when and and if it becomes degraded or harmed or damaged by things that we do or things that happened to us. How can we restore it? And that is, I think, a big goal for work in the future.