Mapping the immense universe of the human gut
New research looks at trillions of bugs living in our digestive systems
In two major studies published Thursday, scientists have analyzed thousands of fecal samples to tackle one of the biggest questions in the red-hot field of microbiome research: what exactly is a “normal” gut microbiome, and what are the factors that shape it?
The new research, published in the journal Science, found links between the gut microbiome — the trillions of bugs inside our digestive tracts — and nearly 200 environmental and biological factors: everything from depression and heart attacks to birth control, sugary soda and a love of dark chocolate.
But while these sprawling studies are the largest published in the microbiome space, they still barely scratch the surface when it comes to defining the “healthy” gut.
“Defining ‘normal’ in the microbiota is very important . . . and I think we, for the first time, really did that,” said Jeroen Raes, a microbiology professor at Belgium’s Leuven University and a co-author on both studies. “But even though this is one of the biggest studies worldwide, it’s still the tip of the iceberg.”
The past decade has seen a deluge of research into the gut microbiome, which is so important to human health that it’s sometimes called a “second genome” or extra organ.
Researchers are probing potential links between gut microbes and everything from asthma to Alzheimer’s disease. But while microbiome research shows thrilling potential, most studies are still preliminary.
A major bottleneck is puzzling out what a “normal” gut microbiome is supposed to look like. “If we know what a healthy microbiome is, then we can try to get there,” explained Karen Madsen, director of the University of Alberta’s Centre for Excellence for Gastrointestinal Inflammation and Immunity Research, who was not involved with the Science papers.
These latest papers are the largest “population-level” studies to tackle this question. Both appeared in a special microbiome-themed issue of the journal Science.
In one study, Raes’ team used gene sequencing technology to identify the gut microbes inside 1,106 fecal samples provided by Belgian volunteers. The other paper, conducted by Dutch researchers, analyzed 1,135 fecal samples collected in the Netherlands.
Raes’ team tried to define a “core microbiota” that spanned both study groups, as well as people living in the United States and United Kingdom — a total sample size of 3,948 people.
They found a “core microbiota” of 17 genera, or families of microbes — in other words, bugs that appear in the guts of 95 per cent of people in the study.
These people also collectively harboured 664 different genera — but even this is just a tiny sliver of the entire microbial spectrum, Raes acknowledges. Understanding the full microbial universe of the “normal” western gut, his study estimates, would “require sampling an estimated additional 40,739 individuals.”
Both studies go beyond simply cataloguing the microbes present in people’s guts, however, and also use clinical tests and exhaustive questionnaires to tease out factors that could be influencing our gut microbiomes.
“It’s an important first effort to not only capture ‘normal’ — or some portion of normality — but also to understand the kinds of factors that are potentially most important in explaining the variation,” said Dr. David Relman, a microbiome researcher at Stanford University, who was not involved with the studies. “These are really important leads that will prompt a whole range of future studies.”
The two studies identified nearly 200 factors linked to the microbiome’s composition, diversity or gene richness, but these explain less than 20 per cent of the total variation between different gut microbiomes.
“The vast majority of variation we haven’t yet explained,” Relman said. “That’s a really interesting finding.”
Raes said the most surprising factor identified by his study was stool consistency, which had a “shockingly strong” association with the gut microbiome. He noted that stool consistency has been largely ignored by past research looking into the links between the microbiome and disease, and perhaps some of those studies now need re-evaluation.
In both studies, drugs were important factors in influencing the mi- crobiome — not just antibiotics but everything from female hormones to statins and proton pump inhibitors, used to treat acid reflux. Heart attacks, interestingly, were also linked with a lower abundance of a bacterium called Eubacterium eligens.
Unsurprisingly, diet is also influential in shaping the gut microbiome. But both papers found specific associations between foods and bacteria — in Belgium, for instance, a love of dark chocolate was associated with more Lachnospiraceae bacteria in people’s guts. But these observations are just correlations, researchers caution — and what they actually reveal about the gut microbiome remains anyone’s guess.
“The problem now is that people are going to have to take this information and figure out what does this really mean,” Madsen said.
One thing researchers do know already is that a rich and diverse gut microbiome is better for health than one with low diversity. “I think this is the only thing that we are really quite sure about,” said Alexandra Zhernakova, a geneticist with the University of Groningen and the first author on the Dutch study.
In her paper, the factors linked to higher diversity were fruits, coffee and red wine. Western-style diets, carbohydrates and sugary sodas were associated with low diversity, as was a fecal protein called chromogranin A, which had never been reported before in past microbiome studies but showed a “massive effect,” Zhernakova said.