The Most Heritable Gut Bacterium is… Wait, What is That?

The twisting helices of DNA within our bodies influence everything from our height to our personality to risk of diseases. Now, it’s clear that our genes also shape our microbiomes—the trillions of microbes that live within us.

By studying 416 pairs of British twins, Julia Goodrich and colleagues from Cornell University have identified the gut microbes whose presence is most strongly affected by our genes. And chief among them was a mysterious bacterium called Christensenella minuta, the one and only member of a family that was discovered just three years agodiscovered just three years ago.

Genetically and physically, it’s rather mundane. It’s yet another rod-shaped, oxygen-hating, nutrient-fermenting bacterium from the Firmicute dynasty—one of the two major groups in our guts. And yet, more than any other microbe, its presence in our body is strongly influenced by our genes. Christensenella also seems to sit at the centre of a large network of microbes; if it’s there, these others are likely to show up too. And it influences our weight: it’s more common in lean people, and it can reduce weight gain in mice.

All of these traits suggest that Christensenella might (emphasis on might) be a keystone species: one that wields a disproportionate influence upon the world around it. The term was first used to describe a starfish, whose absence could entirely change the nature of a seashore. It has since been used to describe sea otters, wolves, and mistletoe. These species might be relatively rare, but they are ecologically powerful. Perhaps Christensenella is similarly important in the world of our guts. And yet, until recently, no one even knew it existed.

“I’d never heard of it before,” says Ruth Ley, who led the study. “It illuminates this real problem in the field. We only talk about things that have names.”

Christensenella aside, this study also provides the strongest evidence to date that our genomes dictate the memberships of our microbiome. There were hints of that before; for example, we knew that the microbiomes of family members are more similar than those of unrelated individuals. But that could just be because they live in similar environments and eat similar diets. To what extent are genes important?

To find out, scientists have turned to twins. If a trait is strongly influenced by genes, then identical twins (who share 100 percent of their DNA) should be more similar in that trait than non-identical twins (who share just half of their DNA). In 2008, a group led by Peter Turnbaugh studied the microbiomes of 44 pairs of American twins and couldn’t find any species or genes that were more consistently shared by identical twins than non-identical twins. A later study led by Tanya Yatsunenko, which included 87 twin pairs from the USA and Malawi, found the same thing. “The overall heritability of the microbiome is low,” wrote the group.

But Ley, who was involved in the 2008 work, suspected that these studies were just too small. She wanted more twins. To find them, she teamed up with Tim Spector from Kings College London, who set up the world’s largest registry of twins two decades ago. The team gathered stool samples from 977 of them, including 171 pairs of identical twins and 245 non-identical pairs. That’s more than five times the size of the biggest previous study.

They found that the identical twins did have slightly more similar microbiomes than the non-identical ones. “I think we’ve put that question to rest,” says Ley. They also found starker differences when they looked at specific families: certain groups of microbes are far more heritable than others. Christensenella topped the list with a heritability of 0.4. In other words, some people have it and others don’t, and around 40 percent of that variation is down to our genes.

Christensenella often co-exists with an entourage of other microbes, including other mystery groups that haven’t been properly named. Their concurrence might be coincidence: the same genes could be selecting for many microbes independently. Alternatively, the entourage might actually be partners, producing nutrients that nourish each other. Either way, they form a consistent social network with Christensenella at its core.

The team found the same thing when they looked at the data from old studies. Christensenella is also the most heritable bacterium in American and Malawian guts, and co-exists with the same network of neighbours. This suggests that the results are real, and that they aren’t unique to the UK.

Christensenella and its consortium were especially common in lean people. Are skinny people better at carrying it, or does the bacterium affect our weight? To find out, the team transplanted the stools from some of their twins into specially reared mice that had no bacteria of their own. Back in 2006, Ley helped to run similar experiments, which showed that germ-free mice gained weight when implanted with the stools of obese people. This time, her team found the same thing, but with a twist: if the stools also contained Christensenella, the mice put on fewer pounds.

The team confirmed this by deliberately adding Christensenella to a stool sample before transplanting it into germ-free mice. Without the microbe, the mice put on 15 percent more weight and had 25 percent body fat. With it, they put on just 10 percent more weight, and had just 21 percent body fat. For comparison, that’s the equivalent of a 70 kilogram person putting on seven extra kilograms rather than ten.

The team are now trying to figure out exactly what Christensenella does, and how that affects our weight. “We haven’t a clue,” says Ley. “We’re butting up against the same problem everyone has. You can associate a microbe with a trait, and you can even produce the trait by adding [the microbe], but what’s the mechanisms?”

It doesn’t help that we know so little about this mysterious microbe. It’s there from birth: when Ley looked at an older study involving a single infant, she found that Christensenella made up 20 percent of the microbes in the baby’s stool. It’s much rarer in samples from adults. Its abundance doesn’t depend on our diet, unlike many other gut bacteria. And it is influenced by our genes.

But which genes? That’s another mystery, but one that might prove easier to solve. There are DNA samples for all the twins in Spector’s registry, so it should be possible to identify the genes that foster Christensenella and other heritable microbes.

And that might help to explain another intriguing result: the majority of the most heritable bacteria are more common in thin people than in fat ones. Does that mean that our genes are selecting for bacteria that promote a healthier weight? Or that diets which lead to obesity also mask the genetic influences on our microbiome? Or that people who become obese have genes that promote different groups of bacteria? All of these explanations make sense, but none of them are proven. There is so much we have yet to discover about the microbes that share our lives.

Reference: Goodrich, Waters, Poole, Sutter, Koren, Blekhman, Beaumont, Van Treuren, Knight, Bell, Spector, Clark & Ley. 2014. Human Genetics Shape the Gut Microbiome. Cell http://dx.doi.org/10.1016/j.cell.2014.09.053