“With all the knowledge we’ve gathered, we made the best possible effort to capture all the factors we could imagine, and we could only explain 8 percent of the total variation,” says Jeroen Raes from the University of Leuven, who led the Belgian study. “It’s very humbling.”
If this sounds familiar, it’s because geneticists went through a similar period of humility. Complex traits like height, intelligence, and schizophrenia risk are strongly heritable, but finding the genes that underlie them has been monstrously hard. Early on, researchers used small experiments to identify many genetic variants that are linked to diseases and physical traits. But later, larger studies revealed that many of these results were false alarms, prompting a move towards more rigorous methods.
The microbiome field is negotiating the same cycle of hype, backlash, and introspection. Thousands of studies have linked the microbiome to almost every condition you can imagine, but many of these correlations are likely to be illusory. “A lot of people have been annoyed by the hype surrounding our area, and I think they were probably right,” says Raes. “It’s time that, from within the field, we look critically at what we’re doing ourselves. We tried to do that with our paper. Yes, we’ve had the hype. Now, it’s time for the consolidation.”
Raes is right to be cautious. For example, his team found that the single thing that most strongly correlates with the make-up of the gut microbiome is the consistency of one’s stool. Virtually no clinical studies have measured or accounted for that. This means that in the past, when scientists found differences between the microbiomes of sick and healthy people, those differences might have had nothing to do with disease. Maybe the sick people just had runnier poop. “It’s a wake-up call for all of us to start taking these things into account,” says Raes.
Medications are also important, from obvious ones like antibiotics and laxatives, to less intuitive ones like antihistamines, antidepressants, and metformin, which is used to treat type 2 diabetes. “It’s one of those elephants in the room,” says Raes. “Everyone knew [that drugs are important] but no one controlled for them.”
Several factors predictably affect the microbiome, including weight, age, gender and consumption of several foods and nutrients, whether it's bread, fruit, soda, coffee, tea, red wine, or dietary fiber.
Others links were inexplicable. The Dutch team found that the levels of chromogranin A (CgA), a protein secreted by intestinal cells, is strongly linked to the levels of 61 common species of microbe. “We don’t have a good explanation for that, and we know relatively little about this protein,” says Alexandra Zhernakova, who led the study. Meanwhile, Raes found that some Lachnospiraceae bacteria are more common in people who like dark chocolate. (“We don’t understand it, but I think it’s hilarious that you do a Belgian study and one of the factors that comes out is chocolate,” he says.)