The microbiomes of the stressed corals had become more varied. They didn’t shift in any particular direction—they changed in every direction. And shortly after Zaneveld realized this, he spotted the same pattern—but this time in chimpanzees. Researchers at Yale University had studied the gut microbiomes of chimps that were infected with an HIV-like virus, and found that their microbiomes had also become more variable.
Zaneveld and Vega Thurber now think that this trend applies to all kinds of microbiomes, whether in corals, chimps, or humans. All of these hosts use a range of tactics to control which species and strains get to share their bodies. When the hosts are stressed or diseased, their control breaks down, and their microbiomes start to change. But they change randomly, rather than predictably. They don’t shift to any one specific unhealthy state. Rather, they veer off in unpredictable directions and enter a wide range of new states.
Since each disrupted microbiome is its own unique little snowflake, “we were originally going to call this the snowflake hypothesis,” says Vega Thurber, “but there’s a lot of negative connotation around that word now.” So, instead, Zaneveld has called the idea the Anna Karenina Hypothesis, after the opening lines of Tolstoy’s novel: “All happy families are alike; each unhappy family is unhappy in its own way.” Similarly, every unhealthy microbiome is unhealthy in its own way.
The hypothesis is something of a Grand Unified Theory of Unhealthy Microbiomes. “We started in corals but we started seeing the same pattern in human studies,” says Vega Thurber. “Now it’s something I can’t unsee. Whenever I see a microbiome paper that compares healthy and sick individuals, this pattern jumps out.”
By scouring the data from past studies, she and Zaneveld have found Anna Karenina effects in the bodies of human alcoholics and cigarette smokers, mice that are fighting off gut infections, and sponges living in acidifying water. The immune system is critical for controlling the microbiome, so unsurprisingly, Anna Karenina effects can also be triggered by diseases where the immune system is suppressed (like HIV) or hyperactive (like type 1 diabetes, Crohn’s disease, and other autoimmune disorders).
“Have I missed this trend in my own data? Yes and no,” says Valerie McKenzie from the University of Colorado Boulder, who studies how the skin microbiomes of frogs react to a killer fungus. “We have definitely seen greater dispersion of the community following infection. I recall presenting that finding in a talk a while ago, but I didn't know how to explain it. Having read this paper, I will revisit that question.”
Not every past study conforms to this pattern. In several cases, scientists have found that stress or disease can change the microbiome in specific ways. But Vega Thurber says that such results often come from reductionist experiments, involving laboratory animals that are studied under tightly controlled conditions. And it’s the messiness of the real world that contributes to Anna Karenina patterns. If a host can’t control its microbiome, its body could be invaded by microbes that are in the environment, or that come in through food. Those potential invaders would vary significantly from one setting to another, which is why no disturbed microbiome changes in quite the same way as the others.