The big, weird world of creatures inside you may be even bigger and weirder than anybody thought.
Fungi are the latest addition to human menagerie, joining bacteria and viruses in forming the teeming, biological kingdom-spanning superorganisms of our bodies.
"We were all fascinated with the diversity and sheer mass of microorganisms that live inside our intestines," said immunobiologist David Underhill of the Cedars-Sinai Medical Center. "So we started asking: What do we know about fungus in the gut?"
In a June 8 Science study, researchers led by Underhill and postdoctoral student Ilian Iliev link gut fungus to colitis, an inflammatory bowel disease.
While the findings may be presently useful to colitis researchers, the implications are sweeping: Scientists might ask the same questions of internal fungi as they do internal bacteria, the importance of which is now a buzzing research frontier.
In the last decade, researchers have linked resident communities of bacteria – which outnumber human cells in a body by 10 to 1 – to diseases and fundamental processes, from diabetes and heart disease to metabolism and immune system function. Even viruses are in on the act.
Appreciation of this so-called microbiome represents a sea change in awareness of bacteria: No longer are they external entities that sometimes cause disease, but rather an essential, positive component of human health.
Whether fungi also play a part is a question relatively few researchers have asked. A handful of studies have suggested a limited role, primarily in skin and mouth conditions.
"There's not a whole lot out there at this point. People have understood that fungi are there, but that's been a relatively vague notion," Underhill said.
He and Iliev were intrigued several years ago by population-wide genomics studies that linked a cellular component called CARD9 to slightly higher rates of inflammatory bowel disease.
CARD9, the researchers knew, played a crucial role in the immune system's detection of fungal cells, and mice with CARD9 deficiencies were especially vulnerable to fungal infections.
"That got us to ask: How could a signaling molecule involved in antifungal immunity be involved in inflammatory bowel disease? Is there a fungus in there?" Underhill said.
The new study represents three years of research on that question. Underhill and Iliev's team first designed molecular probes to detect fungi in mouse stools. They found hundreds of species and then, to make sure it wasn't a mouse-specific phenomenon, repeated the search in rats, rabbits, dogs and people.
Again and again, they found a wealth of gut fungi.
Next they engineered a strain of mice lacking dectin-1, a cellular component that interacts with CARD9 in tagging fungal cells for immune system disposal. With their fungal detection systems haywire, the mice developed severe intestinal inflammation, similar to colitis.
"We think the fungus gets into the tissue and isn't recognized and killed," Underhill said, and to test this possibility they dosed the mice with an antifungal drug. The mice recovered.
Underhill and Iliev then looked at genetic data from hundreds of ulcerative colitis patients seen at Cedars-Sinai. Among people with the most severe afflictions, who could not be treated and required surgery to remove their colons, they found strong links to mutations affecting dectin-1.