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 irritable bowel syndrome.
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 irritable bowel syndrome? 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.
"I think it makes a pretty strong case that there are common fungi in the gut that are normally non-pathogenic that can cause problems if not properly managed," said Andrew Gewirtz, an Emory University gut bacteria specialist who was not involved in the study.
Underhill warned that the findings haven't yet been duplicated in another patient group, a necessary step in ensuring the link to colitis.
A fungal link to colitis is, however, just a first hypothesis. Underhill and Iliev's mouse scans found some 200 fungal species, fully half of which had never been described before. Only a few species were present in mouse food, suggesting that fungi are an established part of gut communities.
"The paper is great. It raises awareness for the fungal microbiome in the gut that we know is there but somehow is underappreciated," said Peer Bork, a bioinformaticist at the European Molecular Biological Laboratory.
Bork's own research on gut bacteria has found global patterns analogous to blood type distributions. Whether that holds true for fungi is a now a question to be investigated, along with possible fungal roles in metabolism, immunity and other physiological processes.
"People study all that in the context of the gut bacteria, in the context of viruses in our microflora," Underhill said. "You can map all those questions to fungi."
Citation: "Interactions Between Commensal Fungi and the C-Type Lectin Receptor Dectin-1 Influence Colitis," by I.D. Iliev; C.N. Reyes; C.A. Becker; M. Dubinsky; D.P.B. McGovern; D.M. Underhill; V.A. Funari; K.D. Taylor; Q. Nguyen; S.P. Strom; J. Brown; J.I. Rotter; P.R. Fleshner at Cedars-Sinai Medical Center in Los Angeles, CA; H.L. Wang; D.M. Underhill. Vol 336, Issue 6085, June 8 2012.
Image by Iliyan Iliev
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