Mycobiome Joins Microbiome as Player in Health and Disease
By Anette Breindl
The microbiome has garnered much attention in recent years for its role in health and disease. But that attention has been focused pretty much exclusively on bacteria.
Last week, researchers reported that there is also a community of fungi, which they dubbed the mycobiome, in the human gut. Furthermore, individuals with mutations in a certain receptor, the dectin-1 receptor, appear to be susceptible to developing severe ulcerative colitis because they cannot control the most common fungal inhabitant of the gut, Candida tropicalis. Their researcher was published in the June 8, 2012, issue of Science.
In some sense, fungi in the gut were hiding in plain sight. Antibodies against the world's favorite fungus, Saccharomyces cerevisiae or brewer's yeast, are strongly associated with Crohn's disease. (Their name aside, such antibodies are also produced in response to other fungi than brewer's yeast.) Still, despite the presence of antifungal antibodies, and although a few studies have noted that there are intestinal fungi as well as bacteria, none had looked at how they interacted with either the bacterial microbiome or the immune system.
But Iliyan Iliev, a research scientist at Cedars-Sinai Medical Center, and his colleagues reasoned that where there is an antibody, an antigen cannot be far.
The team first set out to see whether fungi might play a role in inflammatory bowel disease. They suspected such a link might exist for two reasons. In addition to the association between yeast antibodies and Crohn's disease, polymorphisms in the gene CARD9 are strongly tied to susceptibility to both Crohn's disease and ulcerative colitis. CARD9 is a downstream signal of the dectin-1 receptor, which is the major immune system receptor for fungi.
Both Crohn's disease and ulcerative colitis fall into the general category of inflammatory bowel disease, which affects about 1.4 million Americans. Ulcerative colitis is a common form of bowel disease, and one that appears to predispose its sufferers to colon cancer.
They found that when they induced ulcerative colitis in mice by intestine-damaging chemicals, knockouts that had no dectin-1 receptor developed worse disease than their wild-type littermates.
Using deep sequencing methods, Iliev and his colleagues next looked at the composition of the mycobiome in more detail and "came up with a huge number of species" of fungi that live in the gut of mice – more than 100, although 10 species make up the bulk of them and the most common species alone, Candida tropicalis, accounts for a full two-thirds of the total fungal load.
During the development of colitis, the composition of the mycobiome changed. Specifically, fungi that are "opportunistic pathogens" increased their share of the total fungal load, while harmless species decreased. And C. tropicalis migrated to parts of the gut where it does not belong.
Iliev said that the situation is reminiscent of the bacterial microbiome, which also changes in composition during some diseases. Under normal circumstances, fungi, like bacteria, "live in our guts and we are fine." And even people who have the good gene variant of dectin-1 "still have that fungus." The difference is that they are able to continue to control C. tropicalis better when the gut develops inflammatory bowel disease due to other reasons.
C. tropicalis "is not setting off the disease," Iliev clarified. "But once disease develops, Candida tropicalis becomes invasive because the body can't control it anymore."
Though its downstream signaling molecule CARD9 has been tied to Crohn's disease and ulcerative colitis, dectin-1 itself has not. Iliev and his colleagues suspected that this might be because in their animal studies, lack of the Dectin-1 receptor was not setting off disease, and so they compared the dectin-1 genes of a group of patients with medically refractory ulcerative colitis, a severe version of the disease, to those with ulcerative colitis who responded to treatment. They found two gene markers that distinguished patients with severe disease, but not those with milder disease, from healthy controls.
Iliev and his team want to investigate the link between fungi and ulcerative colitis in more detail, as well as look at how fungi and their interactions with bacteria on the one hand, and the human immune system on the other, contribute to "keeping up the ecosystem of the gut," Iliev said.
"We've identified a whole new community," he added. "It will keep us busy for a while."
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