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Candida grows on a mouse's tongue (left), but is nearly eliminated by secretions from rival fungus Pichia (right).

Friendly fungus. Candida grows on a mouse's tongue (left), but is nearly eliminated by secretions from rival fungus Pichia (right).

Mukherjee et al., PLOS Pathogens

Friendly Fungus Protects Our Mouths From Invaders

When we talk about the human microbiome, bacteria usually get all the press. But microscopic fungi live in and on us, too. New research shows that a little-known fungus called Pichia lives in healthy mouths and may play an important role in protecting us from an infection caused by the harmful fungus Candida. The friendly fungus makes a substance that may even lead to a new antifungal drug.

Most of the time, Candida is a peaceful passenger that lives with the other harmless microbes in our mouths, but when a person's immune system is compromised, the fungus can run rampant, causing a yeast infection in the mouth known as thrush. This infection is common in people with HIV, where it can make swallowing difficult and contribute to poor nutrition. Any difference in the mouth microbiomes of people with HIV and those without the virus could give scientists clues about how a healthy population of oral microbes might help keep Candida in check, says medical mycologist Mahmoud Ghannoum of Case Western Reserve University in Cleveland, Ohio. "If you have a disturbance in the community, you are likely to have disease."

So Ghannoum's group compared the microbes, both bacterial and fungal, in the mouths of 12 people with HIV and 12 healthy controls. One hypothesis holds that bacteria keep fungi in check, but Ghannoum's team didn't find any major differences between the bacterial populations in the two groups. The fungi, though, were a different story: Healthy people had more species of fungi in their mouths, and one particular fungus stood out as a possible competitor to Candida. Its name is Pichia.

Mouths where lots of Pichia lived tended to have lower levels of Candida, Ghannoum’s team found. If a lack of Pichia is failing to keep Candida in check in people with HIV, that could help explain why they are more susceptible to thrush. To confirm that Pichia is killing off Candida and not the other way around, researchers studied the fungal rivalry directly by mixing cultures of both microbes in the lab. When the two were incubated together, Pichia flourished and Candida withered.

The researchers suspected Pichia was producing a chemical that poisoned Candida, so they filtered out the fungal cells from the Pichia cultures. The leftover chemical soup proved to be a powerful antifungal, interfering with Candida's growth and its ability to form sticky mats called biofilms. When given to mice with Candida infections, the Pichia-produced concoction killed the Candida on their tongues, the researchers report online this week in PLOS Pathogens. The Pichia-based treatment even outperformed the standard treatment for thrush, an antifungal called nystatin.

"The other fascinating thing is it was able to inhibit other fungus that causes disease," Ghannoum says, including Aspergillus and Fusarium. That means the Pichia-derived solution shows promise as a broad-spectrum antifungal. Ghannoum also envisions a mouthwash containing live Pichia that could be used as a probiotic by HIV patients or others at risk for Candida infection.

"This is a tremendous advance in the field," says Anna Dongari-Bagtzoglou, an oral microbiologist at the University of Connecticut Health Center in Farmington. Besides being the first study of the fungal microbiome in people with HIV, it's also the first study that compares bacterial and fungal populations in the same patients, she says. "These correlations are important because for many years we thought the two kingdoms were in competition," she says, adding that research from her lab has shown that some bacteria can even combine with Candida to make infections more severe.

While Pichia clearly inhibits Candida in the lab, more work is needed to tell if a lack of Pichia is the reason HIV patients are at a higher risk for thrush. The biggest mystery in the microbiome field is whether microbial changes are a cause or an effect of problems with the immune system, Dongari-Bagtzoglou says. "It's a chicken-or-the-egg question."