One Fungus May Keep Another in Check for a Healthy Mouth

Daniel M. Keller, PhD

October 23, 2011

October 23, 2011 (Boston, Massachusetts) — By characterizing, for the first time, the core oral mycobiome and bacteriome of HIV-infected patients and control individuals, researchers at The Cleveland Clinic in Ohio have shown that Pichia, a genus in the yeast family, inhibits Candida from forming biofilms, suggesting that changes in oral microbiota significantly affect human health and disease.

Mahmoud Ghannoum, PhD, director of the center for medical mycology and professor at the Case Western Reserve University School of Medicine in Cleveland, Ohio, reported these results at a news conference here at the Infectious Diseases Society of America (IDSA) 49th Annual Meeting. He said this knowledge might facilitate the development of novel strategies to manage candidiasis in HIV-infected and other immunocompromised patients.

The microbiome consists of microbial communities at sites throughout the body, Dr. Ghannoum explained. The bacterial component has been described more than the fungi, viruses, and other microbes in the same samples. Microbes in the mouth have been linked to oral and oropharyngeal infections, such as dental caries, periodontitis, and tonsillitis, and to systemic conditions, such as cardiovascular disease, diabetes, and pneumonia.

To define the healthy oral fungal microbiome, termed the "mycobiome," Dr. Ghannoum recruited 20 healthy nonsmoking, nondiabetic subjects 21 to 60 years of age (8 female). A sample of the oral microbiota was collected from a sterile saline rinse used for 1 minute. DNA was extracted from cells obtained from the rinse, and consensus sequences present in a wide range of fungi were amplified by polymerase chain reaction, sequenced, and compared against the GenBank database.

The investigators detected 74 culturable and 11 nonculturable genera of fungi in the samples, comprising 101 identified species. Between 9 and 23 species were identified in each individual, with 15 genera present in at least 20% of the subjects. Candida species were isolated from 75% of the subjects, followed by Cladosporium (65%), Aureobasidium and Saccharomycetales (50% for each), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%).

Dr. Ghannoum noted that 4 of these predominant genera contain known human pathogens.

From these findings, Dr. Ghannoum concluded that in healthy individuals, the oral mycobiome contains a variety of fungal species in 85 genera, some of which were expected, such as Candida, and others that were not (Aspergillus, Fusarium, and Cryptococcus species). One third were not culturable, and there was great variation in the fungal flora among individuals.

The investigators then set out to look for changes in the oral microbiome and to define microbial interactions in individuals infected with HIV. They obtained oral rinse samples from 12 adult uninfected and 12 HIV-infected individuals without signs of oral mucosal disease. They also collected demographic, medication, viral load, CD4 cell count, and smoking status information. Exclusion criteria were the recent use of any antimicrobial agents or topical or systemic steroids, pregnancy, and insulin-dependent diabetes.

Dr. Ghannoum reported that the numerical range of bacterial taxa detected in the HIV-infected (9 to 14) and HIV-uninfected (8 to 14) were similar. However, the most prevalent genera differed — Prevotella, Streptococcus, and Rothia were found in the former; and Fusobacterium, Prevotella, and Steptococcus were found in the latter. Comparing the abundance of organisms between the 2 groups, Haemophilus and Serratia were elevated in the noninfected group, and Veillonella, Fusobacterium, and Porphyromonas were elevated in the HIV-infected group. The 2 groups shared 13 of 14 genera in their core oral bacteriomes.

Shifting Oral Mycobiome With HIV Infection

When the researchers determined the presence of oral fungi, they found that there was a shift in the core mycobiome. Both groups shared the presence of Candida and Penicillium. But whereas uninfected individuals had relatively more Pichia, Cladosporium, and Fusarium, the HIV-infected group had more Alternaria, Epicoccum, and Trichosporon.

Importantly, the presence of Pichia correlated with an absence of Candida, and vice versa, Dr. Ghannoum said. In uninfected individuals, Pichia accounted for about 17% of the mycobiome, but none was found in HIV-infected individuals. In addition, Candida was much more abundant in the infected group (61%) than in the uninfected one (37%).

The researchers hypothesized that Pichia inhibits Candida growth, so they grew Candida biofilms in the presence and absence of spent culture media of Pichia, using media from Penicillium as a control. They monitored the effects on biofilm architecture using laser scanning confocal microscopy. They confirmed an effect of Pichia on Candida biofilm formation (P = .019 vs untreated biofilms), and found that the effect was specific to Pichia.

Dr. Ghannoum concluded that the characterization of the core oral mycobiome and bacteriome in HIV-infected and uninfected individuals, for the first time, supports "the notion that changes in the oral microbiota may have significant impact on human health and disease." He predicted that "the discovery of the interaction between Pichia and Candida could lead to the development of new ways to control Candida in HIV patients, and also in other immunocompromised patients." He noted that Pichia has been identified by European regulatory bodies as a safe organism, so from that point of view it might make a good probiotic.

David Relman, MD, professor in the Departments of medicine, and microbiology and immunology at Stanford University in Palo Alto, California, and vice president of IDSA, said at the news conference that "one of the important messages from this work is that these communities that live on and within us are not random collections of organisms. They are all there with a purpose and, in fact, recognize and interact with each other. There's a structure, and there is an incredibly important set of communication events and interactions that can be exploitable potentially for maintaining health or restoring health."

However, he advised that the results are in the early stages, are associations and do not prove causality, and need to be validated as part of the process of determining how they may be exploited for benefit.

There was no commercial support for the study. Dr. Ghannoum and Dr. Relman have disclosed no relevant financial relationships.

Infectious Diseases Society of America (IDSA) 49th Annual Meeting: Abstract 786. Presented October 21, 2011.

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