Novel Fungal Commensal Shaping Mouse Immune Responses

Researchers from Weill Cornell Medicine have found a fungus in the stomach of mice that may provide a clue to the evolution of fungi in the gastrointestinal tract. The result implies that a significant determinant of mouse physiology has been missed by preclinical research up to this point.

Recently, scientists have realized how important the naturally occurring microorganisms in the gut, generally referred to as “commensals,” are to human health and illness.

For instance, it is well-recognized that bacterial commensals significantly impact human immunity; aberrant alterations in these populations have been linked to inflammatory diseases, depression, and cancer. However, because there is not a reliable mouse model of fungal commensalism, it is unclear how gut fungal commensals impact immunity.

According to the study published in the journal Nature, a yeast known as Kazachstania pintolopesii, which is common in wild mice's stomachs, is remarkably well suited to mice and helps them by strengthening their immune systems' defenses against parasites. Still, it also makes them more susceptible to certain allergies.

For years we have been looking for a true fungal commensal in mice, but fungal populations in lab mice, as identified by analyzing fungal DNA, tend to be transient and vary greatly from colony to colony.”

Dr. Iliyan Iliev, Study Senior Author and Associate Professor, Weill Cornell Medicine

Iliev is also a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and a faculty member in the Immunology & Microbial Pathogenesis graduate school program at Weill Cornell Medicine.

A group from the National Institutes of Health, led by co-author Dr. Barbara Rehermann, discovered in 2019 that “wildling” lab mice, which are raised with gut microorganisms similar to those of wild mice, are more effective than conventional lab mice at simulating human immune responses.

According to Dr. Iliev's team, which participated in the study, these mice had much higher levels of fungal DNA in their guts than had been previously seen in lab mice.

This was the start of a kind of Sherlock Holmes story as we went looking for the dominant fungus, extending our study to other mouse populations. And what better place to find wild mice than New York City!”

Dr. Iliyan Iliev, Study Senior Author and Associate Professor, Weill Cornell Medicine

The scientists obtained samples from several research organizations that employ or sell lab mice and searched for signs of the fungus in fecal samples and other materials supplied by pest-control companies in New York City and Los Angeles. They concluded that whereas K. pintolopesii is highly prevalent in wild mice, it is also frequently found in lab mouse colonies without the researchers' knowledge.

The presence or absence of this fungus should be taken into account in many types of mouse studies.”

Dr. Yun Liao, Study Co-First Author and Postdoctoral Researcher, Weill Cornell Medicine

“K. pintolopesii can completely change the experimental outcome,” said Co-First Author Dr. Iris Gao, who was a graduate student in the Iliev lab during the study.

The fact that K. pintolopesii can quickly colonize laboratory mice's gastrointestinal tracts, is consistently passed on to mouse offspring, and somehow avoids its host's antifungal immunity while partially inhibiting the growth of other fungal species suggests that this fungus is a true commensal and has evolved to live in mice.

However, by triggering the creation of a cytokine known as IL-33, the fungus makes itself apparent to the immune system in response to changes in gastrointestinal mucus brought on, for instance, by dietary modifications or medications.

A “type 2” immune response is subsequently triggered by this cytokine. Through this heightened type 2 immune response, the fungus symbiotically protects its hosts against worms and suppresses other fungi, but the study also found that it exacerbates food allergies.

“If you are using mice to research allergies, parasite infections, cancer development, or any other area where type 2 or type 17 immune responses are relevant, then this fungus may be an important factor that you should not omit,” Dr. Iliev said.

The work raises significant problems even though it indicates that K. pintolopesii is an excellent model for fungal commensalism: Is this fungus a typical part of the mouse microbiota that should always be present in laboratory mice, particularly in immunology-related studies? Does a fungal commensal have a comparable function in enhancing human type 2 immunity?

In a research partnership between labs from several institutions, including the Broad Institute, the National Institutes of Health, and Pennsylvania State University, Dr. Iliev and his team are currently looking for answers to these issues in samples gathered around the continent.