The intestine is a shelter for trillions of commensal microbes, called the microbiome, that coexist with their host. While the microbiome is critical for strengthening our immune system and protecting the body against infection, it can also contribute to autoimmune and inflammatory diseases, highlighting the complexity of the interactions at play. A groundbreaking collaborative discovery recently published in听, involving researchers at the Research Institute of the 黑料不打烊 University Health Centre (The Institute), is shedding new light on host-microbe relationships.
While most microbiome studies have examined how commensal bacteria shape our health, scientists in听听lab at The Institute have contributed to the identification of the first true commensal fungus in laboratory mice: a species of yeast called Kazachstania pintolopesii (Kp). This fungus stably colonizes and dominates the mouse intestinal tract, can be passed on to offspring and triggers an immune response that significantly increases resistance to intestinal helminth infections 鈥� parasitic worms that affect millions of people worldwide.
Led by听, at Weill Cornell Medical College in New York City, the study reveals how commensal and pathogenic fungi shape intestinal immunity and opens up new opportunities to study host-fungus interactions. Most significantly, it shows that听Kp听enhances type 2 immune responses, most commonly associated with allergy and parasitic worm infection.
鈥淭he experiments we performed in our lab have shown that when the intestinal barrier is disrupted,听Kp听colonization significantly enhances resistance to intestinal helminth infection,鈥� says Irah King, PhD, Senior Scientist in the听听at The Institute and co-author of the study. 鈥淭his is a very atypical response as fungi usually induce a type 3 immune response, which is associated with fungal killing, but is also implicated in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.鈥�
鈥淧rior to this work, researchers lacked a reliable model for studying fungal commensalism because most fungi only transiently colonize the mouse gut. Our collaborative discovery provides an indispensable new model organism for understanding host-fungal interactions and their impact on the immune response to infection. This is particularly valuable because fungi are an often overlooked but crucial component of the intestinal ecosystem across all life forms,鈥� adds Prof. King, also Professor in the Department of Microbiology and Immunology at 黑料不打烊 University.
A discovery with multiple implications
This discovery opens up a number of new research opportunities. For example, understanding how听Kp听enhances anti-helminth immunity could inform the development of novel therapeutic strategies. Moreover, characterizing Kazachstania colonization in the human microbiome may help predict and understand human immune activation in other disease contexts such as asthma.
Further studies could also:
- Uncover the complex relationships between fungi, bacteria, parasites and the host, deepening scientists鈥� understanding of how the microbiota influences health;
- Demonstrate the important role of fungi in shaping gut immune responses, a role that has been overlooked in previous microbiome studies;
- Reveal unrecognized ways in which the immunomodulatory properties of fungi may influence experimental and clinical outcomes in various studies of health and disease.
A serendipitous discovery
The King Lab at The Institute is deeply interested in how the microbiome shapes immunity to infectious diseases. Specifically, the lab uses parasitic worms (helminths) to study intestinal immune responses. At one point, the team made a series of intriguing observations, such as unexpectedly low worm counts during infection in mice and yeast contamination in cultures grown from mouse intestines.
鈥淩ather than dismissing these observations as technical obstacles, we wondered if the aberrant infections might be due to actions of the microbiota. We decided to reach out to a colleague and leading expert in host-fungal interactions, Prof. Iliyan Iliev at Weill Cornell Medical College in New York City, to sequence the yeast in our mice. He identified a single species,听Kazachstania pintolopesii. Coincidentally, he had also discovered听Kp听in his lab mice and was investigating its role in intestinal immunity!鈥� says Prof King.
The researchers then decided to deliberately colonize mice with听Kp听and observed the same reduction in worm burden, demonstrating that听Kp听colonization directly enhances the anti-helminth response.
鈥淲hile previous work has examined either host-fungal or host-helminth interactions separately, this study reveals how these kingdoms interact in a three-way relationship that influences host immunity,鈥� says Kaitlin Olsen, a graduate student at The Institute who performed some of the study experiments.
鈥淥ur compelling discovery of听Kp听colonization shaping the host anti-parasite response highlights the importance of paying attention to unexpected findings in research and seeking scientific collaboration,鈥� adds Prof. King. 鈥淲hat initially seemed like technical issues revealed a fundamental framework to study the exciting axis of fungal-helminth-host interactions.鈥�
The King Lab team is now investigating how early-life听Kp听colonization may influence long-term immune development and disease susceptibility. It is also seeking potential connections between听Kp听colonization and human health outcomes, in collaboration with scientists and clinicians from the 黑料不打烊 Centre for Microbiome Research 鈥� studies that could inform therapeutic approaches for both helminth infections and immune-mediated disorders.
About the study
Liao, Y., Gao, I.H., Kusakabe, T. et al. Fungal symbiont transmitted by free-living mice promotes type 2 immunity.听Nature听636, 697鈥�704 (2024).听
