How a new gut microbe drives the gut-lung axis

Their findings highlight how a little-known member of the gut microbiome reshapes the lung immune environment to have both beneficial and detrimental effects on respiratory health.

"Peaceful gut microbes living inside our intestine are essential players in controlling our immune system. Growing evidence implicates these commensal microorganisms in conditions that affect other organs such as the lungs, brain, skin or joints," says Arthur Mortha, associate professor of immunology at U of T's Temerty Faculty of Medicine.

Over the past decades, changes in the composition of the gut microbial community have been linked to a range of traits and conditions including obesity, allergies, cancer and mental health disorders. However, these studies have largely focused on bacteria, which represent the largest fraction of microbes found in the gut community.

In a new study published today in the journal Cell, Mortha and his colleagues focused on a different category of microorganism called protozoa. These microbes are also single celled like bacteria, but much bigger in size and with more complex bodies. While most known protozoa are classified as parasites, several lesser-known species can live in symbiotic relationships with their animal hosts.

"Our aim was to understand how commensal protozoan species in the gut impact the outcome of diseases and our overall health," says Mortha, who is also the Canada Research Chair in Mucosal Immunology.

The project was led by Kyle Burrows, a postdoctoral fellow in Mortha's lab who will be joining Simon Fraser University as an assistant professor in early 2025.

For their study, the researchers looked at a protozoan called Tritrichomonas musculis, or T. mu, that resides harmlessly in the gut of mice.

They found that mice colonized with T. mu had unexpectedly high levels of specific immune cells in their lungs. Importantly, the researchers showed that some of these immune cells originated from the gut and moved to the lungs, where they fine-tuned the local immune environment and changed outcomes related to respiratory illnesses and infections.

By triggering the production and migration of these immune cells from the gut to the lung, T. mu functions as "a conductor in the intestine that orchestrates the immune system to populate other regions of the body," says Mortha.

One of the study's key findings was that T. mu-driven immune changes in the lung worsened airway inflammation caused by allergic asthma but appeared to have a protective effect against respiratory infections.

Collaborating with molecular genetics professor Jun Liu, the researchers worked in the Toronto High Containment Facility to study the impact of the altered immune landscape on tuberculosis. They found that higher levels of immune cells in the lungs of T. mu-colonized mice served as an antimicrobial shield in the airways, helping to contain tuberculosis infections and delaying its spread into other organs.

Mortha notes that these results are consistent with what his team previously observed about the opposing effects of T. mu on different aspects of gut health in mice. "This protozoan has a very strong impact on the immune system in the intestinal tract," he says. "It exacerbates colorectal cancer development and inflammatory bowel disease, but it also gives the host the ability to withstand very severe infections."

The researchers also analyzed sputum samples from people with severe asthma. They looked for genetic signatures of human-associated protozoa and identified a higher signal in samples from severe asthma patients compared to patients who had a non-asthmatic inflammatory lung condition, suggesting that their observations in mice may also be relevant in patients.

Mortha believes these findings open the door to new diagnostic and treatment approaches for asthma and potentially other chronic inflammatory illnesses.

For example, the presence of specific protozoa could be used to predict whether a patient will develop severe asthma and may inform which medications will work best for them based on the immune pathways that are activated by the protozoa.

"Could we prevent or slow the development of asthma with treatments that are not restricted to the lung but, rather, are tailored to the intestinal tract?" he asks.

Beyond the lung, the researchers are now turning their attention to other organs that may also be modulated by the gut microbiome and to tracking the journey of immune cells from the gut to these organs.

"The migration of immune cells from one organ to another represents a new way of how organs can communicate with each other, especially through microbes in the gut," says Mortha.

"It changes the way we perceive our relationship with our microbiome and shows that we should not only focus on bacteria but also include protozoa and other neglected microbes to further our understanding of health and disease."