Tiny bugs and big lung diseases: An emerging link

Today we know that we co-exist in a world teeming with trillions upon trillions of microbes. They survive on the frozen tundra of the Antarctic, endure the thermal vents in the bottom of the ocean, and thrive in our guts and on our skin. Yet for centuries scientists pushed a theory that at least one part of our body – the lungs – were sterile, completely void of microbes that take up residence, despite that they’re exposed to 7000 liters of microbe-filled air every day.

“The belief was that you would only find bacteria in the lungs if you had an infection,” said David O’Dwyer, M.D., Ph.D., associate professor in the Division of Pulmonary and Critical Care Medicine at the University of Michigan and an NHLBI-funded researcher.

But a 2010 landmark paper would challenge that assumption and prove it faulty, opening the door to what is now the complex – and consequential – study of how microbes throughout the body work to maintain health or cause diseases of the lung.

It started with a simple experiment using new sequencing technology to see if scientists could identify bacteria in the lungs of patients with asthma. Using a long tube passed through the nose and into the lungs, the study authors collected samples of different parts of the respiratory tract to see what they could find. “They identified bacteria in the lung – even when the patients were showing no signs of active infection,” said O’Dwyer.

So, the lungs indeed had microbes. And like the gut, these tiny bugs made up their own microbiome inside the body’s larger microbiome – the community of both helpful and harmful bacteria, fungi, and viruses that affect our health.

But the researchers found something else: in adult patients with asthma, certain harmful bacteria were present in bigger numbers in the bronchi – the tubes that connect the windpipe to the lungs – than they were in patients without asthma. This signaled that the lung microbiome could look and act differently from one patient to the next, depending on the person’s asthma type and severity – and have wildly different effects on their health.

Since that groundbreaking finding, scientists have come to realize that the relationship between lung disease and the lung microbiome – or other microbiome communities in the body – is a lot more complicated than they’d thought. The simple idea that only harmful bacteria can cause disease is no longer the only one in play. And this, the researchers said, could have profound implications for disease treatment in the future.

Cross-talking microbiome

“We’re just barely scratching the surface of characterizing how the microbiome as a whole works,” said Emmanuel Mongodin, Ph.D., program director in NHLBI’s Division of Lung Diseases. What we do know, he said, is that the microbiome is in constant crosstalk with the immune system. When interactions go the way they’re supposed to, then health abounds. But when the microbiome is out of whack, the immune system can go haywire, leading to diseases such as asthma.

“In essence, the microbiome is part of the immune system,” said Mongodin. That means, for example, that an imbalance in the gut microbiome can impact immune functions in the lungs, too. “So when a patient has asthma, we know that what’s happening in their gut microbiome is almost as important as what’s happening in their lung microbiome.”

What’s happening precisely – Mongodin can’t yet say. “We’re seeing little bits of the picture that they might be linked, but in most cases,” he conceded, “we have no idea yet how it all works and what might be connected.

“But we’re working on it.”

More clues from a different disease

While they do, researchers are also focusing on idiopathic pulmonary fibrosis (IPF), which develops when lung tissue becomes thick and stiff for unknown reasons. It’s a fatal disease, and currently the only treatment known to prolong survival is a lung transplant. Data suggests that, just as in asthma, the lung microbiome might somehow be involved.

In 2014, an NHLBI-funded study found a link between having more bacteria in the lung and increased risk of death in patients with IPF. A follow-up study showed that specific bacterial groups such as Streptococcus and Staphylococcus are also associated with an elevated risk of disease progression and death. And findings from a handful of smaller studies suggested improved outcomes for patients with IPF who were given antibiotics. Given the results of these studies, NHLBI funded a large clinical trial, known as CleanUP-IPF, to rigorously test the impact of antibiotics in patients with IPF.

“The CleanUP-IPF investigators thought that if they could reduce the bacterial burden in the lung through long-term antibiotics, then it would imply that the microbiome causes disease development,” said O’Dwyer. “Except the trial didn’t work, suggesting that the link to the microbiome and IPF is much more complex.”

He explained that antibiotics may not be the best choice to treat the abnormalities in the microbiome, as the drugs may result in the increase or decrease of certain bacteria that are harmful, leading the lung microbial community to adapt to the effects of antibiotics and become resistant. Additionally, antibiotics can’t be targeted to just the lungs and so can also impact other important microbiome communities, such as the gut.

“At the end of the day, we really don't know what antibiotics do to the microbiome,” he said.

A better lung microbiome

So, given the slowly emerging understanding of the lung microbiome’s role in health and disease, it makes sense to wonder about how to give our lungs the best fighting chance. Though some things may be out of our control, Mongodin said there are steps people can take.

“The lung is a filter, and you are what you breathe,” he said. “I know it sounds a little cliché, but one step can be as simple as breathing clean air.” (Learn more through NHLBI’s Learn More Breathe Better program.)

Keeping our teeth healthy may also help. Emerging research has shown that oral health is critical for lung health, as small amounts of saliva – and the bacteria that live in it – gets drawn into lungs. Poor oral health has already been linked to respiratory diseases such as COPD and pneumonia.

And O’Dwyer recently published a study using the same cohort of patients from CleanUP-IPF to determine associations between the oral microbiome and IPF severity. His results suggest that, just as in the lungs, increasing microbial diversity in the oral cavity can predict how severe a patient’s IPF may be or their risk of dying. The results also suggest that a friendly bacterial species in the mouth, a species of Streptococcus, may help preserve lung function and improve survival in IPF patients.

To better understand this link between the health of our mouths and lung disease, O’Dwyer is collaborating with an oral microbiome expert.

It’s just one more step, he said, in the overall effort to fully understand the role the microbiome plays in health and disease. Once researchers make more inroads there, the opportunities for interventions may well be limitless.

“If we can figure out which bacteria are causing the immune system to overact, we can tweak the microbiome to get it to a steadier state,” said Mongodin. “In some cases, we might not need to use antibiotics. We’ll just need to replace some of the bad actors with good ones.

“And that,” he said, “will be game-changing.”