Oxygen therapy could potentially harm lung microbiome

ANN ARBOR, Mich.—One of the hallmarks of severe COVID-19 is shortness of breath and significantly reduced levels of oxygen in the blood, also known as hypoxemia. When these patients are hospitalized, they are administered oxygen in an attempt to bring their levels back up to normal. However, a new study in Science Translational Medicine hints that this universal therapy may have unintended consequences via an unexpected source — the microbiome.

“It had been assumed that the lungs were relatively clean and free of bacteria,” said Shanna Ashley, Ph.D., a former post-doctorate Fellow with the Division of Pulmonary and Critical Care Medicine at University of Michigan Medical School. “We now know that the balance of bacteria inside the lungs matters much like it does in the gut.”

Ashley worked with a team led by Robert Dickson, M.D., assistant professor of Pulmonary & Critical Care Medicine and Microbiology and Immunology, whose lab has spent years exploring the role of the lung microbiome in health and disease. Their work has found that oxygen disrupts this balance, contributing to lung injury.

Scientists were previously aware that oxygen is capable of damaging the lungs.

“Oxygen is actually a potent lung toxin. If I put healthy mice in 100% oxygen, they will die in five days, and they’ll have the same kind of severe lung injury that patients with COVID-19 or other lung damage have,” Dickson added.

Patients in intensive care units (ICU) are frequently treated with high concentrations of oxygen for long periods of time. The research team began to explore how therapeutic oxygen was affecting the lung microbiome. They looked at critically ill patients who were on a ventilator for more than 24 hours, and studied bacteria detected in specimens from their lungs.

The researchers found marked differences in the bacteria species present in samples from patients, depending on whether they received low, intermediate or high concentrations of oxygen. Patients who received high oxygen concentrations were much more likely to grow Staphylococcus aureus, a common cause of lung infections in ICUs.

“Different types of bacteria vary quite a bit from each other in how well they can handle oxygen. So we wondered if the oxygen we give our patients might be influencing the bacterial communities in their respiratory tract,” noted Dickson.

To better understand the relationship between oxygen and lung bacteria, the team designed a series of experiments in mice. They exposed healthy mice to high concentrations of oxygen to determine the effects of oxygen on lung bacteria.

“When we gave high concentrations of oxygen to healthy mice, their lung communities changed quickly, and just like we predicted,” Ashley explained. “The oxygen-intolerant bacteria went down, and the oxygen-tolerant bacteria went up.”

After three days of oxygen therapy, oxygen-tolerant S. aureus was by far the most commonly detected bacteria in mouse lungs.

The team next designed experiments to answer a key question: do altered bacterial communities contribute to lung injury? Or are bacterial communities altered because the lung is injured? Researchers first addressed this by comparing the relative timing of changes in lung bacteria as compared to the onset of lung injury.

The team then demonstrated that while the lung microbiome was changed by high oxygen concentrations after only a day, lung injury wasn’t detectable until after 3 days — proving that damage to the lung followed the disruption of the microbiome, and not the other way around. Researchers also showed that natural variation in lung bacteria was strongly correlated with variation in the severity of inflammation in oxygen-exposed mice.

“We wanted to see whether there was a selective advantage or disadvantage to having bacteria-free lungs when exposed to therapeutic oxygen,” stated Ashley.

To strengthen the causal link, the researchers turned to germ-free mice, which completely lack a microbiome. When comparing two groups of genetically identical mice — one with bacteria and one without — the mice without bacteria were protected from oxygen-induced lung injury.

“That was an extraordinary finding for us,” Dickson pointed out. “Compared to conventional mice, these germ-free mice have the same genetics and receive the same oxygen dosing, but their lungs are protected from injury. Nothing in our current understanding of oxygen-induced lung injury can explain that finding.”

“It really makes the case that the microbiome is somehow playing a role in lung injury,” said Ashley.

Patients who receive oxygen are typically administered antibiotics as well. The team wondered if antibiotics could alter the severity of oxygen-induced lung injury in mice.

“The short answer is yes, we can affect the severity, but it wasn't in the direction we predicted,” explained Dickson.

Vancomycin, an antibiotic which targets gram-positive bacteria like S. aureus, had no effect on lung injury. But ceftriaxone, a gram-negative antibiotic, made things worse.

“The microbiome is not all good and not all bad. That’s why it’s important for us to figure out the mechanisms here,” Dickson continued. “We’re currently using very non-specific interventions, when what we need is targeted manipulation of the microbiome.”

“We need to think about using the microbiome as a therapeutic target to prevent doing further damage to patients’ lungs while they are on a ventilator or receiving oxygen,” added Ashley.

Dickson cautions against changing clinical practice prematurely based on these findings: “The question of how much oxygen to give critically ill patients is a complex one, and a topic of intense study,” he stated. “Our findings are exciting, but I still look to randomized controlled trials to inform my decisions about how to dose oxygen in sick patients.”

“This study provides important insights into the contributions of the microbiome toward inflammation and damage in lungs exposed to varying levels of oxygen, and supports the continued importance of understanding how the microbiome and related factors impact lung disease and clinical outcomes,” added James Kiley, director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.