One of the hallmarks of extreme COVID-19 is shortness of breath and considerably decreased ranges of oxygen in the blood, known as hypoxemia. Upon hospitalization, these sufferers are administered oxygen in an try to deliver their ranges again as much as regular. However, a brand new examine hints that this common therapy might have unintended penalties through an sudden supply—the microbiome.
“It had been assumed that the lungs were relatively clean and free of bacteria,” says Shanna Ashley, Ph.D., a former Post-Doctorate Fellow with the Division of Pulmonary and Critical Care Medicine at U-M Medical School. “We now know that the balance of bacteria inside the lungs matters much like it does in the gut.” Ashley labored with a group led by Robert Dickson, M.D., Assistant Professor of Pulmonary & Critical Care Medicine and Microbiology and Immunology, whose lab has spent years exploring the function of the lung microbiome in well being and illness. Their work has discovered that oxygen disrupts this stability, contributing to lung damage.
Scientists have lengthy identified that oxygen can injury the lungs. “Oxygen is actually a potent lung toxin,” says Dickson. “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.”
Patients in intensive care are sometimes handled with excessive concentrations of oxygen for lengthy durations of time. Their group started to discover how therapeutic oxygen was affecting the lung microbiome. They checked out critically unwell sufferers who have been on a ventilator for greater than 24 hours and studied micro organism detected in specimens from their lungs. They discovered marked variations in the micro organism species current in samples from sufferers relying on whether or not they obtained low, intermediate, or excessive concentrations of oxygen. Specifically, sufferers who obtained excessive oxygen concentrations have been more likely to develop Staphylococcus aureus, micro organism which can be very oxygen-tolerant and a standard reason for lung infections in the ICU.
“Different types of bacteria vary quite a bit from each other in how well they can handle oxygen,” Dickson says, “So we wondered if the oxygen we give our patients might be influencing the bacterial communities in their respiratory tract.”
To higher perceive the connection between oxygen and lung micro organism, the group designed a collection of experiments in mice. They first uncovered wholesome mice to excessive concentrations of oxygen to find out the consequences of oxygen on the lung micro organism of wholesome mice.
“When we gave high concentrations of oxygen to healthy mice, their lung communities changed quickly, and just like we predicted,” mentioned Ashley. “The oxygen-intolerant bacteria went down, and the oxygen-tolerant bacteria went up.” After three days of oxygen therapy, oxygen-tolerant Staphylococcus was by far probably the most generally detected micro organism in mouse lungs.
The group subsequent designed experiments to reply a key “chicken or the egg” query: do these altered bacterial communities contribute to lung damage? Or are bacterial communities altered as a result of the lung is injured? They first addressed this by evaluating the relative timing of modifications in lung micro organism as in comparison with the onset of lung damage.
Using mice, they have been in a position to exhibit that whereas the lung microbiome was modified by excessive oxygen concentrations after solely a day, lung damage wasn’t detectable till after three days, proving that injury to the lung adopted the disruption of the microbiome, and never the opposite means round. Furthermore, they confirmed that pure variation in lung micro organism was strongly correlated with variation in the severity of irritation in oxygen-exposed mice.
To additional strengthen the causal hyperlink, they turned to germ-free mice, which utterly lack a microbiome. “We wanted to see whether there was a selective advantage or disadvantage to having bacteria-free lungs when exposed to therapeutic oxygen,” says Ashley. When evaluating two teams of genetically equivalent mice—one with micro organism and one with out—the mice with out micro organism have been shielded from oxygen-induced lung damage.
“That was an extraordinary finding for us,” mentioned Dickson. “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,” mentioned Ashley.
Targeting the microbiome
Critically unwell sufferers receiving oxygen are usually administered antibiotics as effectively. The group questioned: Could antibiotics 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,” says Dickson. Vancomycin, an antibiotic that targets gram-positive bacteria like Staphylococcus, had no impact on lung injury, whereas ceftriaxone, a gram-negative antibiotic, made issues worse.
“The microbiome is not all good and not all bad,” feedback Dickson. “That’s why it’s important for us to figure out the mechanisms here. We’re currently using very non-specific interventions, when what we need is targeted manipulation of the microbiome.”
Ashley agrees. “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.”
Dickson cautions towards altering medical observe prematurely based mostly on these findings. “The question of how much oxygen to give critically ill patients is a complex one, and a topic of intense study,” says Dickson. “Our findings are exciting, but I still look to randomized controlled trials to inform my decisions about how to dose oxygen in sick patients.”
James Kiley, director of the Division of Lung Diseases on the National Heart, Lung, and Blood Institute, a part of the National Institutes of Health, agrees. “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.”
S.L. Ashley el al., “Lung and gut microbiota are altered by hyperoxia and contribute to oxygen-induced lung injury in mice,” Science Translational Medicine (2020). stm.sciencemag.org/lookup/doi/ … scitranslmed.aau9959
University of Michigan
Oxygen therapy harms lung microbiome in mice (2020, August 12)
retrieved 12 August 2020
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