Oxygen therapy harms lung microbiome in mice
Study could have implications for treatment of reduced oxygen levels in critically ill patients

Date:
August 12, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
A new mouse study hints that oxygen therapy may have unintended
consequences via an unexpected source -- the microbiome.



FULL STORY ==========================================================================
One of the hallmarks of severe COVID-19 is shortness of breath
and significantly reduced levels of oxygen in the blood, called
hypoxemia. Upon hospitalization, these patients are administered oxygen
in an attempt to bring their levels back up to normal. However, a new
study 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," 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 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 have long known that oxygen can damage 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 often treated with high concentrations of oxygen for long periods of time. Their 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. They found marked differences in the bacteria species present in samples
from patients depending on whether they received low, intermediate,
or high concentrations of oxygen. Specifically, patients who received
high oxygen concentrations were much more likely to grow Staphylococcus
aureus, bacteria that are very oxygen-tolerant and a common cause of
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 better understand the relationship between
oxygen and lung bacteria, the team designed a series of experiments in
mice. They first exposed healthy mice to high concentrations of oxygen
to determine the effects of oxygen on the lung bacteria of healthy mice.



========================================================================== "When we gave high concentrations of oxygen to healthy mice, their
lung communities changed quickly, and just like we predicted," said
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 the most commonly detected bacteria in mouse
lungs.

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

Using mice, they were able to demonstrate 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. Furthermore, they showed that natural variation in lung bacteria
was strongly correlated with variation in the severity of inflammation
in oxygen-exposed mice.

To further strengthen the causal link, they turned to germ-free mice,
which completely 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 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," said 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," said Ashley.



========================================================================== Targeting the microbiome Critically ill patients receiving oxygen
are typically administered antibiotics as well. The team wondered:
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 effect on lung injury, while ceftriaxone, a gram- negative antibiotic, made things worse.

"The microbiome is not all good and not all bad," comments
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 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," 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 at the National Heart, Lung, and Blood
Institute, 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." Funding for this study was provided by the National Institutes
of Health/ National Heart, Lung, and Blood Institute.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Shanna L. Ashley, Michael W. Sjoding, Antonia P. Popova, Tracy
X. Cui,
Matthew J. Hoostal, Thomas M. Schmidt, William R. Branton,
Michael G.

Dieterle, Nicole R. Falkowski, Jennifer M. Baker, Kevin J. Hinkle,
Kristine E. Konopka, John R. Erb-Downward, Gary B. Huffnagle,
Robert P.

Dickson. Lung and gut microbiota are altered by hyperoxia and
contribute to oxygen-induced lung injury in mice. Science
Translational Medicine, 2020; 12 (556): eaau9959 DOI:
10.1126/scitranslmed.aau9959 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200812144114.htm

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