Doctors already know that misusing antibiotics can cause antibiotic resistance, which can make it difficult to fight bacterial infections, such as pneumonia. Now, a study in mice suggests that antibiotic use could also make the lungs more vulnerable to viral infections, such as the flu.
Antibiotic resistance has become a pressing issue for researchers and healthcare professionals. This phenomenon occurs when a bacterial infection no longer responds to the antibiotics that doctors typically use to treat it.
This resistance often develops due to the misuse or overuse of antibiotics, as many individuals across the world mistakenly opt for antibiotics to treat viral infections, such as the influenza virus (the flu), against which these drugs are ineffective.
A new study in mice by researchers from the Francis Crick Institute in London, United Kingdom, now suggests that antibiotics could actually also “prime” the lungs for viral infections.
The researchers’ findings, which feature in the journal Cell Reports, also show that gut bacteria drive a type of protein signaling that helps the cells that line the lungs keep the flu virus from spreading.
Antibiotic use, it seems, interferes with this protein signaling and thus impairs this first line of defense.
“We found that antibiotics can wipe out early flu resistance, adding further evidence that they should not be taken or prescribed lightly,” explains lead researcher Andreas Wack, Ph.D.
Antibiotics leave mice vulnerable to the flu
In the new study, Wack and team used a group of mice with healthy gut bacteria at baseline. Over 4 weeks, they gave these mice a mix of antibiotics through their drinking water before infecting them with the flu virus. They also infected some mice that they had not treated with the antibiotic mix so that they could compare the outcomes.
The team noticed that approximately 80% of the untreated mice with healthy gut bacteria survived the infection with the flu virus. Yet, of the mice who had previously received the antibiotic mix, only one-third were able to survive the viral infection.
“Inappropriate use [of antibiotics] not only promotes antibiotic resistance and kills helpful gut bacteria, but may also leave us more vulnerable to viruses,” says Wack.
“This could be relevant not only in humans but also livestock animals, as many farms around the world use antibiotics prophylactically. Further research in these environments is urgently needed to see whether this makes them more susceptible to viral infections,” he argues.
The defensive role of gut bacteria
How exactly did ingesting antibiotics weaken the mice before their exposure to the flu? The researchers may have an explanation for this phenomenon.
As part of the study, the team also found that type I interferon signaling — a form of protein signaling that regulates the response of a type of cell that lines the lungs — is key to stopping the flu virus from replicating in the lungs.
Usually, gut bacteria would drive interferon signaling, “telling” the lung cells to react to the virus, stopping it from replicating, and thus making survival and recovery more likely.
“We were surprised to discover that the cells lining the lung, rather than immune cells, were responsible for early flu resistance induced by microbiota,” notes Wack.
The process by which antibiotics seem to render the lungs more vulnerable to viral infections is a complex one, and it relates, in part, to when and how the immune response occurs.
Gut bacteria usually send interferon signals that switch on the antiviral gene Mx1 in mice, corresponding to a similar gene called MxA in humans. However, antibiotic treatment delays the switching on of the antiviral gene, affecting the efficiency of the response that the body initiates against the virus.
“It takes around 2 days for immune cells to mount a response, in which time the virus is multiplying in the lung lining,” explains Wack.
“Two days after infection, antibiotic-treated mice had five times more virus in their lungs. To face this bigger threat, the immune response is much stronger and more damaging, leading to more severe symptoms and worse outcomes,” he continues.
An issue of timing
When the researchers tried repopulating the gut bacteria of antibiotic-treated mice to restore microbiota balance, they found that this brought interferon signaling back to normal and reestablished flu resistance in the lungs.
This experiment confirmed that healthy gut bacteria are important for the regulation of immune responses and that antibiotics may upset this balance.
“Taken together, our findings show that gut bacteria help to keep nonimmune cells elsewhere in the body prepared for attack. They are better protected from flu because antiviral genes are already switched on when the virus arrives. So, when the virus infects a prepared organism, it has almost lost before the battle starts,” explains Wack.
“By contrast, without gut bacteria, the antiviral genes won’t come on until the immune response kicks in. This is sometimes too late as the virus has already multiplied many times, so a massive, damaging immune response is inevitable,” he says.
This discovery may have implications for researchers’ understanding of the mechanisms driving the body’s natural defenses against viral infections, and it may give rise to further studies on this topic.
“Previous studies have focused on immune cells, but we found that the [lung] lining cells are more important for the crucial early stages of infection. They are the only place that the virus can multiply, so they are the key battleground in the fight against flu. Gut bacteria send a signal that keeps the cells […] prepared, preventing the virus from multiplying so quickly.”
Andreas Wack, Ph.D.