Study connecting gut microbiome to immune system development raises questions about how antibiotics are prescribed
by Tim Bonfield

Doctors have long understood that antibiotics that protect infants from infection also can disrupt the normal growth of their gut bacteria. However, a new study reveals that the consequences of routine antibiotic use may be deeper and longer lasting than expected. 

In the short term, disrupting gut bacteria makes infant mice more likely to develop pneumonia. It also makes them more likely to die from it. Longer term, continued disruption to gut bacteria appears to cause permanent immune system damage.   

These are the key findings of a study published Feb. 8, 2017, in the journal Science Translational Medicine.  The study, led by experts at Cincinnati Children’s, may spark a wider conversation about antibiotics use, including the near-automatic practice of prescribing them to women before Cesarean section (C-section) deliveries.

Hitesh Deshmukh, MD, PhD.

Hitesh Deshmukh, MD, PhD, says it may be possible to protect infant immune systems from antibiotic damage.

“It is time to begin pushing back on practices that were established decades ago, when our level of understanding was different,” says Hitesh Deshmukh, MD, PhD, lead author of the study. “To prevent infection in one infant, we are exposing 200 infants to the unwanted effects of antibiotics. A more balanced, more nuanced approach is possible.”  

In addition to Deshmukh, co-authors included Jeffrey Whitsett, MD, Co-Director of the Perinatal Institute at Cincinnati Children’s; Theresa Alenghat, VMD, PhD, Division of Immunobiology; research assistants Jerilyn Gray and Katherine Oehrle; and George Worthen, MD, Children’s Hospital of Philadelphia.

Too Much of a Good Thing?

Nearly every C-section in the U.S. involves prescribing antibiotics to mothers shortly before delivery. Up to 30 percent of newborns in neonatal intensive care units also receive antibiotics.

The treatments help prevent Group B streptococcal infections—the leading cause of deadly infections in newborns. However, in most cases the drugs are given as a precaution, not because infections have been confirmed, Deshmukh says. 

Once taken, the antibiotics act against a wide range of bacteria, be they good or bad. It turns out that commensal—or “good”—bacteria play a vital role in building a healthy immune system.

Lung Development Relies on Gut Bacteria Signaling

Even after birth, an infant’s lungs are still forming. Their immune defenses remain under construction.   

For more than two years, Deshmukh and colleagues conducted experiments in mice to define how this process works. They found that strong defenses depend on a flow of molecular signals occurring as the body reacts to waves of normal bacteria colonizing the gut. 

Specifically, the presence of commensal bacteria triggers the production of group 3 innate lymphoid cells (ILC3). These sentinel cells migrate to mucosal linings in the lungs, where they produce interleukin-22 (IL-22). This vital signaling protein helps activate the immune response to infection. 

The problem: when antibiotics wipe out good bacteria, they cut off that important flow of signals. As a result, the lungs build weaker defenses against future infections.

Damage Can Become Permanent

If antibiotic use is limited and early, a human infant would have some time to replenish commensal bacteria. But the process can take months, Deshmukh says, and the result may not be a normal mix of bacteria. 

After about a year, human infants have completed building their immune systems. That means any construction weaknesses are likely to be permanent. 

This outcome of excess antibiotic use may help explain why some people with no obvious genetic risk factors develop asthma or other lung diseases later in life, Deshmukh says.

Rapidly Restoring Good Bacteria May Help

The need to use antibiotics to save lives when dangerous infections strike has not changed. However, these findings do suggest re-thinking routine preventive use in newborns, the researchers say. 

The good news: methods exist for restoring normal bacteria levels. In fact, when the researchers used such methods in mice, it restored their resistance to pneumonia.

But do these mice experiments apply to humans? A clinical study has begun to evaluate the safety and benefits of limiting antibiotic use among expectant mothers and newborns, Deshmukh says. Several other next steps are planned.