Hospitalized premature babies are routinely given antibiotics during their first weeks of life to help prevent or treat potentially deadly bacterial infections. While such drugs can literally save lives, they may also cause long-lasting “collateral damage” to the developing infant gut microbiome, according to the results of research by scientists at Washington University School of Medicine (WUSM) in St. Louis.

Their study in 58 infants showed that even a year and a half after leaving the neonatal intensive care unit (NICU), the gut microbiomes of preemies who had received antibiotics in the hospital contained more bacteria associated with disease, fewer species linked to good health, and more antibiotic-resistant strains compared with the gut microbiomes of healthy full-term babies who had not received antibiotics.

The findings suggest that antibiotic use in premature babies should be carefully considered to minimize disrupting the infant gut microbiota (IGM), and potentially reduce the risk of health problems later in life. “The type of microbes most likely to survive antibiotic treatment are not the ones we typically associate with a healthy gut,” said research lead Gautam Dantas, PhD, a professor of pathology and immunology, molecular microbiology, and biomedical engineering. “The makeup of your gut microbiome is pretty much set by age 3, and then it stays pretty stable. So if unhealthy microbes get a foothold early in life, they could stick around for a very long time. One or two rounds of antibiotics in the first couple weeks of life might still matter when you’re 40.”

Dantas is senior author of the team’s published paper in Nature Microbiology, which is titled, “Persistent metagenomic signatures of early-life hospitalization and antibiotic treatment in the infant gut microbiota and resistome.”

More than 11% of live births worldwide are preterm, and as preterm infants are at an increased risk of bacterial infections, about 79% of very low birthweight infants, and 87% of extremely low birthweight newborns in NICUs in the United States receive antibiotics within the first 3 days of birth, the authors explained. However, they pointed out, it is not known whether the short-term effects of antibiotics on the gut microbial communities in the infant gut will when they go home from hospital, or whether they may have even longer-term effects on the risks of metabolic disorders later in life. “… emerging data suggest that early-life gut microbial alterations correlate with chronic metabolic and immune disorders later in life, including allergies, psoriasis, adiposity, diabetes, and inflammatory bowel disease,” they wrote. And while a causal link between antibiotic disruption of gut microbiota and such disorders hasn’t been identified, the authors acknowledged, “ … antibiotic treatment during infancy is associated with permanent immune alterations and inflammatory bowel disease in childhood, highlighting the damaging long-term potential of early-life antibiotic treatment.”

To find out whether the microbiomes of antibiotic-treated preterm babies do re-equilibrate over time, Dantas and colleagues used whole-metagenome shotgun sequencing and culture techniques to analyze the bacteria in 437 fecal samples collected from 58 infants, aged from birth to 21 months. Forty-one of the infants were born around 2.5 months premature, and the other 17 were born at full-term. All of the preterm babies had been treated with antibiotics in the NICU. Nine had received one course of antibiotics, and the other 32 infants had each been given an average of eight courses and spent about half their time in the NICU being treated with these drugs. None of the full-term babies had received antibiotics.

The researchers’ analyses showed that those preterm infants who had been heavily treated using antibiotics carried significantly more drug-resistant bacteria in their gut microbiomes at 21 months of age than preemies who had received just one course of antibiotics, or full-term infants who had not been given antibiotics. The presence of drug-resistant bacteria wasn’t causing the infants any immediate problems, because most gut bacteria are harmless, and it’s only if they escape the gut and travel to the bloodstream, urinary tract, or other parts of the body, that they can make any resulting infection harder to treat.

By culturing bacteria from fecal samples taken 8 to 10 months apart, the researchers also discovered that drug-resistant bacterial strains present in older babies were the same ones that had become established early on. “They weren’t just similar bugs, they were the same bugs, as best we could tell,” Dantas said. “We had cleared an opening for these early invaders with antibiotics, and once they got in, they were not going to let anybody push them out. And while we didn’t show that these specific bugs had caused disease in our kids, these are exactly the kind of bacteria that cause urinary tract and bloodstream infections and other problems. So you have a situation where potentially pathogenic microbes are getting established early in life and sticking around.”

Further tests indicated that all of the babies developed diverse microbiomes by 21 months of age. This was a positive finding, given that lack of microbial diversity is associated with immune and metabolic disorders in children and adults. However, the heavily treated preemies developed microbiome diversity more slowly than the full-term infants or those premature infants who had been treated less aggressively with antibiotics. There was also a difference in the overall makeup of gut microbial communities between the infants. Heavily treated premature infants carried fewer groups of healthy bacteria such as Bifidobacteriaceae, and increased forms of unhealthy bacteria such as Proteobacteria. “These data support an enduring and transmissible pathological microbiome scar associated with preterm birth, early-life hospitalization, and antibiotic treatment,” the authors wrote.

“… we found compelling evidence for the underappreciated lasting effect of prematurity and the associated hospitalization and antibiotic treatment on the microbiome,” they concluded. “These perturbations may play a role in chronic pathologies associated with prematurity for which the etiology is unclear.” The scientists suggest that from a clinical perspective the findings highlight the need to look for alternatives to using broad spectrum antibiotics as a routine strategy for managing infection in preemies. “This should not only entail therapeutic approaches, such as narrow spectrum antibiotics and probiotic therapies, but also improved accuracy and speed of diagnostics to reduce unnecessary courses of antibiotics.”

The findings are already prompting changes to how antibiotics are used to treat preemies, the researchers noted. “We’re no longer saying, ‘Let’s just start them on antibiotics because it’s better to be safe than sorry,'” commented co-study author Barbara Warner, MD, director of the division of newborn medicine. “Now we know there’s a risk of selecting for organisms that can persist and create health risks later in childhood and in life. So, we’re being much more judicious about initiating antibiotic use, and when we do start babies on antibiotics, we take them off as soon as the bacteria are cleared,” Warner stated. “We still have to use antibiotics—there’s no question that they save lives—but we’ve been able to reduce antibiotic use significantly with no increase in adverse outcomes for the children.”

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