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preterm infants

Neonatology

Gut fungi can predict BPD, study shows

Research shows that the gut composition of fungi in the second week of life predicts the later development of BPD.

By Jeff Hansen (UAB)

Extremely preterm newborns who weigh less than 3.3 pounds have immature lungs that often require high levels of ventilation oxygen in the hospital. This contributes to the chronic lung disease bronchopulmonary dysplasia, or BPD, the most common cause of death for these tiny infants. BPD exacts a devastating toll on the immature lung.

In one of the most extensive studies of the microorganisms in the intestines of very preterm infants, University of Alabama at Birmingham (UAB) and University of Tennessee Health Science Center researchers show that the gut composition of fungi in the second week of life predicts the later development of BPD, weeks to months before diagnosis of that disease. They analyzed gut fungi in the first true non-meconium stool produced before two weeks of life and found that the fungal intestinal microbiome—known as the mycobiome—of infants who later developed BPD differed in community diversity, composition and interconnectivity from the infants who never got BPD, as measured by the most up-to-date bioinformatic techniques. The researchers did not find significant differences in the bacterial microbiome in those first true stools.

To show causality, researchers transferred samples of the first true stool that predicts BPD or the first true stool of newborns who did not get BPD into female mice to give them a pseudo-humanized gut microflora. In a mouse model of BPD, newborn pups from those BPD dams showed an increased in the severity of lung injury compared with newborn pups from the no-BPD dams. In loss-of-function experiments, when the female mice with the BPD-predictive stool transplant were treated with an antifungal agent before birth, that inhibition of perinatal fungal colonization reduced lung injury in the newborn pups. In contrast, a gain-of-function experiment, where the perinatal fungal colonization of dams was augmented with a species of Candida fungus common in mice, amplified BPD severity in the newborn pups.

Kent Willis, M.D.

“These findings demonstrate that features of the initial intestinal fungal microbiome are associated with the later development of BPD in premature neonates and exert a microbiome-driven effect that is transferable and modifiable in mouse models,” said Children’s of Alabama neonatologist Kent Willis, M.D., who’s also an assistant professor in the UAB Department of Pediatrics Division of Neonatology. “This suggests causality, and it suggests that the gut fungi may represent a therapeutic target in newborn lung disease.”

Willis and Ajay J. Talati, M.D., University of Tennessee Health Science Center, Memphis, Tennessee, co-led the study, published in Microbiome.

“Collectively, our analyses demonstrate that the composition of the intestinal mycobiome of infants who did not develop BPD was more uniform,” Willis said. “In contrast, those who eventually developed BPD had more disparate mycobiomes. This suggests that a particular pattern of mycobiome development may be necessary to impart resistance to the development of BPD, and failure to do so in various ways is associated with disease development.”

The first defecations of newborn infants are meconium, composed from materials ingested while in the uterus. The first true stools in the second week, the ones analyzed by Willis and Talati, are digested milk. It is known, Willis and Talati say, that fungi in adults are vital members of the human microbiota; but compared to bacteria, their non-pathological and non-parasitic functions are still poorly understood, especially in newborns.

This prospective observational cohort study included newborn stool samples collected over six years from 2017-2020 in Memphis and 2021-2022 in Birmingham. The 64 very-preterm infants in the study who did not develop BPD had an average birthweight of 2.5 pounds, and the 38 very-preterm infants who did develop BPD had an average birthweight of 1.6 pounds. Only one of the 64 no-BPD infants in the study died, while six of the 38 BPD infants died.

July 23, 2025 by
Neonatology

Risk factors for BPD-PH in preterm infants

Studies led by Children’s neonatologists show early indicators of bronchopulmonary dysplasia with pulmonary hypertension.

It’s well-known that preterm infants are prone to breathing difficulties due to their underdeveloped lungs. But the most common lung disease in these babies, bronchopulmonary dysplasia (BPD), is only recently becoming better understood more than a half-century after it was first described.

Now, Children’s of Alabama neonatologist Samuel Gentle, M.D. is expanding that knowledge by focusing on the most severe type of BPD—the form associated with pulmonary hypertension (PH)—in research that teases out contributing factors to this deadly disease.

It’s a major threat: nearly half of preterm infants develop BPD, which can lead to long-term breathing and health problems. About 20% of these babies also develop PH, and an estimated 40% of them will die of BPD-PH before turning 2 years old.

Samuel Gentle, M.D.

“This is a disease for which there’s growing research interest. It can be lethal, is not uncommon in extremely preterm infants, and we have little understanding of how to prevent or treat it,” said Gentle, who’s also an assistant professor of neonatology at the University of Alabama at Birmingham (UAB). “And children who do survive have long-term complications that persist into adulthood. It’s not a disease they just grow out of.”

“I’ve also had many interactions with families who lost a child to this,” he added. “Oftentimes, a child will be stable and doing well, and then collapse. I’ve seen how this can ravage a family.”

Since research has been scant about what causes the development of BPD-PH—as well as how to screen, treat and prevent it—Gentle wanted to fill the vacuum. Currently, a single ultrasound of the heart is the standard diagnostic method, though UAB performs this testing more frequently.

“We need to get better at identifying this disease in real time, rather than doing ultrasounds at arbitrary time intervals,” Gentle said. “Even with UAB’s testing approach, I believe it will become possible to diagnose it sooner, allowing earlier initiation of PH-targeted therapies.”

Along with UAB colleagues, Gentle published two studies that assessed factors that may contribute to BPD-PH in preterm babies. Published in the American Journal of Respiratory and Critical Care Medicine, they found two important associations: The duration of intermittent hypoxia events and the presence and persistence of a patent ductus arteriosus (PDA) after birth are both novel risk factors for BPD-PH.

In the first study, Gentle found that infants who experienced intermittent hypoxia events lasting longer than one minute were twice as likely to develop BPD-PH. “If an infant has longer intermittent hypoxia events, we might be more proactive in screening that infant for BPD-PH,” he said.

In the second study, preterm babies born with BPD-PH between 22 and 28 weeks’ gestation were more likely to have a PDA vessel that stayed open longer than 28 days. Babies with longer PDA duration were also more likely to die due to complications of BPD-PH than infants with only BPD. “The PDA could be interfering with the development of pulmonary vasculature resulting in PH,” Gentle said.

UAB will be participating a multicenter trial to determine whether closing PDAs with a catheter-closure device might lower the risk of this PH variant. But far more study is needed, Gentle pointed out.

“While this research focused on a specific phenotype of BPD, we need a comprehensive approach to identifying each infant’s specific type of lung disease from which we can decide on the best therapeutic course for every child,” he said.

August 6, 2024 by