Enteric Nervous System Therapy for Preterm Newborns

According to the Centers for Disease Control, preterm births have been on the rise in the United States since 2014. Fortunately, the survival rate for newborns delivered before 37 weeks of pregnancy has been increasing, but doctors face a significant challenge in caring for babies born at the extreme limit of viability (before roughly 22 weeks) because internal organs are still growing. Preterm newborns require milk to develop, but due to restricted gut motility—the movements that drive food through the digestive tract—these babies frequently develop severe intestinal blockages or infections.

Through fundamental research on the enteric nervous system (ENS), researchers at Stanford’s Wu Tsai Neurosciences Institute want to improve gut motility and health outcomes for preterm neonates.

The scientists discovered how and when the neurons that control gastrointestinal motility grow in an article published on May 9, 2023 in Nature Communications, and found possible therapy pathways to enhance outcomes for preterm neonates.

“We’ve now looked at both human and mouse intestines and found that the neurons that control motility organize themselves into a striped pattern,” said Julia Kaltschmidt, Ph.D., a faculty scholar at the Wu Tsai Neurosciences Institute and associate professor of neurosurgery at Stanford Medicine. “The emergence of these stripes coincides with the onset of gut motility in both species, which supports the hypothesis that these stripes are important for gut function.”

The ENS, which lines the gut walls and regulates gut motility, is frequently referred to as “the second brain.” The ENS, which is made up of 500 million neurons and may act independently of the central nervous system, uses many of the same neurotransmitters that govern mood and cognitive function in the brain.

Because of this complexity, there are still significant gaps in our understanding of the ENS, which Lori Bowe Dershowitz, an MD, Ph.D. candidate in the lab, set out to fill. Dershowitz previously examined and studied the anatomy of the embryonic mouse ENS, discovering that neurons in the intestines evolved in a striped fashion. She wondered if the neural arrangement in human intestines was similar.

“When we looked at human fetal intestines, we found the same striping pattern,” Dershowitz said. “This allowed us to make new conclusions about the structure of the enteric nervous system.”

A complicated neural grid atop the neuronal stripes was one of the structures discovered by the team. The researchers believe that their understanding of neuronal stripes in the human stomach will lead to novel treatments to help preterm newborns absorb food.

“One of the major challenges with preterm infants is that they can’t receive intravenous nutrition alone. If the intestines don’t get milk, they’ll atrophy,” said senior co-author Anca M. Pasca, MD, an assistant professor of pediatrics at Stanford Medicine and a Wu Tsai Neuroscience Institute affiliate.

“The intestines of preterm infants have minimal motility, so their stool can’t be eliminated. This can cause obstructions and perforations that require surgery. We desperately need a better understanding of the ENS to help us find treatments that improve motility and milk tolerance.”

Preterm newborns have poor motility because their ENS is still developing. Material passes through the intestines via a sequence of synchronized contractions toward the colon in a fully established digestive system.

The researchers discovered that, at roughly 18 weeks, the neurons in the embryonic intestines were active but not coordinated. Constriction of the intestines was intermittent and moved in both directions—toward and away from the colon. They discovered that coordinated contractions appeared as early as 21 or 22 weeks.

The team believes that uncontrolled gastrointestinal motions in preterm newborns are caused by unequal neuron development. Those that relax the intestines emerge first and outnumber those that contract them until about 21 weeks.

Seeing how this ratio of neurons changes over time will help us find pharmacological treatments to increase motility in preterm infants. We know that drugs used to increase motility in adults don’t work in the preterm infants, and that may be because the composition of enteric neurons is very different,” said Dershowitz.

The lab is discovering indications that greater mobility can be achieved in embryonic mice using specific medicines that block certain neurons in recent, unpublished research. This allows the contraction-associated neurons, which are less developed, to move materials through the intestines.

The researchers anticipate that their findings will aid in the identification of medications that can be used to enhance gastrointestinal motility in preterm newborns, potentially maximizing their growth and survival rates.

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