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Providing enteral nutrition:
Using the laboratory
to solve an old problem in premature newborns
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Newborn |
TPN |
TPN+GLP-2 |
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H&E staining of newborn piglet intestine in cross-section. GLP-2 prevents
TPN-associated mucosal atrophy.
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By David A. Horst, M.D.
Many of the unique clinical challenges in the field of
Neonatology stem from the underdeveloped organ systems of
premature infants who have been born as much as 16 weeks early.
One of the most challenging problems is providing nutrition to
infants whose gastrointestinal tract is not prepared to handle
breast milk or formula.
Infants who remain in the womb through the third trimester
receive their nutrients for growth and organ development from
their mother through the placenta. In the case of premature
birth, however, nutrition for critical organ development,
including brain growth, must be provided by milk or formula
feedings through an undeveloped gastrointestinal tract. As a
result, catastrophic intestinal failure, most commonly known as
necrotizing enterocolitis (NEC), occurs in as many as 10 percent
of premature infants following attempted feeding. Many of these
infants require surgery to remove damaged intestine, and many
don’t survive. Problems in survivors include protracted hospital
stays associated with an inability to tolerate use of the
gastrointestinal tract. This intolerance leads to complications
from long-term use of intravenous nutrition, including
infections, TPN cholestasis and poor bone mineralization severe
enough to cause fractures.
Despite years of study of various feeding strategies for
premature infants, no clear consensus on the best approach has
emerged, and the incidence of NEC has remained unchanged for
decades. Questions about when to start and how rapidly to
advance feedings remain unanswered, and neonatologists continue
to walk the fine line between the optimal provision of enteral
nutrition for growth and development and intestinal failure. My
research is focused on gaining a better understanding of the
response to feeding in infants, including the difference between
responses in premature and term infants. I hope to use knowledge
gained in the laboratory and animal studies to develop new
approaches to feeding, as well as treatments to prevent NEC and
alleviate the complications of intestinal failure in the
Neonatal Intensive Care unit (NICU).
GLP-2 may be the key
The gastrointestinal tract responds to milk and formula feeding
by producing digestive enzymes and hormones that aid in the
digestion of food and contribute to its own function and
development. Feeding also initiates a local increase in
intestinal blood flow and motility to facilitate digestion and
absorption of nutrients. General underdevelopment of this
response to feeding likely contributes to poor feeding tolerance
and gastrointestinal failure, including necrotizing
enterocolitis. The secretion of glucagon-like peptide 2 (GLP-2)
by enteroendocrine cells in the small intestine is stimulated by
feeding and has been shown in animal models to be a primary
mediator of a specific increase in blood flow to the small
intestine and colon by Douglas Burrin, Ph.D., associate
professor of pediatrics at the USDA Children's Nutrition
Research Center. He also has shown that TPN-induced intestinal
mucosal atrophy occurs rapidly and is correlated with acute
changes in intestinal blood flow. GLP-2 secretion helps to
maintain the growth and integrity of the absorptive surface of
the intestines, and GLP-2 administration can prevent the atrophy
associated with the lack of formula feeding during dependence on
TPN (Fig 1). GLP-2 is approved for use in humans and has been
used in trials for treatment for short-bowel syndrome and bone
resorption in post-menopausal women.
In collaboration with Dr. Burrin, I have developed a model using
primary intestinal cells obtained from piglets at various
gestational ages to evaluate differences in GLP-2 receptor
function that may underlie different responses to feeding at
different gestational ages. We are also completing a pilot study
comparing bone mineralization in piglets that receive their
nutrition from formula, TPN or TPN with GLP-2 infusion. Our
hypothesis is that piglets receiving GLP-2 infusion will have
improved bone mineralization.
Our ultimate goal is to take knowledge gained from laboratory
studies of the critical cellular and hormonal signals that
mediate the stimulatory effects of enteral nutrition on the
growth and functions of the neonatal intestine and use it to
improve the care and feeding of infants in the NICU. GLP-2 is
approved for limited use in humans, but establishing the safety
of GLP-2 administration in premature neonates is an important
initial step. Studies of the effect of GLP-2 administration on
regional blood flow to organs besides the intestine using
implanted ultrasonic flow probes and fluorescent microspheres
are under way in animal models, and I will eventually use
established ultrasound methods to evaluate regional blood flow
in human infants. GLP-2 may be able to improve feeding tolerance
and have a role in the prevention of NEC. It is also a promising
therapy for both improving bone mineral content in osteopenia of
prematurity and intestinal adaptation following surgery for NEC.
David A. Horst, M.D., is a pediatrician at Texas Children’s Hospital and assistant professor of pediatrics-Neonatology at Baylor College of Medicine.
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