UC Davis Study Finds Probiotic Decreases the Risk of Necrotizing Enterocolitis

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Adding bacteria to milk formula improved outcomes in rat model of severe disease of newborns.

A team of UC Davis and University of Arizona researchers discovered that adding the bacteria Bifidobacterium longum subsp. infantis (B. infantis) to formula fed to newborn rats reduced the incidence of necrotizing enterocolitis, an often deadly intestinal infection. The findings were published as a cover story in Pediatric Research, a journal of the Nature Publishing Group, and is available online. The discovery sets the stage for clinical trials in human premature newborns.

“The discovery in an experimental model that this organism can dramatically reduce the risk of developing necrotizing enterocolitis is very encouraging,” said Mark Underwood, lead author of the study and chief of the division of Pediatric Neonatology at UC Davis Children’s Hospital. “It potentially offers another important strategy for prevention of this very difficult-to-treat disease.”

Necrotizing enterocolitis (NEC) is the second most common cause of death among premature newborns after the first two weeks of life. The disease rapidly attacks the lining of the intestines and may require removal of part of the bowel. Feeding babies exclusively breast milk is the most effective way to prevent the condition from developing. For infants who cannot receive breast milk or do not have it available, adding a probiotic to infant formula — consisting of live bacteria that are expected to colonize the intestinal tract and create a healthier bacterial environment — is believed to be the next best alternative. Identifying the best bacteria for this purpose is the goal of considerable research.

The investigators took premature newborn rats and allowed them to nurse or alternatively fed them either a milk substitute or milk substitute fortified with B. infantis. After four days, in which the rats were exposed to brief periods of low oxygen and cold temperatures in order to induce stressful conditions that can lead to NEC, the intestines were examined for evidence of the disease.

Rats who were nursed did not develop NEC, while those who were fed formula without the probiotic developed it at twice the rate of those given the fortified formula. The rats provided formula with probiotic also had inflammatory responses — as measured by multiple pro-inflammatory cytokines — that were more similar to the nursed rats than to the rats given unfortified formula.

Other studies have demonstrated a protective effect conferred by a different Bifidobacterium species, but the organism used in this study is believed to have several advantages: it is better able to adhere to cells lining the intestine and colonize the intestinal tract, and it has been associated with improved growth in human babies as well as increased responsiveness to childhood vaccines. B. infantis is part of the normal gastrointestinal flora of human infants who are breast fed.

The investigations resulted in some puzzling findings as well: despite the improved outcomes in rats provided with the probiotic, the microbial makeup of the intestines did not differ significantly between the two formula-fed groups, and considerable individual differences within the groups themselves were evident. It is believed that an altered microbial environment is associated with NEC, but whether it is the cause or the consequence of the disease is still not well understood.

“Although it is clear that probiotics reduce the risk of NEC in premature infants, the precise mechanisms of protection are uncertain,” said Underwood. “Understanding these mechanisms will likely help us develop better preventive and therapeutic strategies for NEC.”

Underwood’s group is next planning to conduct a large-scale clinical trial that will randomly assign premature newborns to receive either B. infantis or not. They will monitor infant growth as well as development of NEC and other diseases. The outcome of this study is expected to help determine whether this probiotic should be routinely provided to premature newborns.

The article is titled “Bifidobacterium longum subsp. infantis in experimental necrotizing enterocolitis: alterations in inflammation, innate immune response, and the microbiota.”

Other study authors from UC Davis are Karen Kalanetra and David Mills of the Department of Viticulture and Enology, and Anchasa Kananurak and Charles Bevins of the Department of Medical Mircobiology and Immunology. The other authors, Jennifer Arriola, Colin Gerber, Ashwini Kaveti and Bohuslav Dvorak (principal investigator), are from the Department of Pediatrics and the Steele Children’s Research Center of the University of Arizona in Tucson.

The study was funded by the National Institutes of Health (HD059127, AI32738, AT007079, HD039657), the Development and Promotion of Science and Technology Talents Project, Mead Johnson and Meiji Dairies Co.

UC Davis Children's Hospital is the Sacramento region's only nationally ranked, comprehensive hospital for children, serving infants, children, adolescents and young adults with primary, subspecialty and critical care. It includes the Central Valley's only pediatric emergency department and Level I pediatric trauma center, which offers the highest level of care for critically ill children. The 129-bed children's hospital includes the state-of-the-art 49-bed neonatal and 24-bed pediatric intensive care and pediatric cardiac intensive care units. With more than 120 physicians in 33 subspecialties, UC Davis Children's Hospital has more than 74,000 clinic and hospital visits and 13,000 emergency department visits each year. For more information, visit http://children.ucdavis.edu.

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Tricia Tomiyoshi
UC Davis Children's Hospital
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