—-Study is the First to Demonstrate How the Premature Newborn Gut Microbiome May Lead to the Mucosal Injury Underpinning NEC—-
—-Results Provide Insights Into Clinical Management of NEC—-
DAVIS, Calif., Aug. 23, 2022 /PRNewswire/ — Results of a study published today in Frontiers in Pediatrics have revealed critical missing information linking potentially pathogenic gut microbes to intestinal injury and necrotizing enterocolitis (NEC). NEC is one of the leading causes of death and disease in premature newborns. Although studied for decades, the precise cause of NEC remains undefined. This new study heralds a novel understanding of NEC and provides the rationale for potential prevention strategies.
NEC is an inflammatory condition of the newborn gut that can lead to significant intestinal injury. In severe cases, this injury extends through the intestinal wall leading to irreversible tissue death and perforation. Translocation of harmful bacterial contamination through the perforation can cause peritonitis and sepsis, both life-threatening conditions.
The most severe cases of NEC are associated with a significant risk of death (40% – 50%). Babies with NEC are at heightened risk of neurodevelopmental impairment. Those who survive and recover from NEC can face life-long health challenges resulting from inflammation and intestinal malfunction. These in turn decrease the body’s ability to absorb nutrients and thus negatively affect the infant’s growth, leading to developmental delays.
In the study published today, researchers combined metagenomics and targeted metabolomics with functional in vivo and in vitro assessment to define a novel molecular mechanism of NEC. Analyses of stools in infants with NEC revealed that the short chain fatty acid formate was significantly elevated at disease onset and dissipated during recovery. Formate levels were positively correlated with the degree of intestinal injury. Formate was responsible for dose- and development-dependent cytotoxicity in human cells and intestinal injury in newborn mice, respectively. Enterobacter cloacae and Klebsiella pneumoniae were the most common gut bacteria found in the stools of patients who developed NEC and were determined to be genetically capable of elevated formate production in the study’s metagenomic analysis.
“This landmark study released today shows how detrimental bacteria in the preterm infant are linked to the intestinal injury developed in NEC, a disease not only carrying a high risk of infant death but also significant life-long health challenges”, explains attending Neonatologist Jennifer Bragg, MD.
This study is the first to demonstrate a significant relationship between infant gut dysbiosis (a negative disruption in the infant gut microbiome), NEC, and a mechanism of intestinal injury caused by microbial fermentation and the overproduction of formate. “Formate production by specific Proteobacteria (the gut bacteria most strongly associated with NEC), including the Enterobacteriaceae family members Enterobacter cloacae and Klebsiella pneumoniae as demonstrated in this study, provides insights into the mediator of intestinal injury resulting from premature newborn gut dysbiosis. The findings implicate aberrant pattern of gut fermentation and metabolism as the pathophysiologic link between Proteobacteria colonization and NEC in newborns born premature,” explains study lead author Karl Sylvester, MD.
The metabolic model defined by the researchers is consistent with and extends prior studies suggesting the key role of specific members of the newborn enteric microbial community as a necessary first step toward the development of NEC. The results of this study demonstrate the potential importance of novel therapies to prevent NEC by targeting the newborn gut microbiome to displace the potential pathogens identified in this study and others, with microbes that promote a healthy gut in newborns.
These newly published results bring us closer to understanding the biological underpinnings of NEC while providing information to link mechanisms of action, with clinical observations derived from use of B. infantis EVC001 to alter the preterm infant microbiome,” notes neonatologist Brian Scottoline, MD, PhD, Associate Professor of Pediatrics at Oregon Health & Science University (OHSU). He continues “The OHSU NICU has been using enterally-administered B. infantis EVC001 to address intestinal dysbiosis in very low birth weight infants most at risk for NEC since 2018, and the incidence of NEC in these infants has decreased significantly. We published some of these findings earlier this year using a retrospective chart review and found that infants who had received B. infantis EVC001 had a 73% risk reduction of NEC relative to when our unit hadn’t implemented any measures to address dysbiosis; the same result was true for the subgroup of extremely low birth weight infants. Knowing from other studies that infants who receive B. infantis EVC001 have a lower abundance of Enterobacteriaceae capable of producing formate as described in this new study, I am looking forward to seeing future research that connects interventions aimed to address intestinal dysbiosis in preterm infants with the kind of mechanistic observations described in this paper.”
“Together with clinical research partners all over the world, Evolve is on a mission to establish an optimal standard of care for all infants leading to an improved lifelong health trajectory,” emphasizes Kaile Zagger, CEO of Evolve. She continues “This study provides further scientific evidence of the pioneering science that provides the foundation for Evolve’s discovery engine and expanding product pipeline. Our goal is to bring discoveries to market that clinically demonstrate improvement to not only the immediate health of newborns but that can positively impact their life-long health.”
To read the study, please visit: doi: 10.3389/fped.2022.893059
Evolve BioSystems, Inc. is a privately held infant health company on a mission to give babies the biggest chance to lifelong health. Dedicated to discovering and marketing microbiome-based products that improve short and long-term health of infants worldwide, Evolve has built substantial science and technology assets focused on the nutrition, biochemistry, physiology, and immunology of the developing infant. Launched at the University of California, Davis, following more than a decade of pioneering research on breast milk at the Food for Health Institute, Evolve continues to expand its pipeline of synbiotic-based solutions that can revolutionize human health. Evolve has a strong foundation of partners and investors such as; Johnson & Johnson Development Corporation, Horizons Ventures, Cargill, Manna Tree Partners, The Bill & Melinda Gates Foundation, Spuce, Acre Ventures, Bow Capital, Tate & Lyle Ventures. Since 2014, Evolve has built substantial science and technology assets, focused on the nutrition, biochemistry, and physiology of the developing infant gut microbiome, and has now added strong data science and technology platform capabilities.
Tobias J, Olyaei A, Laraway B, et al. Bifidobacterium longum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants. J Pediatrics. 2022;244:64-71.e2. doi:10.1016/j.jpeds.2021.12.070
Casaburi G, Wei J, Kazi S, et al. Metabolic Model of Necrotizing Enterocolitis in the Premature Newborn Gut Resulting from Enteric Dysbiosis. Frontiers. Pediatrics.2022; doi: 10.3389/fped.2022.893059
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