Photo Credit: Alexander Grey
Scientific Frontline: Extended "At a Glance" Summary: Microbiome Predictors for Necrotizing Enterocolitis
The Core Concept: Predictive biomarkers for necrotizing enterocolitis, a sudden and fatal intestinal illness in premature infants, have been identified within the viral and bacterial genetic material of the infant gut microbiome.
Key Distinction/Mechanism: Unlike previous approaches that focused solely on profiling harmful bacteria, this predictive model analyzes viral "dark matter" (bacteriophages that integrate their DNA into bacterial hosts) and the accumulation of bacterial antibiotic resistance genes to forecast disease onset up to eight days before clinical symptoms appear.
Origin/History: Necrotizing enterocolitis was first described 65 years ago with virtually no predictive capabilities until Washington University researchers published these AI-driven findings on September 16, 2026, in the journal Gut, demonstrating up to 83% predictive accuracy.
Major Frameworks/Components:
- Early-onset necrotizing enterocolitis (occurring in the first month of life) is primarily signaled by phage-bacterial interactions within the gut microbiome.
- Late-onset necrotizing enterocolitis (occurring six weeks or later) is driven by the accumulation of antibiotic resistance genes, typically linked to prolonged antibiotic exposure in the neonatal intensive care unit.
- Artificial intelligence prediction models utilize computational algorithms to analyze phage genomic sequences and antibiotic resistance genes embedded inside gut bacterial DNA.
Branch of Science: Neonatology, Microbiology, Genomics, Bioinformatics, Pathology, and Immunology.
Future Application: This computational approach could pave the way for the early diagnosis and intervention of other inflammatory illnesses, including inflammatory bowel disease, sepsis, and drug-resistant bacterial infections precipitated by antibiotics.
Why It Matters: With high mortality rates and severe long-term complications for survivors, early prediction offers clinicians a critical window of opportunity to intervene with established treatments before the disease inflames and destroys the fragile, undeveloped intestinal lining.
In a discovery that challenges long-standing assumptions about necrotizing enterocolitis, a sudden and often fatal intestinal illness that affects premature infants, researchers at Washington University School of Medicine in St. Louis have identified previously unknown predictors of the disease.
Although bacteria have been proposed as key drivers of this devastating disease, scientists have been unable to identify specific intestinal bacterial features that reliably predict its onset. In a new study, the researchers found that, within the gut microbiomes of babies, bacteria-infecting viruses and bacterial antibiotic-resistance genes are additional harbingers of necrotizing enterocolitis.
The findings, published September 16 in Gut, are the first to show that these biomarkers in stool can predict human disease risk up to eight days before clinical symptoms appear.
“The mortality rate for necrotizing enterocolitis has changed little since it was first described 65 years ago, and our ability to predict it has been virtually nonexistent—until now,” said Gautam Dantas, PhD, the Conan Professor of Laboratory and Genomic Medicine in the Department of Pathology and Immunology at WashU Medicine and a co-corresponding author of the study. “By showing that bacteria-infecting gut viruses and bacterial drug-resistance genes can accurately signal a baby’s risk days in advance, we are offering clinicians a window of opportunity to intervene.”
Viral Dark Matter
Necrotizing enterocolitis strikes a fragile and undeveloped gut lining. As inflammation flares, blood flow to the intestinal tissue is choked off, causing sections of the delicate intestine to swell, break down, and die.
“With high mortality rates and severe long-term complications for survivors, the disease remains one of the most feared and challenging diagnoses in the neonatal intensive care unit,” said co-corresponding author Barbara Warner, MD, the F. Sessions Cole, MD, Chair in Newborn Medicine and director of the Division of Newborn Medicine at WashU Medicine, who treats premature infants with necrotizing enterocolitis at St. Louis Children’s Hospital.
For nearly two decades, Dantas and Warner have been collaborating with Phillip I. Tarr, MD, the Melvin E. Carnahan Professor of Pediatrics at WashU Medicine and a co-corresponding author of the study, to better understand the gut ecosystem in premature infants, focusing on harmful gut bacteria as the driver of necrotizing enterocolitis.
Sprinkled throughout the genomes of bacteria living in the gut is the genetic material of viruses. Rather than infecting human cells as the flu virus does, these viruses—called bacteriophages or phages—target bacteria, integrating their DNA into that of their bacterial hosts. Such integration can shuttle genes for antibiotic resistance or virulence between microbes, converting harmless bacteria into deadly, drug-resistant pathogens.
“When dealing with a disease as sudden and devastating as necrotizing enterocolitis, every day counts.” —Barbara Warner
This viral dark matter within bacterial genomes has been largely ignored, said Dantas. When Kailun Zhang, PhD, a postdoctoral research associate and the first author of the study, joined the Dantas lab, she asked a simple question: What if this often-discarded phage information has an important role to play in necrotizing enterocolitis?
Zhang used advanced computer algorithms to analyze existing genetic data obtained from the stool samples of 43 premature infants who developed necrotizing enterocolitis and 86 healthy premature infants. The samples came from infants born between 23 and 33 weeks’ gestation who spent time in the neonatal intensive care units at St. Louis Children’s Hospital, Norton Children’s Hospital in Louisville, Kentucky, or Oklahoma Children’s Hospital OU Health. She pieced together phage genomic sequences and antibiotic-resistance genes embedded inside gut bacterial genomic DNA and fed those genetic sequences into artificial intelligence prediction models to identify premature infants at risk of developing necrotizing enterocolitis.
The analysis revealed that phage–bacterial interactions were an important early warning signal for early-onset necrotizing enterocolitis, which occurs in the first month of life. By tracking the genetic footprints of phages, the team’s predictive models identified, with approximately 75% accuracy, which premature infants would develop the disease up to eight days before physical symptoms appeared.
“When dealing with a disease as sudden and devastating as necrotizing enterocolitis, every day counts,” said Warner. “Improving predictive power will help clinicians intervene earlier than ever before with tried-and-true measures, without having to wait years for new drugs to make a difference today.”
The researchers also found that late-onset necrotizing enterocolitis, which strikes approximately six weeks or later after birth, appears to be biologically distinct from early-onset cases. They discovered that late-onset necrotizing enterocolitis is marked by the accumulation of antibiotic-resistance genes in gut bacteria, driven by cumulative antibiotic exposure during longer NICU stays. By tracking this gene buildup, the team could also predict late-onset necrotizing enterocolitis, with 83% accuracy, up to eight days before symptoms appeared.
“By showing that the phages that infect gut bacteria play an important role in disease, this computational approach opens doors to early diagnosis of other inflammatory illnesses, including inflammatory bowel disease, sepsis, and drug-resistant bacterial infections, that plausibly involve phages or are precipitated by antibiotics,” said Tarr. “Phage biology could also be within the causal pathway leading to necrotizing enterocolitis, and, if so, could inform new approaches to interventions.”
Reference material:
Funding: This work was supported in part by awards from the National Institutes of Health (NIH) Human Virome Project (HVP) through the National Center for Complementary and Integrative Health (grant number U01AT012998); the National Institute of Diabetes and Digestive and Kidney Diseases (grant number P30DK052574); the National Institute of Allergy and Infectious Diseases (grant numbers R01AI155893 and UH3AI083265); the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number R01HD092414); the Children’s Discovery Institute of Washington University; St. Louis Children’s Hospital; and the Pediatric Gastroenterology Research Training Program (grant number T32 DK077653).
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Disclosure: G.D. is a consultant to and a member of the Scientific Advisory Board of Pluton Biosciences, which is developing methods for discovering environmental microbes for commercial applications. G.D. has consulted for SNIPR Technologies Ltd. in the last five years. P.I.T. is an equity holder in, a consultant to, and a member of the Scientific Advisory Board of MediBeacon Inc., which is developing a technology to noninvasively measure intestinal permeability in humans. P.I.T. is a co-inventor on patents assigned to MediBeacon (U.S. patents 11,285,223 and 11,285,224, titled “Compositions and Methods for Assessing Gut Function,” and U.S. patent application 2022-0326255, “Methods of Monitoring Mucosal Healing”), which might earn royalties if the technology is commercialized. He is a member of the Data Safety Monitoring Board of Inmunova, which is developing an immune biologic targeting Shiga toxin-producing Escherichia coli (E. coli) infections, for which he receives no compensation, except for reimbursement of expenses. P.I.T. receives royalties from UpToDate for two sections on intestinal E. coli infections. The authors declare no other competing interests.
Published in journal: Gut
Authors: Kailun Zhang, Mark G. Gorelik, Janice E. Sullivan, Paula Radmacher, Marilyn Escobedo, Barbara B. Warner, Phillip I. Tarr, and Gautam Dantas
Source/Credit: Washington University School of Medicine in St. Louis | Marta Wegorzewska
Edited by: Scientific Frontline
Reference Number: mcb091726_01
