Immediately after birth, human babies begin to develop a complex intertwined web of microbes in their gut. Collectively known as the gut microbiome, this diverse ecosystem is made up of bacteria, archaea, viruses and fungi, numbering billions. All have important roles to play in health and disease, and researchers are competing to better understand their enigmatic activities.
In a new study published in the journal Natural microbiology, Efrem Lim and his colleagues are exploring the galaxy of viruses found in the gut, known as the gut virome. They find that some premature babies experience marked changes in their gut virus profile shortly before developing a serious and often fatal disease known as necrotizing enterocolitis (NEC).
Professor Lim is a researcher at the Biodesign Center for Fundamental and Applied Microbiomics. He is also principal investigator at the ASU Center for Viral Genomics and Adjunct Professor at the ASU School of Life Sciences.
The study was conducted in collaboration with ASU colleagues and researchers from Washington University School of Medicine.
Although the bacterial component of the gut microbiome has received considerable research attention, the viruses that inhabit the gut remain a largely hidden area. The viral signature highlighted in the study, coupled with changes in gut bacterial communities, could provide an early warning signal that a child is at risk of developing NEC, allowing doctors to take urgent action.
“The microbiome has been suspected of being involved in this rapidly developing disease for many years,” says Lim. “Studies have shown that changes in the gut microbiome in these preterm infants appear to predict progression to NEC disease. “
Yet it has been difficult to untangle the specific microbial changes that lead to the disease, and the precise mechanism behind the affliction is still unknown. The current study is the first to comprehensively study changes in the viral microbiome that appear to lay the foundation for the development of NEC in preterm infants.
A microbial world is born
Microbes begin colonizing the baby’s gut during birth, when a baby encounters a variety of microorganisms from its mother’s vaginal tract. While the baby is breastfeeding, he collects additional microbes from his mother’s skin in addition to those that are filtered into his breast milk.
The child acquires new microbes from other family members and unfamiliar members and even from pets. These are all incorporated into the developing gut microbiome, which is made up of approximately 20-100 billion microbes.
This vast microbial community will continue to shape many aspects of an individual’s health throughout their life. Unsurprisingly, abnormal changes in the gut microbiome can lead to serious problems, and premature babies are particularly vulnerable to such disruptions.
ahead of their time
Premature birth generally refers to babies born less than 37 weeks of pregnancy. The condition appears to be on the rise, although the causes for this are not entirely clear. Factors such as HIV, infections, malaria and high rates of teenage pregnancy have been involved in many low-income countries.
In 2020, preterm birth affected 1 in 10 babies born in the United States. Babies born too early (especially before 32 weeks) have higher death and disability rates. Those who survive can experience lasting health problems, including feeding difficulties; breathing, visual and hearing problems; and abnormalities, including developmental delays and cerebral palsy.
Babies born prematurely are also at risk for NEC. The disease often strikes suddenly. When babies are born after less than 32 weeks of gestation, the incidence of NEC ranged from 2 to 7% in high-income countries. Mortality in infants with necrotizing enterocolitis ranges from 22 to 38%.
A stealth disease
Although rarely occurring in full-term infants, this largely mysterious condition affects 1 in 1,000 premature babies. The condition strikes without warning and can cause a child to go from apparently healthy to seriously ill within hours. The disease usually occurs two to six weeks after birth.
The disease produces severe inflammation of the intestinal tissue, causing its death. These conditions are known as necroinflammatory diseases. A perforation can also form in the intestine, allowing bacteria to enter the abdomen or bloodstream. The sequence of steps leading to NEC remains unclear, although risk factors are thought to include prolonged use of antibiotics in the first few years of life and artificial feeding (in addition to premature birth).
Although studies have strongly implicated changes in the gut microbiome as contributors to the development of NEC, no bacterial genes have been consistently associated with the disease.
Children who survive the affliction often face lifelong health problems, which can include neurodevelopmental disorders and a condition known as short bowel syndrome.
The role of viruses
In the present study, 138 stool samples were collected during the first 11 weeks of life. The samples were from 23 premature babies in a neonatal intensive care unit in St. Louis, Missouri. Nine of these infants developed NEC, while 14, matched for weight and gestational age, did not.
The study explored the samples using metagenomics, a sequencing method that allows researchers to comprehensively sample the genes of all organisms in a sample. This allows microbiologists like Lim to assess bacterial diversity and detect microbial abundance in various environments. The technique also allows the detailed study of microorganisms that are difficult or impossible to grow in the laboratory. (In early 2020, Lim used metagenomic sequencing to quickly probe the 30,000-letter code of the SARS CoV-2 virus, identifying a unique mutation.)
The study shows that NEC infants showed a convergence of viral and bacterial signatures in the intestinal virome. Notably, children with NEC showed reduced diversity in viral composition between communities in the gut, a feature known as? -Diversity. The decrease in viral α diversity occurred over a 10-day period prior to the start of NEC, providing a potential biomarker, warning doctors of impending danger. The findings suggest that the developing virome contains vital clues to the health of preterm infants.
The research could lead not only to faster diagnoses and better therapies for NEC, but also for a wide range of microbiome-mediated diseases. Furthermore, existing therapies aimed at modifying the intestinal microbiota, such as fecal transplant therapy, could be further improved by taking stock of the viral component.
The study shows that the under-explored viral constituents of the microbiome have a lot to teach us and almost certainly play an important role not only in the transition to NEC in preterm infants, but in other diseases as well. With rapidly evolving new sequencing technologies, researchers can begin harnessing the virome to find valuable diagnostic markers of the disease and develop more effective therapies.
Efrem Lim is the 2022 recipient of the ASU Faculty Research Achievement Award, awarded during the university’s Founder’s Day celebration on March 17.