Soon after birth, human babies begin to develop a complex, intertwined fabric of microbes in their gut. Collectively known as the gut microbiome, this diverse ecosystem contains bacteria, archaea, viruses and fungi, numbering in the billions. All have important roles to play in health and disease and researchers are racing to better understand their enigmatic activities.
In a new study published in the journal Nature MicrobiologyIn this article, Ephraim Lim and colleagues traced a galaxy of viruses present in the gut, known as gut viromes. They find that some premature babies have marked changes in their patterns of gut viruses shortly before they develop a serious and often fatal disease called necrotizing enterocolitis (NEC).
Professor Lim is a researcher at the Biodesign Center for Fundamental and Applied Microbiomics. He is also the principal investigator in the Center for Viral Genomics at ASU and an assistant professor in ASU’s School of Life Sciences.
The study was conducted in collaboration with ASU colleagues and researchers from Washington University School of Medicine.
Although considerable research attention has been paid to the bacterial component of the gut microbiome, the viruses that live in the gut remain largely hidden. The viral signature highlighted in the study, along with changes in gut bacterial communities, may provide an early warning sign that an infant is at risk of developing NEC, allowing physicians to take emergency action.
“For many years, there has been some sense that the microbiome is implicated in this rapidly evolving disease,” says Lim. “Studies have shown that changes in the gut microbiome in these preterm infants predict NEC disease progression.”
Yet teasing out the specific microbial changes that lead to disease has been challenging and the exact mechanism that causes disease is still unknown. The present study is the first to comprehensively investigate into the viral microbiome that sets the stage for the development of NEC in preterm infants.
A microbial world is born
Microbes begin to colonize in the baby’s abdomen during birth, when a baby encounters a variety of microorganisms from its mother’s vaginal tract. As the baby sucks, it picks up the extra germs that infiltrate their mother’s skin as well as their breast milk.
The baby will acquire new germs from other family and non-family members and even household pets. All of these become 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 a person’s health throughout a person’s life. Unsurprisingly, abnormal changes in the gut microbiome can cause serious trouble and premature infants are particularly vulnerable to such disruptions.
before their time
Preterm birth usually refers to babies born after less than 37 weeks of pregnancy. The condition appears to be on the rise, although its causes are not fully understood. In many low-income countries, all factors are included, including HIV, infection, malaria and high teen pregnancy rates.
In 2020, one out of every 10 babies born in the United States will be affected by prematurity. Babies born too early (especially before 32 weeks) have higher rates of death and disability. Those who survive may experience permanent health problems, including eating difficulties; breathing, vision, and hearing problems; and abnormalities including developmental delay and cerebral palsy.
Premature babies are also at risk of NEC. The disease often strikes suddenly. When babies are born after less than 32 weeks’ gestation, the incidence of NEC in high-income countries ranges from 2-7%. Mortality in infants with necrotizing enterocolitis ranges between 22–38%.
a hidden disease
While rarely occurs in full-term infants, this largely mysterious disease affects 1 in 1,000 premature babies. The condition strikes without warning and can cause an infant to progress to a serious state of illness within a few hours from appearing healthy. The disease usually occurs two to six weeks after birth.
The disease produces severe inflammation of the intestinal tissue, causing it to die. Such afflictions are known as necro-inflammatory diseases. A perforation can also form in the intestine, allowing bacteria to leak into the stomach or bloodstream. The sequence of steps leading to NEC is unclear, although risk factors are believed to include prolonged use of antibiotics early in life and formula feeding (besides prematurity).
Although studies have strongly implicated changes in the gut microbiome as contributors to the development of NEC, no single bacterial genus has been consistently associated with disease.
Babies who survive the disease often face lifelong health problems, which can include neurodevelopmental disabilities and a condition known as short bowel syndrome.
role of virus
In the present study, 138 stool samples were collected over the first 11 weeks of life. The samples were from 23 preterm infants in a neonatal intensive care unit in St. Louis, Missouri. Nine of these infants developed NEC, whereas 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 genes from all organisms present in a sample. This allows microbiologists such as Lim to evaluate bacterial diversity and trace microbial abundance in different environments. The technique also enables the detailed study of microorganisms that are difficult or impossible to culture in the laboratory. (In early 2020, Lim used metagenomic sequencing to rapidly examine the 30,000 letter code of the SARS CoV-2 virus, identifying a unique mutation.)
The study suggests that NEC infants showed convergence of viral and bacterial signatures in the gut virome. Notably, infants with NEC showed less diversity in viral composition between communities in the gut, a characteristic known as ?-diversity. Going Viral? -Variation occurred in the period of 10 days prior to the onset of NEC, providing a potential biomarker, alerting clinicians to the impending danger. The findings suggest that there are important clues reflecting on the health of premature infants in the developing virome.
The research could lead to faster diagnosis and better treatment not only for NEC, but also for a wide range of diseases mediated by the microbiome. In addition, existing treatments directed at modifying the gut microbiome, for example, fecal transplant therapy, can be further improved by taking stock of the viral component.
The study suggests that unexplained viral components of the microbiome have much to teach us and almost certainly play an important role not only in infection with NEC in preterm infants but also in other diseases. With new and rapidly evolving sequencing technologies, researchers can begin to mine viromes for valuable clinical signposts of disease and develop more effective treatments.
Ephraim Lim is the 2022 recipient of the ASU Faculty Research Achievement Award, given at the university’s Founders Day celebrations on March 17.