Journal: Cell Host & Microbe
Impact factor: 31.316
Published: April 2022
Research team: Liang Guanxiang's research group from Tsinghua University School of Medicine and Frederic Bushman's research group from University of Pennsylvania School of Medicine
1. Research background
Microbes are known to provide humans with nutrients and metabolites, and to promote the development of the immune system, affecting early development and lifelong health. The link between the microbiome and childhood disease has been extensively studied, but the process by which the "virome" colonizes the body with bacteria early in life is poorly understood. A lot of evidence shows that the human virome has huge diversity and heterogeneity, which is closely related to human health. This review summarizes the establishment and maturation of the gut virome during human development and reviews the impact of the virome on children's health.
The composition of human enteroviruses
The human virome includes phages that infect bacteria and viruses that infect human cells. About 8% of the human genome contains integrated viral sequences - endogenous retroviruses. Gregory et al. analyzed 2,697 enterovirome data sets and found that more than 97% of the sequences were from phages. Phages colonize the gut of neonates immediately after birth, whereas eukaryotic viruses are not detectable until 3 or 4 months of age in healthy infants and constitute only a small fraction of the total enteroviral population. Pediatric diseases have been linked to altered phage community structure, and phages may affect gut health by modulating the bacterial microbiota or directly interacting with the host immune system, but causality remains unclear.
1. Prenatal virus
Whether newborn children are born with the virus is a controversial topic. It has been suggested that there may be bacteria in the human placenta, amniotic fluid, and fetus, and it was finally identified as various forms of sample contamination. Furthermore, sterile cesarean section can produce sterile animals, providing strong evidence for the sterility of the uterus. The current consensus is that healthy newborns do not develop an enterovirome prenatally, but that the virome is acquired rapidly after birth.
2. Maturation of the virome in children
During the neonatal period, the predominant colonizing bacteria in the gut are facultative anaerobes. The study identified distinct stages of maturity in microbial composition and function during the first 3 years of life, including developmental, transitional, and stable stages driven by breast milk, intake of solid foods, and other factors. By investigating the origin of early-life viromes, many virome sequences were found to be derived from prophages in the bacterial genomes of infant guts, and the early infant viromes were dominated by lysogenic phages.
The study reanalyzed 11 public virome datasets and found that viral abundance correlates with age. The richness of the virome decreased during the first 3 years, gradually increased in childhood, peaked in adulthood, and then declined in old age. Infant enteroviruses can be regulated by breast milk. Breast milk contains a wide range of nutrients, microorganisms, immune cells, maternal antibodies, oligosaccharides, and other macromolecules that can directly inhibit the colonization of infants by eukaryotic viruses. On the other hand, breast milk may contain both eukaryotic and prokaryotic viruses, which can be transmitted to the infant's gut.
Figure 1 Establishment of the infant enterovirome
3. Modulation of the virome through prophage induction
More than 80% of bacteria isolated from infant feces can induce phage release. Culture-based studies have shown that the majority of phages in the faecal virome of 1-year-old children are mild. These studies highlight the importance of prophage induction in the developing gut virome importance in. The signals that trigger prophage induction in the gut environment are not fully understood, and prophage can also be induced spontaneously.
4. Changes in the virome in childhood diseases
Alterations in the gut microbiome are associated with a variety of pediatric diseases. Some recent discoveries.
Summary of studies on enteroviruses in children with table diseases
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1) Children with IBD
IBD includes Crohn's disease (CD) and ulcerative colitis (UC), and studies have shown that IBD is associated with changes in the virome. The study found that the relative abundance of intestinal tail viruses in children with CD increased, while the relative abundance of Microviridae decreased, and the specific mechanism of action is still unclear. One hypothesis is that intestinal inflammation triggers prophage induction, and that some phages (eg, Vedoviridae) are preferentially induced from bacterial genomes. Another explanation is that changes in the phage population in the gut may directly interact with the host immune system, triggering gut inflammation.
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2) Unexplained diarrhea in children
Diarrheal disease is a common cause of death in children. Viral pathogens that cause diarrhea in children include rotavirus, norovirus, astrovirus, enterovirus, and adenovirus. Virome studies reveal potential novel viruses such as parvovirus bufavirus in patients with diarrhea.
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3) Malnutrition
The importance of the microbiota is also underscored by the altered gut microbiota in malnourished children and the potential for microbiota-directed food therapy to treat malnutrition. One study found that stunted children had fewer temperate phages and a lower diversity than normal controls. The above studies indicate that the changes in the phage population in the gut of stunted children may affect host metabolism or promote intestinal inflammation by regulating the bacterial community, and the exact mechanism remains to be studied.
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4) Autoimmune diseases
Type 1 diabetes is an autoimmune disease that usually develops in childhood and adolescence. In a family study, it was found that type 1 diabetic patients had higher enterovirus than their normal siblings. Frequent enteroviral infections are also associated with other autoimmune diseases, such as celiac disease, suggesting that enteroviral infections are not specific and may also be the result of autoimmune diseases.
3. Summary and Outlook
Pediatric virology research has made tremendous progress since 2008, with initial insights into the initial colonization of the human virome after birth, the dynamics of viral composition, and phage-bacteria interactions during the first 3 years. Prophage induction may be an important regulator of the gut microbiota in children. Breast milk plays a key role in shaping the infant virome, while diet is often a modulator of the virome in adults and children. With a general understanding of disease-associated virome alterations now in place, future research directions can focus on exploring intrinsic causal effects.