Gut Virome: The Next Frontier in the Treatment of Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) remains one of the most devastating gastrointestinal diseases, particularly in preterm infants, and continues to be a leading cause of morbidity and mortality in this vulnerable population. Despite decades of research, the precise mechanisms underlying NEC pathogenesis are not fully understood. Multiple factors, including gastrointestinal tract bacterial colonization, immaturity, and formula feeding, have been implicated in the development of NEC. However, recent advances in metagenomic sequencing have shed new light on the role of gut microbiota, particularly the gut virome, in the progression of this disease. This article explores the emerging understanding of the gut virome as a critical player in NEC and its potential as a therapeutic target.
The Role of Gut Bacteriome in NEC
The gut bacteriome, the community of bacteria residing in the gastrointestinal tract, has been extensively studied in the context of NEC. Research has consistently shown that gut dysbiosis, characterized by an elevated abundance of Proteobacteria, reduced abundance of Firmicutes, and an overall decrease in bacterial diversity, is associated with NEC. Notably, bacterial replication rates, particularly those of Enterobacteriaceae, have been observed to increase rapidly two days prior to NEC diagnosis. These changes in the gut bacteriome are also linked to the severity of NEC, with the presence of pneumatosis intestinalis and air in the gastrointestinal wall indicating impaired mucosal regeneration and bacterial invasion.
The invasion of bacteria or their toxins into the gastrointestinal wall triggers the secretion of inflammatory mediators, which are thought to facilitate the onset of NEC. However, while specific bacterial signatures have been identified as precursors to NEC, the causal relationship between gut dysbiosis and NEC onset remains unclear. Further research is needed to determine the extent to which aberrant gut bacteriome contributes to NEC progression.
The Emergence of the Gut Virome
In addition to the gut bacteriome, the gut virome, often referred to as the viral “dark matter,” has recently gained recognition as a significant component of the gut microbial ecosystem. The gut virome consists of a diverse array of bacteriophages (phages), eukaryotic DNA viruses, and RNA viruses. Among these, phages are the predominant component and function as natural killers of bacteria, potentially preventing bacteria-related diseases such as inflammatory bowel disease (IBD).
A landmark study reported an abnormal gut virome in patients with Crohn’s disease and ulcerative colitis, characterized by increased overall viral richness and a higher relative abundance of Caudovirales. In healthy individuals, a core virome with a prevalence of over 50% is typically present, but this is absent in patients with IBD. Furthermore, increased Siphoviridae viral clusters in IBD are often classified as temperate, with Firmicutes as the predicted host. The multidrug-resistant species Klebsiella pneumoniae (K. pneumoniae) has been linked to the flare-up state of IBD in multicenter cohorts. To address this, researchers have explored the use of phages to specifically eliminate IBD-associated pathobionts without disrupting gut microbial homeostasis or promoting antibiotic resistance. A recent study demonstrated that a combination of five lytic phages effectively suppressed K. pneumoniae in colitis-prone mice, ameliorating gastrointestinal inflammation and disease severity. Importantly, K. pneumoniae-targeted phages were well-tolerated and stably persisted in the human gastrointestinal tract, highlighting their potential clinical applications.
The Early-Life Gut Virome and NEC
The early-life gut virome differs significantly from that of adults. In neonates, the gut virome is initially absent before birth but rapidly colonizes during the first week of life. The diversity and richness of the phage-dominated virome develop gradually, reaching an adult-like profile by 2–3 years of age. This development is highly dependent on external exposures, with initial phage colonizers primarily originating from induced prophages of pioneering gut bacteria acquired from maternal microbiota, including the gut and breast milk.
A recent study identified specific gut viral signatures in preterm infants that precede the onset of NEC. Longitudinal fecal sampling revealed reduced viral beta diversity and the presence of 137 viral contigs in preterm infants more than 10 days before NEC diagnosis. Among these NEC-associated contigs, 68% were predicted to be lytic, while the remainder were temperate. Specific viruses, such as enterovirus and human bocavirus, were found to be present in infants with NEC, while the presence of adenovirus and Epstein–Barr virus was associated with NEC severity.
Therapeutic Potential of the Gut Virome in NEC
The therapeutic potential of the gut virome in NEC has been explored in animal models. In a study using piglets, orogastric administration of fecal filtrate containing pure virus-like particles (but not bacteria) completely prevented NEC. This intervention increased the diversity of the virome in both mucosal and luminal compartments and elevated the relative abundance of the Streptococcus genus. Although the study could not rule out the potential influence of microbial metabolites in the fecal filtrate, it highlighted the intermediate role of the gut virome in modulating the gut bacteriome and reducing NEC severity.
Transkingdom Interactions and Host Immunity
The interactions between the gut virome and bacteriome, often referred to as transkingdom interactions, play a crucial role in maintaining immune homeostasis and overall host health. In normal conditions, the symbiotic relationship between the gut virome and bacteriome contributes to immune homeostasis. However, an abnormal gut virome can lead to dysfunctions in the host immune system, contributing to disease progression.
Phages, in particular, have been shown to directly affect the host’s immunity. Some phages inhabit the intestinal mucosal layer and bind to mucin glycoproteins via their variable immunoglobulin (Ig)-like domains on capsids, creating an antimicrobial layer that reduces the attachment and colonization of bacterial pathogens in the mucus. Additionally, certain phages can cross the intestinal epithelium and enter the human circulation, where they communicate with the host immune system and induce pro- or anti-inflammatory responses by regulating the release of specific cytokines or the activities of T and B cells. For example, feeding Escherichia coli phages or T4 phages to germ-free mice increased the proportion and number of interferon gamma (IFN-γ)-producing T cells in the intestinal mucosal layer, including CD4+ and CD8+ T cells.
Despite these findings, the specific roles of the gut virome in the development of the host immune system in infants with NEC remain largely unknown. With the continued development of metagenomic sequencing technologies and well-designed experimental models, the complex dynamic relationships between the gut virome and bacteriome, as well as their roles in diseases like NEC, will be further elucidated.
Conclusion
The mechanisms underlying NEC pathogenesis in preterm infants are still under investigation. While the role of the gut bacteriome in NEC has been extensively studied, the composition, changes, and functions of the gut virome in NEC remain poorly understood. Given the significant role of the gut virome in shaping bacterial homeostasis directly or indirectly, and the aberrant gut bacteriome involved in NEC progression, future research should focus on the roles of the gut virome and its interactions with the gut bacteriome. This approach may lead to the development of effective strategies for the prediction and prevention of NEC in early life.
Furthermore, the gut virome’s impact on intestinal barrier integrity and immune response may be related to the etiology of NEC in preterm infants. As such, the gut virome represents the next frontier in NEC research, offering new insights into its pathology and paving the way for the development of innovative clinical therapies.
doi.org/10.1097/CM9.0000000000002921
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