INTRODUCTION
This editorial highlights the work which investigates the gut virome’s role in inflammatory bowel disease (IBD) and its interactions with the bacterial microbiome and host immune system[1]. IBD is a chronic condition characterized by recurrent inflammation of the gastrointestinal tract. The two primary forms of IBD, Crohn's disease (CD) and ulcerative colitis (UC), differ in their clinical presentations, pathophysiology, and affected regions of the gastrointestinal tract. However, both conditions share common features, including immune responses, genetic alterations, and environmental factors[2,3]. The etiology of IBD remains elusive. Recent research revealed that the microbiota of the gut plays a crucial role in IBD[4].
The human gut microbiota, a complex community of microorganisms, has been implicated in numerous physiological and pathological processes. Recent bloom in next-generation sequencing technologies have expanded our understanding of the gut microbiota, revealing its intricate composition and dynamic nature[5,6]. Among the microbiota, bacteria have been the primary focus of research. However, the virome—the collection of viruses within the microbiome—has received comparatively less attention. This oversight is particularly significant given the unique and potentially pivotal roles viruses may play in modulating the immune system, influencing microbial ecology, and contributing to disease pathogenesis[7].
The gut virome consists of diverse viral populations, including bacteriophages, eukaryotic viruses, and endogenous retroviruses. Bacteriophages, or phages, are viruses that infect bacteria, and they represent the most abundant viral entities in the gut[8]. Phages can influence the composition and function of bacterial communities through lysogeny or lytic cycles[9]. This phage-bacteria interaction can modulate the microbiome's structure and metabolic activities, potentially impacting host health[10]. Eukaryotic viruses, although less prevalent, can directly infect host cells and contribute to inflammation and immune dysregulation[11]. Endogenous retroviruses, remnants of ancient viral infections integrated into the human genome, may also play a role in gene regulation and immune responses[12].
Emerging evidence suggests that the gut virome is altered in individuals with IBD, characterized by changes in viral diversity, composition, and abundance[13]. Several studies have reported an increase in the relative abundance of Caudovirales bacteriophages in IBD patients, alongside a decrease in Microviridae bacteriophages[14]. These alterations in the virome are thought to influence the bacterial microbiome, potentially exacerbating dysbiosis - a disrupted microbial community associated with disease states[15]. Dysbiosis has been implicated in the pathogenesis of IBD, with shifts in the microbial community structure leading to enhanced immune activation, impaired mucosal barrier function, and increased production of pro-inflammatory mediators[16].
The potential mechanisms through which the gut virome may contribute to IBD pathogenesis are multifaceted. Phages may affect bacterial community dynamics, thereby influencing the overall microbiota composition and its metabolic profiles[17]. For instance, the lytic activity of phages can lead to the release of bacterial antigens and other immunogenic components, which can potentially trigger an immune response[18]. Moreover, phage-derived proteins and genetic material may directly interact with the host immune system, modulate immune responses, and contribute to the inflammation[19].
Given the emerging recognition of the virome's importance in gut health and disease, there is a need to elucidate the specific contributions of the virome to IBD. Understanding the interactions between the virome, bacterial microbiome, and the host immune system may uncover novel insights into IBD pathogenesis and identify potential therapeutic targets.
VIROME COMPOSITION IN HEALTHY INDIVIDUALS AND IBD PATIENTS
In healthy individuals, the gut virome is characterized by a balanced and relatively stable composition, dominated by temperate phages from the Caudovirales and Microviridae families[7]. Caudovirales and Microviridae contribute to intestinal microbiota diversity through bacterial population control, gene transfer, co-evolution, ecological stabilization, and functional modulation. This stability contributes to maintaining a diverse and resilient microbiota, which is crucial for gut homeostasis and immune modulation[9]. In contrast, patients with IBD, encompassing both CD and UC, exhibit notable alterations in their gut virome. Several studies have reported a marked increase in the relative abundance of Caudovirales phages, particularly members of the Siphoviridae family, in IBD patients compared to healthy controls[13]. Caudovirales phages act as predators of specific bacterial species, preventing overgrowth and maintaining microbial balance. Additionally, a reduction in the diversity of Microviridae phages has also been observed[15]. Normally, Microviridae phages induced lysis of host bacteria releases nutrients and genetic material that can be utilized by other microbes in the ecosystem. The above findings suggest a shift towards a more pro-inflammatory viral community. These changes in the virome composition are often accompanied by an overall decrease in viral diversity, which may reflect a disrupted ecological balance within the gut[20].
The observed differences in the gut virome between healthy individuals and IBD patients has multiple mechanisms. One key contributor is the alteration of the bacterial microbiota in IBD, which in turn affects the virome. The gut microbiota in IBD patients is often characterized by dysbiosis, with reduced diversity and an overrepresentation of specific bacterial taxa, such as Enterobacteriaceae and Bacteroidaceae[21]. The altered bacterial landscape may provide a conducive environment for the proliferation of specific bacteriophages, particularly those capable of lysing pathogenic bacteria. This shift could result in an increased presence of lytic phages, contributing to the observed changes in the virome composition[18].
Another contributing factor may be the inflammatory environment characteristic of IBD. Chronic inflammation can lead to increased intestinal permeability, allowing for greater translocation of microbial and viral components across the gut barrier[22]. This heightened exposure may trigger an immune response that selectively targets certain viral populations, leading to a decline in viral diversity. Moreover, the inflammatory milieu may favor the expansion of viruses with pro-inflammatory properties, such as certain lytic phages, further exacerbating the disease[23].
The role of the host immune response in shaping the virome composition is also critical. IBD is associated with an aberrant immune response, characterized by excessive activation of both innate and adaptive immune pathways[3]. This dysregulated immune response can influence the virome by selectively targeting certain viral strains. For example, an increase in IgA-coated viruses has been reported in IBD patients, suggesting a targeted immune response against these viral populations[24]. The selective pressure exerted by the immune system may thus contribute to the observed virome alterations.
VIROME-MICROBIOTA INTERACTIONS
Recent studies have demonstrated the critical role of phages in modulating bacterial populations through mechanisms such as lysis and lysogeny[9]. Phages can selectively infect and lyse specific bacterial hosts, by which they can influence bacterial species within the microbiota. This predator-prey dynamic can lead to the elimination of dominant bacterial populations and the subsequent proliferation of less dominant or rare taxa, resulting in alterations of microbial diversity and ecosystem resilience[25].
In addition to direct effects on bacterial populations, phages can also impact bacterial community dynamics through horizontal gene transfer (HGT). Phages can facilitate HGT by transducing bacterial genes, including those involved in antibiotic resistance, virulence, and metabolic functions[26]. This genetic exchange enhances the adaptability and functional capabilities of bacterial communities, improving their response to environmental challenges and host immune pressures. Furthermore, one study identified several phage-associated genes linked to metabolic pathways, suggesting that phages may play a role in the metabolic versatility of the gut microbiota[10]. The mechanisms through which the virome influences microbiota composition are multifaceted. One potential mechanism is the modulation of bacterial community structure via lysogeny. In lysogenic cycles, phages integrate their genetic material into the host bacterial genome. It often provides the host with beneficial genes that can enhance fitness under specific conditions[27]. It can also lead to the emergence of lysogenic bacteria with altered phenotypes, which can potentially impact their interactions with other microbial species and the host[28]. The presence of prophages within bacterial genomes may also serve as a reservoir of genetic diversity, leading to rapid adaptation to environmental changes. Prophages are dormant bacteriophage genomes integrated into bacterial chromosomes or maintained as plasmids. They arise during lysogenic cycles when a phage infects a bacterium and inserts its DNA into the host genome, allowing it to replicate with the bacterium. Prophages can influence bacterial fitness, virulence, and evolution by carrying genes that confer advantages, such as toxin production, antibiotic resistance, or stress tolerance.
Another mechanism is the induction of microbial dysbiosis. Dysbiosis, characterized by an imbalance in microbial communities, has been implicated in various gastrointestinal disorders such as IBD and irritable bowel syndrome[29]. Phage-mediated lysis of beneficial bacteria can disrupt the equilibrium of the microbiota, leading to the overgrowth of pathogenic or opportunistic bacteria. This shift in microbial balance can compromise the gut's barrier function, promote inflammation, and exacerbate disease symptoms[14].
CONCLUSION
The interplay between the virome and microbiota has far-reaching implications for understanding gut health and disease. The virome's ability to influence bacterial diversity and function suggests that it may play a crucial role in maintaining gut ecosystem homeostasis. Moreover, the virome's involvement in HGT highlights its potential contribution to the dissemination of antibiotic resistance genes, a growing public health concern[30]. Understanding the dynamics of phage-bacteria interactions may provide new avenues for therapeutic interventions, such as phage therapy, which leverages phages' ability to target specific bacterial pathogens[31]. Future research should focus on elucidating the functional roles of specific phages within the gut ecosystem. Advanced metagenomic and metatranscriptomic approaches can provide insights into the active virome and its interactions with the microbiota at the gene expression level. Additionally, longitudinal studies are needed to investigate the temporal dynamics of the virome and microbiota, particularly in response to dietary changes, antibiotic treatments, and disease states. Understanding the complex interactions between the virome and microbiota is crucial for developing targeted therapies and interventions aimed at modulating the gut ecosystem to promote health and prevent disease. An example for virome therapy is faecal virome transplantation (FVT). FVT significantly altered overall bacteriome compositions, however, most of the studies were conducted via mouse models in small sample size. We are hoping to see more promising data in virome targeted therapy in IBD.
ACKNOWLEDGEMENTS
We thank Dr. Thomas Kang for providing research opportunity and approving necessary fundings.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B
Novelty: Grade A, Grade B, Grade B
Creativity or Innovation: Grade A, Grade B, Grade B
Scientific Significance: Grade A, Grade B, Grade B
P-Reviewer: Gugulothu D; Wen R; Zhou C S-Editor: Lin C L-Editor: A P-Editor: Wang WB
