The gut virome and human health: From diversity to personalized medicine

Abstract

The human gut virome plays a crucial role in the gut and overall health; its diversity and regulatory functions influence bacterial populations, metabolism, and immune responses. Bacteriophages (phages) and eukaryotic viruses within the gut microbiome contribute to these processes, and recent advancements in sequencing technologies and bioinformatics have greatly expanded our understanding of the gut virome. These advances have led to the development of phage-based therapeutics, diagnostics, and artificial intelligence-driven precision medicine. The emerging field of phageomics shows promise for delivering personalized phage therapies that combat antimicrobial resistance by specifically targeting pathogenic bacteria while preserving beneficial microbes. Moreover, CRISPR-Cas systems delivered via phages have shown success in selectively targeting antibiotic resistance genes and enhancing treatment effectiveness. Phage-based diagnostics are highly sensitive in detecting bacterial pathogens, offering significant benefits for human health and zoonotic disease surveillance. This synthesis of the current knowledge highlights the pivotal role of the gut virome in regulating microbial communities and its transformative potential in personalized medicine, emphasizing its importance in advancing therapeutic and diagnostic strategies for improving health outcomes.

Keywords: Bacteriophage; CRISPR-Cas system; Dysbiosis; Fecal virome transplantation; Gut virome; Phage therapy.

Graphical abstract

Fig. 1

Contrasting effects of a healthy gut microbiome on dysbiosis. In the normal gut, diverse microbial populations contribute to optimal metabolic processes, immune regulation, and overall health. Conversely, dysbiosis is characterized by an imbalance in microbial diversity, leading to potential adverse effects on metabolism and immune responses and increased susceptibility to diseases.

Fig. 2

Overview of the human gut virome and factors influencing its composition. The adult gut virome predominantly comprises phages (> 90 %) and eukaryotic RNA and DNA viruses. Virome diversity and composition change across life stages, with high phage diversity in neonates, increasing bacterial diversity in infants, homeostasis in adults, and decreased diversity in aging [56]. Key factors influencing the gut virome are highlighted in red and include diet, infections, age, lifestyle, geographic and environmental exposure, antibiotic use, mode of delivery, and feeding practices. Maternal components, such as mucin, cytokines, and microRNAs, are critical in shaping the neonatal gut virome. Abbreviation: VLPs, virus-like particles.

Fig. 3

Illustration of the multifaceted interactions between phages, the gut microbiome, and the host immune system. Three phage replication strategies— the lytic cycle, pseudolysogeny, and the lysogenic cycle—are depicted, demonstrating the mechanisms through which phages propagate and interact with host bacteria. The highly immunogenic outer capsid proteins (Hoc proteins) of T4 phages facilitate interactions with mucin glycoproteins in the gut epithelium, thereby influencing microbial adhesion and colonization. In the gut lumen, phages play a pivotal role in antimicrobial resistance by transferring resistance genes via mechanisms such as transduction, thereby contributing to the spread of resistant bacterial strains. Phage-encoded auxiliary metabolic genes (AMGs) enhance microbial functions, including carbohydrate metabolism, nitrogen cycling, and vitamin synthesis, which are crucial for maintaining gut microbial balance. Phage-mediated disruption of microbial biofilms further modulates the gut microbial dynamics. On the host immune side, phage-bacteria interactions trigger immune responses. Antigen-presenting cells (APCs) stimulate T cells and B cells, leading to the release of antibodies and cytokines such as interferon-gamma (IFN-γ) and interleukin-15 (IL-15). These immune mediators play key roles in regulating immune responses and maintaining gut homeostasis. This comprehensive depiction underscores the critical role of the gut virome in microbial ecology and immune system modulation.

Fig. 4

Development of SNIPR001, a precision antibiotic designed to selectively target Escherichia coli in patients with hematological cancers. Initially, a library of 162 wild-type phages was screened against a panel of E. coli strains to identify phages with broad coverage and complementary binding to bacterial surface receptors. The selected phages were engineered with modified tail fibers and CRISPR-Cas systems to enhance their specificity and efficacy. The resulting complementary armed phages (CAPs) were evaluated for host range, in vivo efficacy, and compliance with CMC specifications. SNIPR001, composed of four CAPs, aims to reduce E. coli load and prevent bacteremia in patients with neutropenia. Reproduced with permission from Refs. [146].