Регулирование на основе Virobiome микробиота-гут-мозговой оси сигнализирует и нейроиммунный гомеостаз.

Introduction

The GBA is a complex and integrated network that facilitates bidirectional communication between the gastrointestinal tract and the CNS [ 1 , 2 ]. This intricate system involves multiple interconnected pathways, including neural, endocrine, and immunological signaling, which work in concert to maintain physiological balance and coordinate responses to internal and external stimuli [ 3 ]. The CNS communicates with the gut through the autonomic nervous system, particularly via the vagus nerve, which serves as a major neural highway transmitting signals from the gut lumen to the brainstem and higher brain centers [ 4 ]. Complementing this neural link is the enteric nervous system (ENS), often referred to as the second brain, which can operate autonomously to regulate gastrointestinal functions such as motility, secretion, and blood flow [ 5 ]. The gut microbiota, composed of trillions of bacteria, viruses, and other microorganisms, plays a pivotal role in shaping this communication by producing neuroactive metabolites, modulating immune responses, and influencing hormonal signaling. Immune cells in the gut interact with microbial components and release cytokines that can signal to the brain, while enteroendocrine cells produce hormones like serotonin and ghrelin that also impact CNS function [ 6 ]. Together the CNS, ENS, vagus nerve, gut microbiota, immune system, and hormonal pathways, form a highly coordinated network through which the gut and brain continuously influence each other, playing a critical role in regulating not only digestion but also mood, cognition, and overall neurological health [ 7 ]. While the microbiota–gut–brain axis has been extensively examined from bacterial and host-centered perspectives, the present review specifically focuses on virobiome-driven mechanisms. Broader microbiota-related processes are discussed only insofar as they provide context for virus-mediated modulation of microbial ecology, immune signaling, and neuroimmune communication [ 8 , 9 ].

Since gut bacteria produce various metabolites such as short-chain fatty acids (SCFAs), neurotransmitters, and tryptophan metabolites, researches have focused on gut microbiota, emphasizing its role in shaping immunity, metabolism, and behavior [ 10 ] (Fig. 1 ).

However, recent advances in metagenomic sequencing have highlighted the importance of the human gut virome, comprising prokaryotic (bacteriophages) and eukaryotic (viruses infecting host cells) components, in microbial ecology and host physiology [ 11 , 12 ]. Bacteriophages (phages), particularly those belonging to the order Caudovirales , regulate bacterial populations through lytic and lysogenic cycles, thereby influencing microbial diversity and resilience [ 12 , 13 ]. Eukaryotic viruses, such as herpesviruses and enteroviruses, also exert significant effects by modulating immune responses and altering bacterial composition via transkingdom interactions [ 6 , 14 , 15 ]. An expanding body of evidence highlights the critical roles of both the virobiome (the collective viral community, including bacteriophages and eukaryotic viruses) and the bacteriome (the ensemble of bacterial communities) in modulating host physiology [ 12 ], particularly within the CNS [ 16 ].

Dysbiosis in these microbial communities has been increasingly implicated in the pathogenesis of various neuroinflammatory and neurodegenerative disorders, such as AD, Parkinson’s disease, MS, and amyotrophic lateral sclerosis [ 17 ]. Recent studies demonstrate that perturbations in viro-bacterial dynamics may be associated with systemic inflammatory responses through mechanisms such as microbial translocation, immune activation, and metabolite dysregulation [ 18 ]. These inflammatory responses are closely associated with increased permeability of the blood-brain barrier (BBB), a tightly regulated interface that normally restricts the passage of peripheral immune cells and harmful substances into the CNS [ 19 ]. Alterations in intestinal and systemic inflammatory signaling have been proposed to influence blood–brain barrier (BBB) integrity, potentially facilitating the infiltration of pro-inflammatory mediators and immune cells into the brain parenchyma, promoting neuroinflammation [ 20 ] (Fig. 1 ). Moreover, altered viro-bacterial interactions have been suggested to influence glial cell function in experimental models, particularly microglia and astrocytes, key regulators of neuroimmune homeostasis [ 21 ]. Glial activation can shift from a protective, surveillant state to a chronically pro-inflammatory phenotype, contributing to neuronal dysfunction and progressive neurodegeneration [ 22 ]. Importantly, the GBA emerges as a pivotal conduit through which viro-bacterial crosstalk may exert its effects on brain health [ 23 ]. The gut microbiota, including both bacterial and viral components, plays a fundamental role in shaping immune development, metabolic regulation, and even neurotransmission [ 24 ]. Disruptions in this microbial balance can alter signaling along the GBA, potentially initiating or exacerbating neurological pathology [ 25 ] (Fig. 1 ). Therefore, investigating the complex interplay between viral and bacterial components within the context of neurobiology offers a novel mechanistic framework for understanding the etiology of neurological diseases [ 26 ]. Such insights could inform the development of precision-targeted therapeutic strategies aimed at restoring microbial equilibrium, modulating neuroinflammation, and preserving CNS integrity [ 27 ].

Here, the term “virome” refers to the total collection of viral genomes and viral particles associated with the host and its microbial habitats, whereas “virobiome” is used to emphasize the virome as a functional ecological component of the broader microbiome. In this review, we focus primarily on bacteriophage-mediated interactions within the gut ecosystem, while distinguishing them from mechanisms mediated by eukaryotic viruses [ 12 , 15 ].

Despite growing interest in the microbiota–gut–brain axis, most previous reviews have focused primarily on bacterial components of the gut microbiome. In contrast, the viral fraction of the microbiome the gut virobiome has received comparatively limited attention in the context of neuroimmune signaling. This review aims to address this gap by integrating current knowledge on bacteriophage–bacterial ecological interactions, eukaryotic viral influences on host immunity, and their potential implications for microbiota–gut–brain axis communication. By synthesizing evidence across microbiology, immunology, and neuroscience, this review proposes an integrative conceptual framework describing how virome-driven ecological processes may influence neuroimmune homeostasis. It is important to emphasize that much of the current evidence linking the gut virobiome to neuroimmune regulation derives from in vitro experiments, animal models, computational analyses, and human association studies. While these findings collectively support biologically plausible mechanisms, direct causal evidence in humans remains limited. Accordingly, this review distinguishes between experimentally supported mechanisms, associative observations, and emerging hypotheses. Where relevant, evidence is discussed according to study type, including in vitro experiments, animal models, and human observational studies, to distinguish mechanistic insights from associative findings.

To improve transparency, the literature included in this narrative review was identified through targeted searches of major scientific databases, including PubMed, Scopus, and Web of Science. Articles published up to 2025 were considered. The search strategy used combinations of keywords such as gut–brain axis, virome, bacteriophages, microbiota, neuroinflammation, and neuropsychiatric disorders. Both experimental and clinical studies were prioritized when they directly addressed virus–bacteria interactions within the gut–brain axis or their potential implications for neurological and psychiatric disorders. Additional relevant articles were identified through reference lists of key publications.

Virus-bacteria interactions in the gut microbiome

Gut microbiota involvement in the GBA

Bacteria are well-studied for their role in producing neurotransmitters, modulating immunity, and generating metabolites like SCFAs [ 28 ]. For instance, Lactobacillus species are commonly found in fermented foods and probiotic formulations [ 29 ]. These bacteria are known to produce gamma-aminobutyric acid (GABA) and other neuromodulatory compounds, and studies have shown that they can reduce anxiety-like behaviors in animal models [ 30 ]. Bifidobacterium species are frequently used in probiotic supplements and have been demonstrated to modulate stress responses and enhance cognitive function in preclinical research settings [ 31 ]. Faecalibacterium prausnitzii is recognized for its anti-inflammatory properties, largely due to its ability to produce butyrate, a SCFA [ 32 ]. This species is often reduced in individuals with inflammatory bowel disease and has also been linked to depressive disorders [ 33 ]. Escherichia coli includes strains that can produce amyloid proteins, which may structurally resemble human amyloids involved in neurodegenerative processes such as those seen in AD [ 34 ]. Clostridium species are known to produce SCFAs and have been the subject of research related to ASD, suggesting a potential role in neurodevelopmental conditions [ 35 ]. Enterococcus faecalis is notable for its capacity to synthesize neurotransmitters such as serotonin and dopamine, highlighting its potential influence on brain function and behavior [ 36 ]. Bacteroides fragilis has been shown to modulate microglial activity and has been associated with ASD-like symptoms in murine models, underscoring its relevance to neurobiology and host behavior [ 37 ]. Compared to Bacteria, viruses particularly bacteriophages, are less studied but increasingly recognized for their ability to shape bacterial populations, influence microbial ecology, and potentially impact host immunity and behavior [ 38 ]. Examples of these are Caudovirales phages , which represent a large order of tailed bacteriophages that play a significant role in shaping the composition of the gut bacterial community [ 39 ]. By influencing microbial ecology, they can indirectly affect host immune responses and contribute to the regulation of neuroinflammation [ 40 ]. Microviridae phages are small viruses with circular single-stranded DNA genomes and are highly abundant in the human gut [ 41 ]. These phages may regulate bacterial populations that are associated with both metabolic and neurological health, suggesting a potential indirect influence on brain function through the GBA. CrAssphage is one of the most commonly found bacteriophages in the human gastrointestinal tract [ 42 ]. It has been shown to associate with members of the Bacteroidetes phylum , which are increasingly linked to gut-brain signaling pathways, highlighting its possible relevance in neurobiology [ 43 ]. In contrast, viruses from the Herpesviridae family , such as herpes simplex virus type 1 (HSV-1 ), EBV , and human herpesvirus 6 (HHV-6), are examples of eukaryotic viruses that can establish lifelong latent infections in the host [ 44 ]. These viruses have the ability to reactivate under conditions of stress or immune compromise and have been implicated in neuroinflammatory disorders, including MS and AD [ 45 ]. The Anelloviridae family of viruses is widespread in human populations, particularly in immunocompromised individuals [ 46 ]. Although their direct pathogenic role remains unclear, they may exert indirect effects on neuroimmunology through mechanisms involving chronic immune activation and systemic inflammation [ 47 ]. Picornaviruses , such as enteroviruses , including coxsackievirus are RNA viruses that have been associated with various neuroinflammatory conditions [ 48 ]. These viruses are capable of directly infecting neural tissues or triggering immune-mediated damage, contributing to CNS pathology [ 49 ]. Together, these viral components of the gut ecosystem underscore the growing appreciation of the microbiome’s influence on brain health and neurological disease [ 50 ].

Types of viral-bacterial interactions

Viral-bacterial interactions encompass a range of mechanisms that influence both the dynamics and functionality of microbial communities [ 51 ]. One such mechanism is lytic infection, where bacteriophages infect and kill susceptible bacterial cells, leading to a decrease in their population and subsequently altering the overall structure of the bacterial community [ 13 ]. Another important interaction is lysogeny, in which phages integrate their genetic material into the bacterial genome, forming prophages [ 52 ]. A prophage is the latent form of a bacteriophage within a bacterial genome, which can influence bacterial behavior through gene transfer and regulation, making it an important factor in microbial ecology and evolution [ 53 ]. This integration can facilitate the transfer of genetic material between bacteria, including genes related to virulence or metabolism, through a process known as horizontal gene transfer [ 54 ]. Next important interaction is phage-encoded virulence factors, which in some cases prophages carry genes that act as virulence factors, enhancing the pathogenic potential of the host bacterium; for instance, the Shiga toxin in certain strains of E. coli [ 55 , 56 ]. Additionally, phages can influence biofilm formation, either by breaking down existing biofilms or promoting their stability [ 57 ]. These effects can significantly impact the colonization behavior of both commensal and pathogenic bacteria within various environments [ 58 ] (Table 1 ). Importantly, the relationships depicted in Table 1 are synthesized from separate lines of evidence and do not imply that all steps of the proposed cascade have been demonstrated within a single biological system.

Phage-mediated modulation of bacterial behavior

Phages influence bacterial quorum sensing, motility, and secondary metabolite production, all of which affect host-microbe interactions [ 79 ]. Bacterial quorum sensing allows bacterial populations to coordinate their behavior collectively [ 80 ]. The fundamental principle of quorum sensing revolves around chemical communication. Each bacterium continuously produces and releases small signaling molecules called autoinducers into its environment, which trigger specific genetic responses across the entire community [ 81 ]. In our gut microbiome, these communication systems likely help maintain ecological balance between different bacterial species [ 82 ]. For instance, lysis of mucolytic bacteria like Akkermansia muciniphila by specific phages may impact mucus layer integrity and immune exposure [ 83 ]. Akkermansia muciniphila is a Gram-negative, anaerobic bacterium that resides in the intestinal mucus layer and constitutes 1–5% of the gut microbiota in healthy individuals [ 84 ]. This mucin-degrading species utilizes host-derived mucin as its sole nutrient source, contributing to mucus layer regulation and preventing bacterial translocation. It produces SCFAs, particularly acetate and propionate, which exert anti-inflammatory and immunomodulatory effects [ 85 ]. Akkermansia muciniphila also supports microbial diversity through cross-feeding interactions with other beneficial bacteria such as Bifidobacterium and Lactobacillus [ 86 ]. Emerging evidence suggests a role for Akkermansia muciniphila in modulating the GBA. SCFA production and bacterial components like Amuc_1100, which is a surface protein, have shown neuroprotective and anti-neuroinflammatory effects in preclinical models of MS and AD [ 87 ]. Some animal studies also associate higher levels of Akkermansia muciniphila with reduced anxiety-like behaviors and improved cognition.

Eukaryotic viruses and bacteriophages and their indirect effects on bacteria

Viruses such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV ) have been reported to promote inflammatory cytokine responses in experimental and clinical studies and induce inflammatory cytokine release (e.g., IFN-γ, TNF-α), which in turn alters bacterial growth and metabolism [ 88 ]. While CMV primarily targets cells such as macrophages and epithelial cells, its relevance to the gut–brain axis lies in its capacity to trigger systemic and mucosal immune activation. Upon infection, viral components are recognized by pattern recognition receptors (PRRs), including TLRs and intracellular sensors, leading to the activation of transcription factors like NF-κB and the subsequent release of pro-inflammatory cytokines such as TNF-α, IL-6, and IFN-γ [ 89 , 90 ].Within the intestinal mucosa, this CMV-induced inflammatory environment can reshape the local microbial ecology by altering bacterial growth conditions and promoting dysbiosis [ 91 , 92 ]. Moreover, these cytokines can compromise intestinal barrier integrity, facilitating the translocation of bacterial products like LPS into the systemic circulation, thereby bridging viral infection with gut-derived neuroinflammatory signaling [ 93 , 94 ]. When CMV enters the body, it begins its life cycle by infecting various types of cells, particularly macrophages [ 95 ]. As soon as the virus makes contact with these host cells, components of the viral structure, like glycoprotein B (gB) are recognized by the body’s immune sensors known as pattern recognition receptors (PRRs) [ 96 ]. These include receptors such as Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) located on the cell membrane, as well as intracellular sensors like RIG-I, MDA5, and cGAS found inside the cell [ 97 ]. These sensors act as early warning systems that detect signs of infection, whether they be foreign proteins, viral RNA intermediates, or DNA that has entered the cytoplasm [ 98 ]. Once CMV is detected, a series of signaling events are set into motion within the infected cell [ 99 ]. These signals activate key transcription factors such as NF-κB, IRF3, IRF7 and AP-1, which travel into the nucleus and begin turning on genes responsible for producing inflammatory cytokines [ 100 ]. The type and amount of cytokines produced depend on which sensors were activated and which signaling pathways were triggered. For example, activation of TLR2 often leads to the production of TNF-α and IL-6, while detection of viral DNA through the cGAS-STING pathway primarily drives the expression of type I interferons [ 101 , 102 ]. Some of the main cytokines released during CMV infection include TNF-α, which enhances inflammation and activates immune cells; IL-6, which contributes to fever and supports T-cell responses [ 103 ]; IL-1β, a powerful pro-inflammatory molecule that boosts local immune activity [ 104 ]; and type I interferons, which induce an antiviral state in neighboring cells [ 105 ]. Chemokines like IL-8 and MCP-1 also play a role by guiding immune cells such as neutrophils and monocytes toward the infection [ 106 ].

In the intestinal mucosa, CMV infects epithelial cells, macrophages, and dendritic cells, triggering local cytokine production through the same pattern recognition receptor pathways described earlier. The resulting inflammatory responses may contribute to disruption of the intestinal epithelial barrier, increasing permeability and allowing bacterial components like lipopolysaccharides (LPS) to enter the bloodstream, a phenomenon known as “leaky gut” [ 107 ]. This process may further amplify systemic inflammatory signaling and primes immune cells throughout the body, including those in the CNS. Additionally, CMV -induced changes in gut immunity can alter the composition of the gut microbiota, leading to dysbiosis, which itself has been linked to neuroinflammatory and neuropsychiatric conditions [ 108 ]. This gut-derived inflammation can reach the brain via several routes. One major pathway involves the vagus nerve, influencing areas such as the hypothalamus and limbic system [ 109 ]. Cytokines such as IL‑1β and TNF‑α produced in the gut can cross the BBB directly or indirectly, inducing neuroinflammatory responses [ 110 ]. These reactions then cause an increase in production of cytokines, perpetuating a cycle of inflammation within the CNS. Over time, this low-grade, persistent neuroinflammation has been associated with cognitive decline, mood disorders, and even neurodegenerative diseases [ 111 ]. In addition to direct and indirect immune effects, CMV’s influence on the GBA may also be mediated through alterations in neurotransmitter systems. Chronic inflammation has been shown to impact the metabolism of serotonin, dopamine, and glutamate, key neurotransmitters involved in mood and cognition [ 112 ]. For instance, elevated levels of pro-inflammatory cytokines have been found to increase the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that diverts tryptophan away from serotonin synthesis and toward the kynurenine pathway, potentially contributing to depressive symptoms and fatigue [ 113 ].

EBV , also known as Human Herpesvirus 4 (HHV-4), is one of the most prevalent human viruses, infecting over 90% of adults worldwide. While best known for causing infectious mononucleosis, EBV establishes lifelong latency within the host, primarily residing in memory B cells [ 114 ]. Recent research has increasingly explored its potential role in modulating the GBA. EBV primarily spreads through salivary contact, which is why it is sometimes referred to as the “kissing disease.” However, it can also be transmitted via blood transfusions, organ transplants, and, less commonly, from mother to child during birth [ 115 ]. Upon infection, EBV targets B lymphocytes and epithelial cells, establishing a lifelong latent infection within memory B cells. Under conditions of immunosuppression or physiological stress, the virus can reactivate, potentially contributing to both local and systemic immune disturbances. These changes can lead to dysbiosis [ 116 ]. Notably, EBV may reside within gut-associated lymphoid tissues, positioning it at the interface between the immune system and the gastrointestinal environment [ 117 ]. Beyond its systemic immunological effects, EBV is increasingly recognized for its potential to modulate the gut–brain axis by influencing the gut-associated lymphoid tissue (GALT) and the resident microbiota [ 118 ].

One of the proposed mechanisms by which EBV affects the GBA is through its impact on intestinal barrier integrity. Chronic immune activation driven by EBV may increase gut permeability [ 119 ]. This allows bacterial products such as LPS to enter systemic circulation, triggering widespread inflammation. These inflammatory signals can reach the brain via multiple routes, including the vagus nerve and direct disruption of the BBB, contributing to neuroinflammation and neurodegeneration. Another significant pathway involves immune cross-talk and molecular mimicry [ 120 ]. This molecular mimicry occurs within a broader context of virome-bacteriome interactions, where EBV-induced immune shifts may indirectly alter the competitive landscape of the gut microbiota, potentially favoring the expansion of pro-inflammatory bacterial taxa linked to CNS autoimmunity [ 73 ]. Certain proteins produced by EBV , such as EBNA1, exhibit structural similarities with host proteins found in the CNS, including GlialCAM [ 73 ]. This resemblance can lead to the development of cross-reactive immune responses, where the immune system mistakenly targets both viral and self-antigens. If these immune reactions originate or are amplified within the gut immune environment, they could represent an early step in the development of CNS autoimmunity, particularly in diseases like MS. Furthermore, EBV’s influence extends to the gut microbiome and its metabolic output. Changes in immune status due to EBV infection may indirectly alter the composition and function of gut bacteria [ 121 ]. For example, reductions in beneficial microbes such as Faecalibacterium prausnitzii , which produce anti-inflammatory metabolites like SCFAs, may occur. Disruptions in their production could have downstream consequences for brain health, including altered neurotransmitter synthesis and impaired synaptic plasticity [ 24 ].

In addition to these indirect effects, EBV may influence the brain through neural signaling pathways activated by peripheral inflammation. Pro-inflammatory cytokines such as TNF-α and IL-6, which are elevated during EBV reactivation, can act on the autonomic nervous system, particularly the vagus nerve, or gain access to the brain through specialized regions lacking a complete BBB. Once in the CNS, these molecules can activate microglia, leading to changes in behavior, cognition, and mood, which is commonly observed in conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), depression, and cognitive dysfunction [ 122 ]. Clinically, EBV has been strongly associated with several neurological and psychiatric disorders. In MS, nearly all patients are seropositive for EBV , while very few individuals who have never been exposed to the virus develop MS [ 123 ]. Moreover, EBV -infected B cells have been detected in brain lesions, suggesting a possible direct involvement in disease pathology. Similarly, ME/CFS often follows an episode of infectious mononucleosis, and persistent EBV reactivation may contribute to ongoing immune dysregulation and neurological symptoms [ 124 ]. There is also growing evidence linking EBV exposure, particularly during prenatal or early life, which may cause an increased risk of schizophrenia, bipolar disorder, and ASD, possibly through early-life immune activation involving the gut-immune interface [ 40 ]. These effects can ripple through the microbiome and reach the CNS via immune or neural routes (Fig. 2 ).

Although bacteriophages are often discussed primarily in terms of their ecological influence on bacterial community composition, growing evidence suggests that the gut virobiome may exert more direct effects on host physiology [ 125 ]. Viral particles and viral nucleic acids can interact with intestinal epithelial and immune cells, triggering innate immune signaling pathways that extend beyond purely microbiota-mediated effects. In addition to reshaping bacterial populations through lytic and lysogenic cycles, bacteriophages can facilitate horizontal gene transfer, thereby altering microbial metabolic potential and virulence traits. These virome-driven ecological and molecular processes may influence host immune tone, microbial metabolite production, and inflammatory signaling pathways that ultimately participate in microbiota–gut–brain axis communication [ 126 – 128 ].

While these virus–bacteria interactions shape the ecological structure of the gut microbiome, their broader biological significance extends beyond microbial community dynamics [ 38 ]. Increasing evidence suggests that virome-driven microbial and immune alterations may influence host signaling pathways that connect the intestinal environment to the central nervous system. The following section therefore explores the molecular and immunological mechanisms through which virus–bacteria interactions may contribute to microbiota–gut–brain axis communication.

Mechanisms linking virus-bacteria crosstalk to the brain

Neural pathways

The vagus nerve serves as a primary conduit for microbial signal transmission to the brainstem and hypothalamus. Representing the longest cranial nerve in the body, it functions as a direct neural pathway connecting the gut to the brain. It contains afferent (sensory) fibers that continuously monitor the gut environment, responding to changes in the presence of microbial metabolites, immune mediators, and hormonal signals released by enteroendocrine cells [ 129 ]. Among the most influential microbial products are SCFAs such as butyrate and propionate, which have been shown to modulate vagal signaling and exert effects on mood, cognition, and autonomic regulation [ 130 ]. Additionally, immune molecules like IL-1β and TNF-α can activate the vagus nerve, initiating either anti-inflammatory reflexes or neuroinflammatory responses, depending on the nature and duration of the stimulus [ 131 ]. This vagal anti-inflammatory reflex, mediated by acetylcholine release from efferent fibers, plays a crucial role in regulating systemic inflammation and preserving neuroimmune homeostasis as part of the cholinergic system. An example of this reflex is the inhibition of macrophage activation in the spleen, where acetylcholine binds to α7 nicotinic receptors, suppressing the release of pro-inflammatory cytokines such as TNF-α and IL-1β in response to circulating LPS. However, under conditions of chronic microbial imbalance, pathogenic infection, or excessive immune activation, this protective cholinergic mechanism may be overwhelmed, which has been associated with persistent neuroinflammation, glial activation, and neurodegenerative processes in several experimental and clinical contexts [ 132 ]. An example of this persistent neuroinflammation is observed in Alzheimer’s disease, where chronic gut dysbiosis and elevated systemic LPS levels lead to sustained microglial activation in the brain, resulting in continuous release of pro-inflammatory cytokines and progressive neuronal damage [ 133 ]. These processes are also increasingly recognized as contributors to a wide range of neurological and psychiatric disorders, including depression, anxiety, ASD, and Parkinson’s disease. Complementing the vagus nerve’s role is the ENS, a vast network of neurons embedded within the walls of the gastrointestinal tract. Often referred to as the “second brain” due to its capacity for autonomous function, the ENS regulates essential gut processes such as motility, secretion, and barrier integrity [ 134 ]. Crucially, the ENS is highly responsive to microbial inputs, including bacterial neurotransmitters like GABA and serotonin, as well as metabolites that modulate neuronal excitability and synaptic transmission. These microbial signals can alter peristalsis, mucosal secretion, and the expression of tight junction proteins, thereby influencing intestinal permeability and contributing to systemic immune activation [ 135 ]. An emerging area of interest involves the role of bacteriophages, viruses that infect bacteria, in shaping the gut ecosystem. Phages can significantly alter bacterial community structures through selective predation, indirectly influencing ENS activity and gut physiology. These phage-induced shifts in the bacteriome may have downstream consequences for host immunity, neural signaling, and ultimately, brain function, underscoring the importance of considering the virobiome in the context of the GBA [ 39 ] (Fig. 3 ).

Immune signaling pathways

Phage particles and bacterial cell wall constituents are potent activators of the innate immune system, primarily through engagement of PRRs such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), and cytosolic DNA sensors (e.g., cGAS). These receptors serve as key sensors for microbial components, initiating immune responses that can either maintain homeostasis or drive inflammation depending on the nature and magnitude of the stimulus [ 97 ]. TLR4 is best known for its recognition of LPS, a major component of the outer membrane of Gram-negative bacteria. However, it also responds to other exogenous ligands, including certain viral proteins and bacteriophage-derived molecules, as well as endogenous damage-associated molecular patterns (DAMPs) released during tissue injury or cellular stress [ 136 , 137 ]. Upon ligand binding, TLR4 recruits adaptor proteins such as MyD88 and TRIF, triggering two distinct intracellular signaling cascades. The MyD88-dependent pathway rapidly activates NF-κB and MAP kinases, leading to the transcription of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. In contrast, the TRIF-dependent pathway induces a delayed but sustained activation of interferon regulatory factors IRFs, promoting the production of type I interferons IFN-α and β and enhancing antigen presentation and antiviral immunity [ 138 ]. Similarly, Toll-like receptor 9 (TLR9) detects unmethylated CpG DNA motifs, which are abundant in bacterial and viral genomes, including those of bacteriophages but are underrepresented and methylated in vertebrate DNA [ 139 ]. TLR9 is predominantly expressed in plasmacytoid dendritic cells (pDCs), B cells, macrophages, and microglia, where it resides within endosomal compartments to avoid self-DNA recognition. Upon sensing microbial DNA, TLR9 also signals through the MyD88-dependent pathway, culminating in NF-κB activation and the expression of pro-inflammatory cytokines and type I interferons [ 140 , 141 ]. The NF-κB signaling pathway serves as a central hub for both TLR4 and TLR9 activation (Fig. 3 ). Under resting conditions, NF-κB is sequestered in the cytoplasm by inhibitory IκB proteins [ 142 ]. Following receptor stimulation, a series of phosphorylation events lead to IκB degradation, allowing NF-κB to translocate into the nucleus and initiate the transcription of numerous genes involved in inflammation, immunity, and cell survival. This includes the aforementioned cytokines IL-6, IL-1β, TNF-α, and IFN-α and β, which play pivotal roles in shaping both peripheral and central immune responses [ 143 ]. In the context of microbial dysbiosis, especially when there is an overgrowth of Gram-negative bacteria or phage-driven shifts in the virobiome-bacteriome equilibrium, circulating levels of TLR4 and TLR9 agonists rise significantly. This phenomenon, often referred to as “metabolic endotoxemia” in the case of LPS, can result in systemic inflammation [ 144 ]. By crossing the BBB through circumventricular organs and endothelial signaling pathways, these cytokines activate resident glial cells in the brain parenchyma, initiating a cascade of neuroinflammatory processes. Activated cells shift toward a pro-inflammatory M1 phenotype, releasing additional cytokines, chemokines, and reactive oxygen species that contribute to synaptic dysfunction, neuronal damage, and BBB disruption [ 145 , 146 ]. Importantly, peripheral immune activation via TLR4 and TLR9 not only influences innate immunity but also shapes adaptive immune responses, particularly CD4 + T-cell differentiation in the gut-associated lymphoid tissue (GALT) [ 147 ] (Fig. 4 ).

Changes in the gut microbial ecosystem, whether due to antibiotic use, diet, infection, or viro-bacterial interactions can alter the cytokine milieu and promote a shift in T-cell polarization [ 148 ]. Under inflammatory conditions, naïve CD4 + T cells preferentially differentiate into Th17 cells, which produce IL-17 A, IL-17 F, IL-21, and GM-CSF, driving further inflammation and tissue damage [ 149 ]. Conversely, under tolerogenic conditions, regulatory T cells (Tregs) expand and secrete anti-inflammatory mediators such as IL-10 and TGF-β, maintaining immune homeostasis [ 150 ]. A skewing of this balance toward Th17 dominance has been strongly implicated in the pathogenesis of autoimmune neuroinflammation, particularly in its animal model, EAE [ 151 ]. NLRs represent a family of cytosolic PRRs that play a critical role in sensing bacterial components released during phage-induced lysis or dysbiosis, thereby linking viro-bacterial interactions to neuroinflammation. These receptors such as NLRP3, NOD1, and NOD2 sense intracellular peptidoglycan fragments, like muramyl dipeptide (MDP) or γ-D-glutamyl-meso-diaminopimelic acid, derived from bacterial cell walls [ 152 ]. Upon activation, certain NLRs (e.g., NLRP3) assemble inflammasomes that activate caspase-1, leading to the maturation of pro-inflammatory cytokines IL-1β and IL-18, both of which are implicated in BBB disruption and microglial activation. This process is particularly relevant in the context of gut barrier dysfunction, where increased intestinal permeability allows bacterial products to access immune cells, triggering systemic inflammation that can propagate to the CNS [ 153 , 154 ] (Table 2 ). RLRs, including RIG-I (DDX58) and MDA5 (IFIH1), are cytosolic RNA sensors that detect viral RNA, making them key players in host defense against eukaryotic viruses. These receptors are activated by double-stranded RNA (dsRNA) or 5’-triphosphate single-stranded RNA (ssRNA), common in replicating viruses, and signal through the adaptor MAVS to induce type I interferons (IFN-α/β) and pro-inflammatory cytokines [ 155 ]. As highlighted in the text, viral reactivation (e.g., HHV-6 , EBV ) can occur under stress or immunosuppression, and the resulting viral RNA may be sensed by RLRs in gut epithelial or immune cells, contributing to local and systemic inflammation [ 156 , 157 ]. This RLR-driven response can disrupt gut barrier integrity and promote neuroinflammation via the GBA, either through cytokine signaling or immune cell trafficking to the CNS, positioning RLRs as important mediators of virus-induced CNS pathology [ 158 ]. CLRs are a diverse family of transmembrane PRRs that recognize carbohydrate structures (e.g., β-glucans, mannans) on the surface of fungi, bacteria, and some viruses. While less emphasized in the context of bacteriophages, CLRs such as Dectin-1, Dectin-2, and Mincle are expressed on myeloid cells and can modulate immune responses in the GALT [ 159 – 161 ]. Their activation influences both innate and adaptive immunity by promoting phagocytosis, reactive oxygen species production, and the secretion of cytokines that shape Th17 and Treg differentiation, processes central to the autoimmune neuroinflammation seen in MS and EAE [ 162 ]. Dysbiosis involving fungal or bacterial overgrowth may engage CLRs, altering the mucosal immune environment and contributing to chronic inflammation [ 163 ]. Although not directly activated by phages, CLR signaling can be indirectly influenced by phage-driven bacterial shifts that alter microbial surface glycans, thereby integrating into the broader network of immune signaling along the GBA. Cytosolic DNA sensors, particularly cyclic GMP-AMP synthase (cGAS), detect double-stranded DNA in the cytoplasm, an abnormal location that signals infection or cellular damage [ 164 ]. cGAS binds microbial DNA from intracellular bacteria or eukaryotic viruses and produces the second messenger cGAMP, which activates the STING pathway, leading to robust production of type I interferons and pro-inflammatory cytokines. This pathway contributes to gut inflammation, increased intestinal permeability, and systemic immune activation, all of which can influence CNS health via the GBA [ 165 ]. Thus, the cGAS-STING axis represents a critical mechanism by which both viral and bacterial nucleic acids contribute to the immune cascade that underlies neurological disorders [ 166 ] (Table 2 ).

Metabolic mediators

Phage-driven alterations in the gut microbial ecosystem can significantly impact host immunity and brain health, particularly by influencing populations of butyrate-producing bacteria such as Faecalibacterium prausnitzii , which are among the most abundant and immunomodulatory commensals in the healthy human gut [ 210 , 211 ]. Several studies suggest that bacteriophage predation can selectively target dominant bacterial taxa within the gut ecosystem, thereby reshaping community composition and metabolite production. These bacteria utilize dietary fiber and resistant starches to generate SCFAs, mainly acetate, propionate, and butyrate, through anaerobic fermentation [ 212 ]. Butyrate, in particular, is produced via the butyrate kinase pathway or the Wood-Ljungdahl pathway, depending on the bacterial species involved. This process not only provides energy for colonocytes but also exerts potent anti-inflammatory effects systemically. SCFAs interact with the host through several key mechanisms [ 213 ]. They engage in G-protein-coupled receptor (GPCR) signaling by binding to receptors such as FFAR2 (GPR43), FFAR3 (GPR41), and GPR109A, which helps modulate immune cell differentiation and regulate cytokine production. Additionally, butyrate functions as a class I histone deacetylase (HDAC) inhibitor, promoting histone acetylation and thereby enhancing the expression of anti-inflammatory genes while suppressing pro-inflammatory pathways such as NF-κB [ 214 ]. SCFAs, particularly butyrate and propionate, also play a role in T-cell differentiation, supporting the expansion of Tregs and inhibiting the development of pro-inflammatory Th17 cells, which aids in maintaining immune tolerance and reducing the risk of autoimmunity [ 215 ]. Furthermore, SCFAs contribute to intestinal barrier integrity by stimulating mucus production and increasing the expression of tight junction [ 216 ]. Reductions in butyrate-producing taxa due to phage-mediated dysbiosis have been associated with leaky gut and systemic inflammation, which may extend to the CNS [ 217 ]. In this context, phage predation targeting SCFA-producing taxa may reduce butyrate availability, thereby weakening epithelial barrier function and altering immune signaling pathways involved in neuroimmune regulation. Diminished SCFA levels have been linked to impaired BBB integrity, increased microglial activation, and altered neuroimmune homeostasis, all of which are implicated in the pathogenesis of neuroinflammatory and neurodegenerative diseases [ 41 ]. In parallel, phage-mediated shifts in gut microbial composition may influence microbial control of the tryptophan–kynurenine metabolic pathway, another key interface between the microbiota and the CNS. Changes in the abundance of tryptophan-metabolizing bacteria may alter the balance between kynurenine-derived metabolites with opposing neuroimmune effects. Gut microbes play a key role in regulating tryptophan metabolism, influencing the balance between neuroprotective and neurotoxic kynurenine derivatives [ 218 ]. Two major metabolites, kynurenic acid (KYNA) and quinolinic acid (QUIN), exhibit opposing effects on neuroinflammation and glutamatergic neurotransmission [ 219 ]. KYNA is generally considered neuroprotective and anti-inflammatory. It functions as an NMDA receptor antagonist and α7 nicotinic acetylcholine receptor agonist, helping to dampen excitotoxicity and modulate glial activation [ 220 ]. KYNA has also been shown to suppress the production of pro-inflammatory cytokines such as IL-6 and TNF-α, and it may contribute to mood regulation and cognitive stability [ 221 ]. QUIN, on the other hand, is traditionally viewed as neurotoxic when present in excess, due to its role as an NMDA receptor agonist, which can drive excitotoxic neuronal damage under chronic inflammatory conditions [ 222 ]. However, QUIN also plays a physiological role in neuroimmune signaling, and at moderate concentrations, it can support neuronal survival and immune defense. Its production is tightly regulated by the enzyme IDO, which is upregulated during inflammation and microbial dysbiosis [ 223 ]. Together, KYNA and QUIN help regulate glutamate homeostasis, neurotransmitter balance, and microglial reactivity, making their modulation by the gut microbiome a promising target for managing neuroinflammatory disorders [ 219 ]. Additionally, certain bacterial genera influenced by phage dynamics, including Lactobacillus and Bifidobacterium , possess the enzymatic machinery to synthesize precursors for monoamine neurotransmitters such as GABA, serotonin (5-HT), and dopamine [ 224 ]. For instance, Lactobacillus species express aromatic amino acid decarboxylases that convert tyrosine into dopamine and tryptophan into serotonin, contributing to the production of key monoamine neurotransmitters [ 225 ]. Some strains of Bifidobacterium and Lactobacillus synthesize GABA through the glutamic acid decarboxylase (GAD) pathway, influencing signaling within both the ENS and the CNS [ 226 ]. Consequently, phage-driven ecological shifts affecting these taxa could indirectly influence neurotransmitter availability within gut–brain signaling pathways. These findings underscore the complex interplay between the gut virobiome-bacteriome, metabolite production, and host neuroimmune function, highlighting a mechanistic cascade in which show how phage-driven microbial shifts, such as reductions in butyrate producers or changes in tryptophan metabolism, can influence both peripheral and central inflammation, which subsequently modulate immune signaling, barrier integrity, and neuroimmune pathways involved in gut–brain communication and offering novel insights into the mechanisms of gut-brain communication and potential therapeutic strategies involving phage therapy, prebiotics, probiotics, or postbiotic supplementation (Fig. 5 ). In the context of the virobiome, neuroactive metabolites such as short‑chain fatty acids are considered primarily as indirect mediators, reflecting virome‑driven alterations in bacterial community composition rather than direct viral metabolic activity.

Blood-brain barrier integrity

Microbial-derived LPS, also known as endotoxins, are major components of the outer membrane of Gram-negative bacteria, such as Escherichia coli , Salmonella , and Pseudomonas species [ 227 ]. LPS consists of a lipid A anchor, a core oligosaccharide, and an O-antigen polysaccharide chain. It is a potent activator of the innate immune system, primarily through interaction with TLR4 and its co-receptor MD-2, triggering robust inflammatory signaling via the MyD88-dependent and TRIF-dependent pathways [ 228 ]. Elevated levels of LPS in circulation, often referred to as metabolic endotoxemia, can result from increased intestinal permeability, which may occur due to gut dysbiosis, dietary changes, or microbial imbalance influenced by phage-driven bacterial shifts [ 229 ]. This heightened immune activation leads to the production of pro-inflammatory cytokines, which includes TNF-α, IL-1β, IL-6 and IFN-γ. These cytokines are key mediators of systemic inflammation and have been shown to increase BBB permeability by disrupting tight junction proteins such as occludin, claudin-5, and ZO-1. As a result, the normally restrictive BBB becomes more permeable, allowing peripheral immune cells, cytokines, and microbial products to infiltrate the CNS, contributing to neuroinflammation and glial activation [ 230 ]. In addition to LPS, other microbial-associated molecular patterns (MAMPs) can also enter the CNS under conditions of BBB dysfunction. These include peptidoglycans derived from Gram-positive bacteria, lipoteichoic acid also originating from Gram-positive bacterial species, flagellin, which is a structural protein responsible for bacterial motility, bacterial DNA containing unmethylated CpG motifs that are recognized by TLR9, and viral nucleic acids such as dsRNA and ssRNA [ 216 ]. Once within the brain parenchyma, these microbial fragments can activate resident microglia and astrocytes, further amplifying neuroinflammation and potentially leading to neuronal damage, synaptic dysfunction, and neurodegeneration [ 231 ]. Moreover, bacteriophages can indirectly exacerbate this process. Phage-induced lysis of Gram-negative bacteria results in the release of stored intracellular contents, including LPS and other endotoxins, into the surrounding environment. This sudden surge in endotoxin levels can further stimulate TLR4-mediated NF-κB signaling, driving systemic and neuroinflammatory responses [ 232 ]. The combined effects of elevated LPS, increased pro-inflammatory cytokine production, and BBB disruption create a permissive environment for peripheral immune cell infiltration and microbial translocation into the CNS [ 19 ]. This mechanism has been implicated in various neuroinflammatory and neurodegenerative disorders, which have been already mentioned (Fig. 6 ).

Integrated hierarchical framework of PRR signaling in virome–host interactions

While individual pattern recognition receptor (PRR) pathways such as TLRs, NLRs, RLRs, and the cGAS–STING axis are often described separately, they function within an integrated and hierarchically organized antiviral sensing network. At the epithelial barrier level, endosomal Toll-like receptors (e.g., TLR3, TLR7/8, and TLR9) detect viral nucleic acids, initiating MyD88- or TRIF-dependent signaling cascades that promote NF-κB and IRF activation. In parallel, cytosolic RNA sensors such as RIG-I and MDA5 recognize viral RNA replication intermediates and signal through MAVS to induce type I interferon responses [ 90 ]. DNA viruses and reverse-transcribed intermediates can activate the cGAS–STING pathway, leading to TBK1-mediated IRF3 phosphorylation and interferon production [ 233 ].

Importantly, these pathways do not operate in isolation. Crosstalk between TLR and RLR signaling enhances interferon amplification, while inflammasome-forming NLRs (e.g., NLRP3) integrate signals from viral PAMPs and host-derived danger signals to regulate IL-1β and IL-18 maturation [ 234 ]. In the intestinal environment, where bacteriophages and eukaryotic viruses coexist with commensal bacteria, coordinated activation of these receptors shapes mucosal immune tone and systemic cytokine profiles. Thus, virome–host signaling should be conceptualized as a multilayered sensing hierarchy involving epithelial detection, innate immune amplification, inflammasome modulation, and downstream neuroimmune communication via circulating cytokines and vagal signaling pathways (Fig. 7 ).

Importantly, the gut virobiome may influence host immune signaling not only indirectly through bacterial modulation but also through direct interactions with host pattern recognition systems. Viral nucleic acids derived from bacteriophages or eukaryotic enteric viruses can be sensed by multiple classes of pattern recognition receptors, including endosomal Toll-like receptors (e.g., TLR3, TLR7, and TLR9), cytosolic RIG-I-like receptors, and DNA-sensing pathways such as cGAS–STING. Activation of these pathways leads to the induction of type I interferons, inflammatory cytokines, and downstream immune cascades that can influence epithelial barrier function, systemic immune tone, and neuroimmune communication [ 11 – 236 ]. These direct virome–host interactions provide an additional mechanistic layer through which the gut virome may contribute to microbiota–gut–brain axis signaling independently of bacterial compositional shifts.

Together, these mechanisms illustrate how viral–bacterial interactions can influence host immune signaling, epithelial barrier integrity, and systemic inflammatory pathways. To better understand the biological relevance of these mechanisms, the next section examines evidence from experimental models and human studies that have investigated virome-associated changes in gut–brain axis regulation.

However, most of these mechanistic links have been inferred from separate experimental systems, and direct end-to-end validation of the complete virome-driven microbiota–gut–brain cascade remains limited.

Evidence from experimental models and human studies

Animal models

Germ-free (GF) mice colonized with altered viromes exhibit notable behavioral and neurochemical differences compared to conventionally colonized control animals. These findings highlight the potential influence of the gut virobiome on brain function and behavior [ 237 ]. A recent study related to this topic showed that GF mice recolonized with defined microbial communities exhibited changes in anxiety-like behaviors, hippocampal gene expression, and monoamine neurotransmitter levels, suggesting that alterations in the gut ecosystem, including viral components, can impact neurodevelopment and emotional regulation [ 238 ]. In addition to bacterial contributions, recent research has begun to explore how changes in the gut virome, particularly through bacteriophage activity, can modulate host immunity and neuroinflammation [ 18 ]. One notable research was conducted to investigate the effects of targeted phage therapy in an experimental model of colitis [ 239 ]. The researchers developed a phage cocktail designed to specifically deplete pathobionts within the family Enterobacteriaceae , which are known to expand under inflammatory conditions [ 240 ]. Administration of this phage cocktail significantly reduced systemic inflammation, including the production of pro-inflammatory cytokines such as TNF-α and IL-6, and led to a measurable decrease in neuroinflammatory markers in the CNS. This suggests that targeted virome manipulation can indirectly influence brain health via immune-mediated pathways. Further supporting the relevance of viro-bacterial interactions in neurological disease, murine models of MS, specifically experimental autoimmune encephalomyelitis (EAE), have shown that phage-mediated depletion of pro-inflammatory bacterial species results in significant improvements in clinical outcomes [ 241 ]. A practical study demonstrated that altering the gut microbiota using bacteriophages targeting pro-inflammatory Escherichia coli led to reduced CNS demyelination and lower EAE disease scores [ 242 ]. The protective effect was associated with decreased Th17 cell infiltration into the CNS and a shift toward Treg cell expansion, indicating that targeted modulation of the bacteriome via phages may serve as a novel strategy for managing neuroinflammatory diseases [ 180 ]. These findings underscore the emerging concept that virobiome–bacteriome interactions play a critical role in shaping host immunity and neuroinflammation. As our understanding of the GBA expands beyond bacterial components to include viral influences, especially bacteriophages, new opportunities arise for developing precision-targeted therapies aimed at restoring microbial balance and reducing neuroinflammatory burden in diseases like MS and potentially other neuroimmune and neuropsychiatric disorders (Fig. 8 ).

Human studies

The role of the gut virobiome, the viral component of the gut microbiota, in neurological and psychiatric conditions is increasingly highlighted in clinical studies. In patients with Alzheimer’s disease, recent research has identified distinct alterations in virome composition, particularly an elevation in Anelloviruses and a reduction in crAss-like phages compared to healthy controls [ 243 ]. Anelloviruses , specifically members of the Anelloviridae family such as Torque teno virus (TTV) , are small, circular, single-stranded DNA viruses that are highly prevalent in human populations, especially in immunocompromised individuals [ 244 ]. While generally considered non-pathogenic under normal conditions, elevated levels of Anelloviruses have been associated with chronic immune activation and systemic inflammation. A recent study found that AD patients exhibited higher levels of Anellovirus sequences in both blood plasma and cerebrospinal fluid, suggesting a potential link between chronic virome shifts and neuroinflammatory processes in neurodegenerative diseases [ 245 ]. Conversely, crAss-like phages , a group of bacteriophages first discovered through metagenomic analysis and named after the cross-assembly technique used for their identification, are among the most abundant viruses in the human gut [ 246 ]. These phages are thought to infect bacteria within the Bacteroidetes phylum , which are themselves involved in maintaining microbial homeostasis and immune regulation [ 247 ]. Several studies have reported a significant depletion of crAss-like phages in AD patients. This depletion may reflect or contribute to bacterial dysbiosis, particularly in relation to SCFA-producing taxa, potentially influencing neuroinflammation and amyloid pathology. In the context of ASD, multiple cohort studies have observed alterations in the gut virobiome, particularly an increase in Caudovirales phages , which include tailed dsDNA bacteriophages such as those from the families Siphoviridae , Myoviridae , and Podoviridae [ 248 ]. These phages are known to influence bacterial community dynamics and host immunity through lytic infection and horizontal gene transfer [ 13 ]. Notably, a new study analyzed the gut viromes of over 150 children with ASD and age-matched controls. The researchers found that ASD subjects had significantly higher levels of Caudovirales phages and lower bacterial diversity, particularly in species associated with neurotransmitter production and immune modulation. These findings suggest that phage-driven microbial imbalance may contribute to the gut-immune-brain axis dysfunction seen in ASD [ 249 ]. Moreover, growing evidence supports a connection between viral components of the gut ecosystem and mood disorders such as depression and anxiety [ 250 ]. Cohort studies have shown that individuals with MDD exhibit higher abundances of eukaryotic viruses, including HHV-6 , and reduced levels of beneficial, SCFA-producing bacterial taxa [ 251 ]. For example, a cross-sectional study analyzed stool viromes and bacterial profiles in over 200 adults with MDD and found that HHV-6 DNA was significantly more prevalent in depressed individuals compared to controls [ 252 ]. HHV-6 has previously been linked to neuroinflammatory responses and altered hippocampal function, supporting its potential involvement in affective disorders [ 253 ]. Additionally, these same cohorts showed reduced abundance of butyrate-producing bacteria, such as Faecalibacterium prausnitzii and Eubacterium rectale , which are essential for maintaining intestinal barrier integrity and anti-inflammatory signaling (Fig. 8 ) [ 254 ].

These findings from experimental models and clinical observations collectively suggest that alterations in gut viral communities may influence host immune and metabolic pathways linked to neurological function. Building upon this evidence, the following section discusses the potential implications of virobiome–microbiota interactions for the pathogenesis of several neurological disorders.

Implications for neurological disorders

Although a growing number of studies have linked alterations in the gut virome with neurological and neuropsychiatric disorders, it is important to emphasize that most current evidence remains associative rather than causal. In many cases, the available data are derived from cross-sectional human studies, small cohorts, or preclinical models, which are valuable for hypothesis generation but insufficient to establish temporal directionality or direct mechanistic causation [ 11 ]. In addition, virome alterations may reflect secondary consequences of disease-associated inflammation, medication exposure, dietary changes, or other host and environmental factors [ 255 ]. Therefore, the disease-related observations discussed in this section should be interpreted as candidate associations that warrant further validation through longitudinal, experimental, and interventional studies. To improve interpretive clarity, the following disease‑specific subsections distinguish between human association studies, experimental evidence from animal or in vitro models, and mechanistic hypotheses derived from microbiome and virome research. This structured approach helps avoid overinterpretation of associative findings as established causal mechanisms.

While bacterial dysbiosis has historically dominated microbiota–gut–brain axis research, increasing evidence indicates that the gut virobiome may represent an additional and partially independent layer of regulation. Viral communities can influence neuroimmune signaling both indirectly through modulation of bacterial ecosystems and directly through host antiviral immune pathways, thereby contributing to inflammatory and metabolic signals that affect brain function [ 255 ].

Although dysbiosis across microbial communities is broadly implicated in these disorders, the present review prioritizes evidence in which viral-driven perturbations specifically initiate or amplify neuroimmune and inflammatory cascades, rather than general bacterial dysbiosis alone.

Autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects how individuals perceive the world and interact with others. It is characterized by differences in social communication, behavioral patterns, and often sensory processing [ 256 , 257 ]. Because it is a spectrum disorder, the ways in which it manifests can vary widely from person to person. Some individuals with ASD may have strong verbal abilities and live independently, while others may be non-speaking and require ongoing support throughout their lives. While its exact causes are still being explored, research has reported associations involving both genetic and environmental factors [ 258 ]. Individuals with ASD frequently experience GI symptoms, such as constipation, diarrhea, and abdominal discomfort [ 259 ]. In recent years, some families and clinicians have explored nutritional strategies and gut-focused interventions based on emerging evidence suggesting an association between gut health and brain function via the GBA (Fig. 9 ) [ 260 ].

Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive cognitive decline, memory loss, and behavioral changes [ 261 ]. The hallmark pathological feature of AD is composed of Amyloid-beta (Aβ) and Hyperphosphorylated tau protein [ 262 ]. Amyloid-beta is a peptide derived from the amyloid precursor protein (APP) and plays a central role in Alzheimer’s disease by aggregating into soluble oligomers and insoluble plaques in the brain. These Aβ aggregates are neurotoxic and initiate synaptic dysfunction, disrupt neuronal communication, and trigger neuroinflammation [ 262 ]. The accumulation of Aβ activates microglia and astrocytes, leading to chronic inflammation and oxidative stress [ 263 ]. It also contributes to blood-brain barrier dysfunction and promotes cerebral amyloid angiopathy, setting the stage for widespread neurodegeneration [ 264 ]. Hyperphosphorylated tau protein is another key pathological feature of Alzheimer’s disease [ 265 ]. Normally, tau stabilizes microtubules in neurons, but in Alzheimer’s, it becomes abnormally phosphorylated, causing it to detach from microtubules and aggregate into neurofibrillary tangles inside neurons [ 266 ]. These tangles disrupt cellular transport, impair neuronal function, and lead to cell death. The spread of hyperphosphorylated tau through neural networks correlates strongly with cognitive decline. Aβ accumulation often precedes and accelerates tau pathology, creating a cascade that drives progressive brain atrophy and dementia [ 267 ]. While the exact cause of AD remains unclear, both genetic predispositions and environmental factors including disturbances in the GBA are increasingly recognized as have been associated with disease risk and progression. one possible mechanism that may accompany disease progression is chronic low-grade inflammation, which microbial translocation from the gut into systemic circulation has been suggested as a potential contributing factor(Fig. 9 ) [ 133 ]. However, direct mechanistic evidence demonstrating that virome alterations or microbial translocation causally drive AD pathology remains limited, and most current findings should be interpreted as associative observations rather than confirmed disease mechanisms.

Multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the CNS, characterized by inflammation, demyelination, and neuronal damage. In MS, the body’s immune system mistakenly attacks the myelin sheath, the protective covering around nerve fibers, disrupting communication between the brain and spinal cord [ 268 ]. This leads to a wide range of symptoms, including fatigue, muscle weakness, vision problems, cognitive decline, and mobility issues. While the exact cause of MS remains unknown, it is believed to result from a combination of genetic susceptibility, environmental triggers, and immune dysregulation [ 269 ]. One of the key immunological features of MS is the imbalance between pro-inflammatory Th17 cells and regulatory T cells Tregs [ 270 ]. Several studies have reported alterations in gut bacterial and phage populations in MS, and these changes have been associated with shifts in immune profiles and inflammatory signaling. Phage-induced changes in bacterial populations may reduce the abundance of immunomodulatory species such as Faecalibacterium prausnitzii and increase the presence of pro-inflammatory taxa like Escherichia coli [ 83 ]. These shifts have been associated with a cytokine-rich environment that favors the differentiation of naïve CD4 + T cells into pathogenic Th17 subsets, which are known to drive inflammation and infiltrate the CNS [ 271 ]. At the same time, reductions in the SCFA -producing bacteria may impair the expansion of Treg cells, weakening immune tolerance and allowing unchecked inflammatory responses. Adding another layer of complexity, recent studies have proposed that molecular mimicry, where microbial proteins resemble host antigens, have proposed a possible autoimmune cross-reactivity in MS [ 272 ]. Notably, some phage-encoded proteins have been found to share structural similarities with myelin-derived peptides, such as myelin basic protein (MBP) or proteolipid protein (PLP) [ 273 ]. When the immune system mounts a response against these phage proteins, especially under conditions of immune dysregulation, it may also target myelin components, could be relevant to neuroinflammatory processes. As our understanding of the virobiome-bacteriome-immune axis expands, targeting harmful microbial interactions offers new potential for preventing or modulating MS through interventions such as phage therapy, probiotics, or immune checkpoint modulation (Fig. 9 ) [ 274 ]. Overall, while epidemiological and immunological studies suggest plausible links between microbial–viral interactions and immune dysregulation in MS, much of the current evidence remains indirect and derived from associative human studies or experimental models.

Depression and anxiety

Depression and anxiety disorders are among the most prevalent mental health conditions worldwide, characterized by persistent feelings of sadness, loss of interest, excessive worry, and physiological symptoms such as sleep disturbances and altered appetite [ 275 ]. While traditionally viewed as primarily brain-centered disorders, growing evidence supports the involvement of peripheral systems, particularly the GBA, in their development and progression [ 276 ]. The gut microbiota plays a key role in regulating mood and cognition through the production of neuroactive compounds, including serotonin, dopamine, and GABA, which are responsible for emotional regulation and stress response [ 24 , 277 ]. Phage-targeted manipulation of monoamine-producing bacterial species, such as Lactobacillus and Bifidobacterium , has been proposed as a potential strategy for neuromodulation via the GBA. By selectively influencing the abundance and activity of these bacteria, phages may enhance the production of neurotransmitter precursors and metabolites that affect mood and behavior. This emerging concept has led to the development of “psychobiotics”, microbial interventions designed to improve mental health, and researchers are now investigating whether phage-based psychobiotics can be used to target specific bacterial taxa linked to emotional well-being [ 278 ]. Although still in its early stages, this field represents an innovative frontier in psychiatric research, with preclinical studies showing promising effects on stress-related behaviors and neuroinflammatory markers [ 277 ] (Fig. 9 ). At present, most supporting evidence for this concept derives from preclinical or experimental studies, and its clinical relevance for human depressive or anxiety disorders remains to be established.

Collectively, current evidence supports an association between virome alterations and several neurological disorders; however, most available data derive from observational studies with inherent methodological limitations, including small sample sizes, cross-sectional design, and variability in viral detection pipelines [ 11 ]. Future longitudinal, mechanistic, and interventional studies will be essential to determine whether virobiome alterations function as causal drivers, secondary consequences, or biomarkers of disease-related immune dysregulation.

Importantly, most evidence linking virome alterations to neurological disorders remains associative rather than causal. The majority of available data derive from cross‑sectional human studies, relatively small cohorts, or experimental animal models. Consequently, it remains unclear whether virome perturbations represent drivers of disease processes or secondary consequences of host pathology. Reverse causation is plausible, as neurological disorders are frequently accompanied by systemic immune dysregulation that may reshape viral ecology in the gut. In addition, several confounding factors including age, diet, medication use, and prior antibiotic exposure may influence both virome composition and disease risk. Longitudinal cohort studies and interventional investigations will therefore be required to determine whether virome alterations play causal roles in the pathogenesis of neurological disease [ 11 , 279 ].

Therapeutic strategies targeting the viro-bacterial axis

Rather than providing an exhaustive overview of microbiome‑based interventions, this section highlights representative virobiome‑targeted strategies, most of which remain at preclinical or early translational stages, to illustrate emerging approaches for modulating viral components of the gut ecosystem.

Precision phage therapy

Tailored bacteriophage cocktails represent a cutting-edge approach in microbiome-based therapeutics, designed to selectively target pathobionts, microbes that are normally benign but can become harmful under conditions of dysbiosis or immune dysfunction, without disrupting beneficial commensal bacteria [ 280 ]. These customized phage mixtures are engineered or selected to specifically infect and lyse problematic species such as Escherichia coli strains associated with inflammation and Clostridioides difficile , a major cause of antibiotic-resistant colitis [ 281 – 283 ]. Unlike broad-spectrum antibiotics, which often deplete protective microbial communities and promote resistance, phage therapy offers high species or strain specificity, preserving the integrity of the gut microbiota [ 284 , 285 ]. The development of these cocktails involves rigorous screening of natural phages from environmental sources (e.g., sewage, soil, or human feces), followed by genomic characterization to ensure they are lytic (not lysogenic) and free of toxin or virulence genes [ 286 , 287 ]. This precision enables targeted microbial remodeling, and represents a promising experimental strategy for treating gastrointestinal disorders and potentially systemic conditions linked to microbial imbalance, including neuroinflammatory and neuropsychiatric diseases [ 288 ]. Beyond the gut, recent advances are exploring the potential for oral delivery and CNS penetration of engineered phages, opening new possibilities for treating brain disorders [ 289 ]. While phages are traditionally considered unable to cross the BBB, studies have shown that certain phages can translocate from the gut into systemic circulation via M cells in the intestinal epithelium or through immune cell trafficking [ 290 ]. To enhance CNS delivery, researchers are developing phage capsid modifications or encapsulating phages within nanoparticles designed to cross the BBB via receptor-mediated transcytosis [ 291 ]. These engineered systems can be loaded with phages that target neuroinflammatory bacteria or even used as gene delivery vectors to modulate host immune responses. In preclinical models, such approaches have been associated with reduced neuroinflammation and improved behavioral outcomes [ 292 ]. As research progresses, tailored phage therapies may evolve into neuro-phage interventions, offering a novel class of microbiome-targeted biologics for conditions ranging from depression to AD and MS (Fig. 10 ) (Table 3 ) [ 293 ]. Despite these advances, most applications of precision phage therapy in neuroimmune and neuropsychiatric contexts remain at preclinical or early translational stages, and robust controlled clinical studies are still limited.

Engineered probiotics

Advances in synthetic biology have enabled the design of engineered bacterial strains capable of resisting viral predation and actively modulating the virome through innovative systems such as CRISPR-Cas-based phage defense mechanisms [ 294 ]. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) and associated Cas proteins function as an adaptive immune system in bacteria, allowing them to recognize and destroy invading phage DNA or RNA [ 295 , 296 ]. By pre-loading CRISPR arrays with spacers derived from known pathogenic or dysbiosis-inducing bacteriophages, scientists can equip beneficial bacterial strains, such as Lactobacillus or Bifidobacterium , with targeted immunity against specific phages that disrupt microbial balance [ 297 ]. This not only enhances the survival and colonization potential of these probiotics in a phage-rich gut environment but also allows for selective suppression of harmful phage populations that may promote inflammation or deplete beneficial bacteria. Furthermore, these engineered strains can be programmed to produce antiviral peptides small proteins that interfere with phage adsorption, DNA injection, or replication, providing a second layer of defense against viral disruption of the microbiome [ 83 ]. Building on this technology, researchers are developing dual-action probiotics that simultaneously modulate both the bacteriome and virobiome, offering a more comprehensive approach to microbiome engineering [ 298 ]. These next-generation probiotics go beyond traditional roles like SCFA production or pathogen exclusion by integrating functionalities that actively shape the entire microbial ecosystem [ 299 ]. For example, a dual-action strain might produce bacteriocins to inhibit pathogenic bacteria while expressing CRISPR arrays or antiviral peptides to neutralize pro-inflammatory phages. Such strains could be used to restore microbial equilibrium in conditions associated with viro-bacterial dysbiosis, including inflammatory bowel disease, neuroinflammatory disorders, and metabolic syndrome [ 299 ]. When delivered orally, these engineered microbes can colonize the gut and exert localized immunomodulatory effects, potentially influencing systemic and even CNS health via the GBA [ 1 ]. As safety, containment, and regulatory frameworks evolve, these smart probiotics may pave the way for precision microbiome medicine, where live biotherapeutics are designed not just to supplement, but to actively reprogram, the gut ecosystem (Fig. 11 ) (Table 3 ) [ 300 ]. However, most CRISPR-based probiotic platforms remain at the experimental or early translational stage, and further studies are required to evaluate their long‑term safety, ecological stability, and therapeutic efficacy in human populations.

Fecal virome transplantation

FVT is an emerging microbiome-based therapy that involves the transfer of purified viral components, primarily bacteriophages, from the stool of healthy donors to recipients with dysbiotic or disease-associated gut viromes [ 281 , 301 ]. Unlike fecal microbiota transplantation (FMT), which transfers the entire microbial community including bacteria, fungi, and viruses, FVT focuses specifically on the virobiome fraction, aiming to restore ecological balance by reintroducing beneficial phages that regulate bacterial populations [ 302 , 303 ]. This targeted approach has been proposed as a potential strategy for conditions where phage-bacteria imbalances contribute to disease, such as IBD, Clostridioides difficile infection, possibly neurological disorders and even MS. By selectively modulating the bacteriome through phage predation, FVT may help suppress pathobionts (e.g., Escherichia coli , Enterococcus faecalis ) without disrupting commensal bacteria, offering a more precise alternative to broad-spectrum antibiotics or whole-microbiota interventions [ 53 ]. Despite its therapeutic potential, FVT faces significant safety and regulatory challenges [ 304 ]. One major concern is the risk of transferring latent eukaryotic viruses, such as herpesviruses (e.g., HHV-6 ), Anelloviruses , or even undetected pathogenic viruses that could reactivate under immunosuppressive conditions or contribute to chronic inflammation. Unlike bacterial components, viruses cannot be easily removed or inactivated without damaging the very phages intended for therapeutic use [ 305 ]. As a result, rigorous donor screening, deep metagenomic sequencing, and viral clearance protocols are essential to minimize transmission risks [ 306 , 307 ]. From a regulatory standpoint, FVT exists in a gray area, which means in most countries, including the U.S. and EU, it is not yet classified or approved as a standalone therapy. Regulatory agencies such as the FDA and EMA currently treat virome-containing preparations under frameworks designed for FMT or investigational biologics, requiring extensive preclinical validation, clinical trials, and standardized manufacturing. Until robust safety data and clear regulatory pathways are established, FVT will remain largely experimental, though its potential continues to drive innovation in precision microbiome medicine (Fig. 12 ) (Table 3 ) [ 303 , 308 ]. At present, most evidence supporting FVT is derived from experimental studies and limited exploratory clinical observations, and well‑controlled clinical trials are still required to determine its safety and therapeutic efficacy.

Multi-omics integration

Multi-Omics Integration refers to the comprehensive and systematic combination of multiple layers of biological data, known as “omics”, to gain a more complete understanding of complex biological systems [ 309 ]. These layers include genomics, which means the study of DNA sequences, metagenomics, which profiles all microbial genes in a sample including bacteria and viruses, transcriptomics, that stands for the analysis of gene expression through RNA, proteomics, which represents the study of proteins, and metabolomics, that means the profiling of small-molecule metabolites such as SCFAs, neurotransmitters, and lipids [ 310 , 311 ]. In the context of neurobiology, multi-omics integration allows researchers to simultaneously examine the composition of the gut virobiome and bacteriome, the functional activity of microbial and host genes, and the resulting metabolic outputs that influence brain function [ 312 ]. By combining these diverse datasets, scientists can move beyond correlations to uncover mechanistic links between microbial dynamics, immune activation, and neurological health. This integrative approach is especially powerful for studying complex, interconnected systems like the GBA, where virus-bacteria interactions may indirectly affect neuroinflammation and behavior. For example, metagenomics can reveal shifts in phage and bacterial populations, transcriptomics can show which microbial or host genes are actively expressed during disease states, and metabolomics can identify neuroactive compounds, such as GABA, butyrate, or kynurenic acid, that are produced as a result [ 313 , 314 ]. When combined, these data provide a high-resolution map of how microbial changes influence host physiology [ 125 ]. To make sense of this vast and complex information, researchers increasingly use machine learning and artificial intelligence algorithms to detect patterns and identify predictive signatures of disease risk, such as a specific virome-bacteriome-metabolite profile linked to early-stage neuroinflammation in AD or MS. These predictive models hold promise for early diagnosis, personalized interventions, and the development of microbiome-targeted therapies (Fig. 13 ) (Table 3 ). Although multi‑omics integration itself does not constitute a therapeutic intervention, it provides an important analytical framework for identifying microbial and virome‑derived targets that may guide the development of future microbiome‑based therapies.

Translational hurdles and safety considerations

Although interventions targeting the microbiome and virome hold promise as an emerging frontier in biomedical research, their translation into routine clinical practice for neurological disorders faces several major challenges.

First, repeated administration of bacteriophages may trigger host immune reactions, notably the production of neutralizing anti-phage antibodies. Evidence from experimental and clinical phage therapy studies indicates that such humoral immune responses can diminish phage persistence and therapeutic efficacy over the course of chronic treatment. Moreover, the immunological dynamics underlying these effects remain poorly characterized, particularly in the context of long-term modulation of the gut microbiome [ 334 , 335 ].

Second, engineered probiotics incorporating CRISPR–Cas antiviral systems raise important biosafety and regulatory considerations. Because such organisms contain genetically modified elements capable of horizontal gene transfer, regulatory agencies including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) generally classify them within the framework of genetically modified organisms (GMOs). This classification requires extensive safety assessment, containment strategies, and long-term ecological monitoring prior to clinical use [ 336 , 337 ].

Third, fecal virome transplantation (FVT), while conceptually related to fecal microbiota transplantation (FMT), presents unique biosafety concerns. Viral preparations may contain latent or poorly characterized viruses, and inadequate donor screening could theoretically permit the transmission of pathogenic viral agents. Indeed, safety alerts issued by the U.S. FDA regarding fecal microbiota transplantation have highlighted the potential risk of pathogen transmission from unscreened donors. Rigorous donor-screening protocols, viral metagenomic characterization, and standardized manufacturing procedures will therefore be essential for the safe development of FVT-based interventions [ 281 , 338 , 339 ].

Overall, these considerations indicate that virome-targeted therapies remain largely experimental. Future research should integrate rigorous preclinical studies, standardized virome profiling, and well-controlled clinical trials to determine whether gut virobiota modulation can safely and effectively impact neurological disease outcomes [ 338 , 340 ]. Emerging evidence from virome ecology, microbial community dynamics, and neuroimmune signaling underscores the gut virobiota as an underexplored component of microbiota–gut–brain axis biology. Addressing these challenges will be critical for translating virome-targeted strategies from experimental concepts into clinically viable microbiome-based therapeutics.

Current limitations and future directions

Despite growing recognition of the gut virobiome as a potentially important component of microbiota–gut–brain axis (MGBA) signaling, several conceptual, methodological, and experimental limitations continue to constrain interpretation of the available evidence.

A major limitation is that much of the current literature remains largely associative. Most human studies examining virome composition in neurological or neuropsychiatric disorders are cross‑sectional and rely on correlations between viral signatures and disease phenotypes, which restricts causal inference [ 8 , 128 ]. Although animal models including germ‑free, antibiotic‑treated, and gnotobiotic systems have provided valuable insights into microbiota–host interactions, they do not fully recapitulate the ecological complexity, stability, and environmental variability of the human gut ecosystem [ 255 ]. Consequently, extrapolation from controlled experimental systems to human neuroimmune physiology should be approached with caution.

Methodological constraints in virome characterization represent another important challenge. In contrast to bacterial microbiome studies that rely on conserved marker genes such as 16 S rRNA, virome analysis generally requires shotgun metagenomic sequencing combined with computationally intensive assembly and annotation pipelines [ 127 , 341 ]. The absence of universal viral marker genes, together with incomplete viral reference databases, means that a substantial proportion of viral sequences remain unclassified often referred to as viral dark matter [ 342 , 343 ]. These limitations reduce taxonomic resolution and complicate functional interpretation of virome datasets. Furthermore, accurately linking bacteriophages to their bacterial hosts remains technically challenging, which limits the reconstruction of phage–bacteria ecological networks within complex microbial ecosystems.

Another key limitation is the lack of integrated experimental validation of the proposed mechanistic cascade linking virome activity to neuroimmune outcomes. Individual components of the hypothesized pathway have been supported experimentally. For example, bacteriophage dynamics can influence the abundance of butyrate‑producing bacterial taxa within the gut microbiota [ 126 ]; short‑chain fatty acids regulate microglial maturation and neuroimmune homeostasis [ 344 ]; and tryptophan–kynurenine metabolites participate in the modulation of neuroinflammatory pathways within the central nervous system [ 345 ]. However, experimental validation of an integrated mechanistic pathway linking bacteriophage dynamics to alterations in bacterial community composition, subsequent changes in microbial metabolite production, and downstream modulation of neuroimmune signaling within a single biological system remains limited.

In addition, the gut virome exhibits substantial inter-individual variability and temporal dynamism. Longitudinal studies indicate that viral communities can fluctuate considerably over time, in some cases even more than bacterial communities [ 346 , 347 ]. This ecological variability complicates the identification of consistent disease‑associated viral signatures and may partly explain discrepancies observed across cohorts, sequencing platforms, and analytical pipelines. These challenges highlight the need for standardized methodological frameworks and improved viral reference databases.

Addressing these limitations will require coordinated methodological and experimental advances. Longitudinal multi‑omics approaches integrating viromics, metagenomics, metabolomics, transcriptomics, and immune profiling represent an important strategy for clarifying temporal relationships between microbial ecology and host neuroimmune responses. Such integrative frameworks may help distinguish causal drivers from secondary ecological changes within complex host–microbe systems [ 348 , 349 ].

Experimental models specifically designed to investigate phage–bacteria–host interactions will also be essential. Gnotobiotic and humanized microbiota systems incorporating defined bacteriophage communities provide a promising platform for determining whether phage‑mediated modulation of bacterial taxa alters microbial metabolite production and influences MGBA signaling pathways. Controlled phage perturbation experiments combined with immune phenotyping, metabolomic profiling, and neurophysiological analyses may help generate more direct mechanistic evidence linking virome dynamics to neuroinflammatory processes [ 305 , 350 ].

Technological progress in viral genomics is equally important. Advances in viral host‑linkage methods including CRISPR spacer matching, viral tagging, proximity ligation approaches, and single‑cell genomics are improving the ability to identify phage–host relationships within complex microbial communities [ 342 ]. Parallel efforts to standardize sequencing protocols, assembly pipelines, and annotation frameworks will enhance reproducibility and facilitate cross‑study comparisons in virome research.

Emerging computational and systems‑biology approaches may further help bridge existing knowledge gaps. Integrative ecological modeling combined with machine‑learning methods can be applied to identify functional viral–bacterial interaction networks associated with specific neuroinflammatory phenotypes. By integrating virome composition with host transcriptomic and metabolomic datasets, such models may reveal functional microbial signatures that predict disease susceptibility or progression more effectively than taxonomic profiles alone.

Finally, translational research exploring virome‑targeted therapeutic strategies remains at an early stage but represents an important future direction. Approaches such as bacteriophage therapy, fecal virome transplantation (FVT), and engineered microbial consortia designed to modulate both bacteriome and virome dynamics are currently being explored. However, rigorous evaluation of safety, ecological stability, and long‑term host responses will be essential before these strategies can be considered viable clinical interventions [ 351 , 352 ].

Collectively, overcoming these conceptual and methodological challenges will require interdisciplinary collaboration integrating virology, microbiome science, immunology, neuroscience, and computational biology. Through carefully designed longitudinal studies, mechanistic experimental models, and standardized analytical frameworks, future research will be better positioned to clarify whether and how the gut virobiome contributes to neuroimmune homeostasis within the microbiota–gut–brain axis.

Conclusion

The intricate network of viro-bacterial interactions within the GBA represents an emerging paradigm in neurobiology, reframing how we understand the molecular origins of neuroinflammation and neurodegeneration. This review underscores that the gut virome particularly its bacteriophage constituents, acts not merely as a passive inhabitant but as a dynamic regulator of microbial ecology, immune signaling, and neural homeostasis. The continuous dialogue between viruses, bacteria, and host cells orchestrates a multilayered signaling cascade that links peripheral immunity with CNS function, suggesting that neurological health is deeply rooted in the balance of the intestinal ecosystem. At the mechanistic level, bacteriophages mediate profound ecological shifts through lytic and lysogenic cycles, horizontal gene transfer, and modulation of bacterial virulence and metabolism. These processes influence immune tone and the release of microbial metabolites such as SCFAs and tryptophan derivatives, both of which play key roles in maintaining BBB integrity and regulating microglial activity. Concurrently, eukaryotic viruses such as EBV, CMV, and HHV-6 can trigger cytokine-driven immune activation and molecular mimicry, providing mechanistic bridges between peripheral infection, dysbiosis, and autoimmune neuroinflammation. By emphasizing virome‑specific mechanisms and representative examples, this review aims to move beyond generalized microbiota–gut–brain axis frameworks and toward a more mechanistic understanding of how the gut virobiome contributes to neuroimmune regulation. Together, these transkingdom interactions generate a continuum of immune perturbations that extend from the intestinal mucosa to the CNS, reshaping our understanding of disorders such as Alzheimer’s disease, multiple sclerosis, autism spectrum disorder, and major depressive disorder. A major conceptual advance emerging from recent findings is the recognition that the gut virobiome may function not only as a biomarker but also as a potential ecological regulator influencing neurological disease processes. Perturbations in virome composition such as depletion of crAss-like phages or expansion of Caudovirales can destabilize bacterial networks and reduce the abundance of beneficial taxa like Faecalibacterium prausnitzii or Akkermansia muciniphila . This microbial imbalance decreases SCFA production, disrupts gut barrier function, and heightens systemic inflammation, ultimately influencing neuroimmune circuits. The discovery that certain phage or viral proteins share epitopes with CNS antigens also reveals a novel layer of autoimmune susceptibility driven by microbial mimicry. These insights collectively position the virobiome as a missing link connecting environmental exposures, immune dysregulation, and neuronal pathology. From a therapeutic perspective, understanding the viro-bacterial axis may open future possibilities for precision microbiome engineering. Tailored phage cocktails are being explored as potential tools to selectively target pathogenic bacterial populations, restore microbial equilibrium, and reduce inflammatory burden without the collateral damage caused by antibiotics. Complementary innovations in synthetic biology have yielded engineered probiotics fortified with CRISPR-based antiviral defenses, capable of modulating both the bacteriome and virome simultaneously. Furthermore, FVT provides a next-generation approach to reintroduce beneficial phages, recalibrating microbial ecosystems in disorders associated with viro-bacterial dysbiosis. When combined with multi-omics integration linking metagenomics, transcriptomics, proteomics, and metabolomics these strategies have the potential to uncover predictive microbial signatures, enable early diagnosis, and personalize interventions for neuroimmune disorders. Future research must now address several pressing challenges. Longitudinal and interventional studies are needed to delineate causality between virome shifts and disease trajectories, while high-resolution viral metagenomics will be essential for identifying functional viral genes involved in host signaling. Experimental models integrating germ-free animals, humanized microbiota, and CNS imaging could help unravel the temporal dynamics of viro-bacterial communication. In parallel, systems biology and machine learning tools should be leveraged to construct predictive models linking specific viral-bacterial configurations with neuroinflammatory phenotypes. Finally, the ethical and biosafety dimensions of virome-based therapies must be carefully regulated to ensure safety, reproducibility, and ecological stability. Concisely, the gut virome stands at the frontier of neuroscience and immunology, representing a powerful but underexplored determinant of brain health. By decoding the molecular grammar of viro-bacterial interactions, we move toward a holistic understanding of the gut-brain continuum one that transcends traditional neurocentric models and embraces a systems-level view of human biology. The integration of viral ecology, microbial genetics, and neuroimmunology heralds a transformative era in which the modulation of microscopic entities within the gut may one day serve as a cornerstone for preventing and treating CNS diseases. The virobiome, once invisible to our scientific gaze, may ultimately become the key to unlocking neurological resilience and precision neurotherapeutics in the decades ahead. While accumulating evidence supports individual components of the virobiome–microbiota–gut–brain signaling cascade, it is important to acknowledge that the integrated mechanistic pathway proposed in this review represents a conceptual synthesis derived from multiple experimental systems rather than a single experimentally validated sequence. Current evidence linking phage activity, microbial community shifts, short-chain fatty acid alterations, intestinal barrier dysfunction, systemic inflammation, and neuroimmune activation originates from diverse models, including germ-free or antibiotic-treated rodents, lipopolysaccharide-induced inflammatory paradigms, and genetically engineered neurodegeneration models. Consequently, although these studies collectively support biologically plausible connections across the microbiota–gut–brain axis, the full end-to-end cascade has not yet been experimentally demonstrated within a single biological system. Future research integrating virome dynamics, microbial metabolism, immune signaling, and neurological outcomes within unified experimental frameworks will therefore be essential to validate and refine this proposed mechanistic model.

Acknowledgements

We would like to thank all our colleagues for their assistance. The facility for this study was provided by Research Deputy of Kashan University of Medical Sciences.

Abbreviations

Gut-brain axis

Central nervous system

Autism spectrum disorder

Alzheimer’s disease

Multiple sclerosis

Major depressive disorder

Fecal virome transplantation

Enteric nervous system

Short-chain fatty acids

Blood-brain barrier

Gamma-aminobutyric acid

Herpes simplex virus type 1

Human herpesvirus 6

Cytomegalovirus

Epstein-Barr virus

Pattern recognition receptors

Lipopolysaccharides

Indoleamine 2,3-dioxygenase

Human Herpesvirus 4

Myalgic encephalomyelitis/chronic fatigue syndrome

Toll-like receptors

NOD-like receptors

RIG-I-like receptors

C-type lectin receptors

Muramyl dipeptide

Double-stranded RNA

Single-stranded RNA

Cyclic GMP-AMP synthase

Damage-associated molecular patterns

Plasmacytoid dendritic cells

Gut-associated lymphoid tissue

Regulatory T cells

G-protein-coupled receptor

Kynurenic acid

Quinolinic acid

Glutamic acid decarboxylase

Microbial-associated molecular patterns

Germ-free

Experimental autoimmune encephalomyelitis

Torque teno virus

Clustered Regularly Interspaced Short Palindromic Repeats

Fecal microbiota transplantation.

Authors' contributions

AA, ASN, MJ, SA, AH, MSH, AHB, SSH, RJR, HHK and YY contributed to the literature review and drafting of the manuscript. All authors critically reviewed and revised the manuscript for important intellectual content and approved the final version for publication.

Funding

No financial support was received.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Alireza Afkhamian and Hamed Haddad Kashani contributed equally to this work.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.