Gut virome plays an extended role with bacteriome in Neurological Health and Disease

Gut virome plays an extended role with bacteriome in Neurological Health and Disease | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 October 2025 V1 Latest version Share on Gut virome plays an extended role with bacteriome in Neurological Health and Disease Authors : Komal Shrivastav 0009-0004-9462-251X , Muskan Pandey , Hetarth Gor , and Vijay Nema 0000-0001-6420-9397 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175983852.28276315/v1 Published Journal of the Neurological Sciences Version of record Peer review timeline 564 views 239 downloads Contents Abstract Abstract: Introduction: Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The gut-brain axis (GBA) is a complex two-way communication system that links the gastrointestinal tract and the central nervous system through neural, immune, hormonal, and microbial pathways. This comprehensive review examines the intricate mechanisms through which gut microorganisms modulate neural function and contribute to neurological health and disease pathogenesis. The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, produces essential neuroactive compounds including neurotransmitters GABA, serotonin, dopamine), short-chain fatty acids (SCFAs), and metabolites that directly influence brain physiology through vagal, hormonal, and immunological pathways. Dysbiosis of the gut microbiome has been implicated in various neurological disorders, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders, and schizophrenia. In healthy conditions, beneficial bacterial strains synthesize GABA and regulate mood, while SCFA-producing bacteria maintain blood-brain barrier integrity and exert neuroprotective effects. Conversely, pathological states demonstrate altered microbial compositions, reduced bacterial diversity, and compromised production of beneficial metabolites. Emerging evidence highlights the previously underexplored role of the gut virome, particularly bacteriophages, in regulating bacterial populations and influencing neurodevelopment. Understanding these complex host-microbiome-virome interactions provides novel therapeutic opportunities for neurological disorders through targeted interventions including probiotics, fecal microbiota transplantation, and phage-based therapies, representing a paradigm shift toward microbiome-centered approaches in neurological medicine. Gut virome plays an extended role with bacteriome in Neurological Health and Disease Komal Shrivastav 1,2 , Muskan Pandey 3 , Hetarth Gor 3 , Vijay Nema 1,2* Affiliation: 1 ICMR-National Institute of Research in Tribal Health, ICMR-NIRTH Campus, Jabalpur 482003, India. 2 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. 3 ICMR-National Institute of Translational Virology and AIDS Research (Formerly NARI), Pune 411026, India . * Author to whom correspondence should be addressed. Abstract: The gut-brain axis (GBA) is a complex two-way communication system that links the gastrointestinal tract and the central nervous system through neural, immune, hormonal, and microbial pathways. This comprehensive review examines the intricate mechanisms through which gut microorganisms modulate neural function and contribute to neurological health and disease pathogenesis. The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, produces essential neuroactive compounds including neurotransmitters GABA, serotonin, dopamine), short-chain fatty acids (SCFAs), and metabolites that directly influence brain physiology through vagal, hormonal, and immunological pathways. Dysbiosis of the gut microbiome has been implicated in various neurological disorders, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders, and schizophrenia. In healthy conditions, beneficial bacterial strains synthesize GABA and regulate mood, while SCFA-producing bacteria maintain blood-brain barrier integrity and exert neuroprotective effects. Conversely, pathological states demonstrate altered microbial compositions, reduced bacterial diversity, and compromised production of beneficial metabolites. Emerging evidence highlights the previously underexplored role of the gut virome, particularly bacteriophages, in regulating bacterial populations and influencing neurodevelopment. Understanding these complex host-microbiome-virome interactions provides novel therapeutic opportunities for neurological disorders through targeted interventions including probiotics, fecal microbiota transplantation, and phage-based therapies, representing a paradigm shift toward microbiome-centered approaches in neurological medicine. Keywords: Gut dysbiosis, neurodegenerative disorders, alzheimer’s, parkinson’s disease, autism spectrum disorder, virome, microbiome. Graphical Abstract: Introduction: The microbiota-gut-brain (MGB) axis constitutes the two-way network or talk among autonomic nervous system,(ANS), central nervous system (CNS), endocrine system, immune system, and the gut microbiota (GM). This complex system enables reciprocal signaling between the brain and the gut microbiota, allowing microbial activity and central neural processes to influence one another. Although substantial studies on both animals and humans implicates the GM in the functioning of the MGB axis, the precise mechanisms through which the microbiota modulates human brain function remain incompletely elucidated. Much of the current understanding is derived from studies utilizing germ-free animal models, as well as investigations involving specific probiotics, microbial strains, pathogenic infections and antibiotics. Furthermore, advances in sequencing technologies and metabolomics have facilitated more detailed characterization of these interactions (1). The GM plays a critical role in neurodevelopment via the gut-brain axis (GBA), impacting both the pathogenesis of neurological disorders and the efficacy of therapeutic interventions. Two major neuroanatomical pathways primarily facilitate communication between the brain and the gut: the ANS and the vagus nerve (VN), which link the central nervous system (CNS) to the gastrointestinal tract (GIT), along with the enteric nervous system (ENS) embedded within the gut wall. The VN, originating from the medulla, regulates a range of physiological functions, including cardiac rhythm, respiratory activity, digestion, and immune responses. Activation of the VN enhances vagal tone, which subsequently reduces pro-inflammatory cytokine production and modulates mood-related disorders. Additionally, the GM influences brain function through the secretion of neurotransmitters like serotonin, and γ-aminobutyric acid (GABA) contributing to anxiolytic and antidepressant effects and underscoring its possibility as a therapeutic target for inflammatory and neuropsychiatric diseases (2). The GBA integrated ENS and CNS using a two-way communication system (1). This network extends beyond direct anatomical connections to include endocrine, humoral, immune, and metabolic pathways. Key components facilitating this communication include the hypothalamic-pituitary-adrenal (HPA) axis, the ANS and the neural circuits within the GIT. Through this interconnected system, the brain can modulate intestinal functions, including the regulation of immune effector cell activity. At the same time, signals originating from the gut exert significant influence over mood, cognitive processes, and mental health (3) . Cortisol acts on gut epithelial, immune, and enteroendocrine cells, directly influencing gut function, while also modulating microbiota composition and diversity by altering transit time, permeability, and nutrient availability (1) (Figure 1). Figure 1: Microbiome-Virome Crosstalk in the Gut-Brain Axis: From Health to Neurological Disease. Created in https://BioRender.com The involvement of GM in neural development was first identified in the starting year of 2000s through studies employing gnotobiotic, antibiotic- treated, specific pathogen-free (SPF) mouse models, and germ-free (GF). In these studies, gut microbiota was disrupted through antibiotic administration and this led to various neurological abnormalities, including altered social interactions, decreased anxiety-like behaviors, and increased locomotor and rearing activities (4). Gut microorganisms significantly contribute to brain function by producing a range of neuroactive compounds, including neurotransmitters, neuropeptides, and microbial-derived metabolites. They have an impact on the release and synthesis of neurotransmitters like dopamine, serotonin, and acetylcholine, with serotonin predominantly synthesized in the gut by enterochromaffin cells. Furthermore, GM regulate production of serotonin by altering availability of tryptophan, thereby indirectly affecting brain function. ‘Short-chain fatty acids (SCFAs), produced by fermenting dietary fibres, have multiple impacts on the brain by modulating immune responses, activating G-protein-coupled receptor (GPCR) signaling pathways, and altering microglial activity. SCFAs also maintain gut homeostasis, influence intestinal motility, and regulate immune function, while serotonin have a crucial role in gastrointestinal motility and immune cells’ activation during inflammatory responses. Dysregulation of gut-derived serotonin has been affected in disorders associated with inflammation such as irritable bowel syndrome (IBS) and ulcerative colitis (UC). Thus, GM and their metabolites are essential signal generators between gut and brain, playing an essential role in maintenance of overall health (5). Gut dysbiosis is the disruption of the composition of the gut microbiome and their function, particularly within the bacterial community, which could potentially have a negative effect on the host’s health. For instance, members of the Caudoviricetes class, a group of bacteriophages with tail, display notable alterations in diversity and abundance in individuals with dysbiosis in contrast to healthy controls. Evolving evidence indicates that fecal microbiota transplantation (FMT), including the transfer of viral components, from healthy donors, can help restore gut microbial balance and ameliorate symptoms of certain chronic diseases. Prophages can exert profound effects on bacterial populations by transferring genes that confer advantageous traits to their bacterial hosts. These phage-encoded genes may enhance bacterial replication or protect against subsequent phage infections through mechanisms such as superinfection exclusion. Moreover, specific phage genomes contribute to bacterial virulence by integrating into host genomes and encoding antimicrobial resistance genes or virulence factors. Notably, many exotoxins of bacterial origin, implicated in pathogenesis of disease are of phage origin. The integration of prophages into bacterial genomes presents significant challenges in studying the gut phageome. To overcome these obstacles, many bioinformatics tools have been made to detect cryptic prophages within bacterial genomes, although the accuracy and efficiency of these methods can vary (6). The gut virome has important role in shaping microbial diversity by modulating bacterial populations through predator-prey dynamics, thereby maintaining a balanced ecosystem among bacteria, viruses, and the host. This dynamic equilibrium is crucial for the stability of the microbiome in gut, which, in turn, is essential for supporting optimal neural function and overall systemic health. A well-regulated gut microbiome, shaped by intricate interactions between the virome, bacteriota, and the host, is fundamental to maintaining both physical and mental well-being (7). Our body harbors a varied range of microorganisms, predominantly located within the gut, including viruses, bacteria, fungi, and bacteriophages. Together called as the gut microbiota (GM), these microbial communities play an indispensable role in maintenance of host health. GM’s composition is governed by various drivers, involving age and gender, and is dominated by major microbial groups such as Bacteroides , Firmicutes , and Actinobacteria , most of which exist in mutualistic or commensal relationships with the host. The GM is important for host metabolic processes, contributing to the production of critical metabolites like SCFAs, neuro-modulatory molecules, and bile acids. SCFAs, in particular, are vital for preserving the integrity of intestinal barrier and are vital regulators of function of immune and nervous system. Disruptions in these microbial-mediated processes can impair gut barrier function and have been attributed in the disease mechanism of different neurological diseases and disorders (8). The brain and gut are intricately linked through the GBA, a bidirectional network of signals that allows gut microbiota to regulate brain function via the production of hormones, immune signaling molecules, and neurotransmitters. This connection emphasizes the significant effect of gut health on overall brain function. Ongoing research, mediated by advancing high-throughput sequencing technologies, continues to reveal the critical role of the GBA in maintaining neurological health (9). Thus, in this review, we have made an attempt to understand the “crosstalk” which refers to the interaction and communication between various cellular signaling pathways, which in turn allows them to influence each other’s activities. It is worth noticing that the crosstalk can be direct. Which involves direct modification of one pathway by another, or indirect, where one pathway modulates the activity or expression of components in some another pathway. As a result of crosstalk, often a biological response is generated which is significantly different from the sum of individual pathways. Though it could be synergistic, additive, or antagonistic (10,11). Gut bacteriome and virome in healthy neurological conditions: Studies from HMP and MetaHIT have shown that the human gut contains about 2,766 types of microbes, making it one of the most diverse parts of the body. Over 90% of these microorganisms belong to four predominant bacterial phyla: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria. Among these, Firmicutes constitute the most abundant group, predominantly comprising Gram-positive species such as Lactobacillus , whereas members of the Bacteroidetes phylum primarily represent Gram-negative bacteria. The remaining 10% of the GM is composed mainly of species from the Fusobacteria and Verrucomicrobia phyla (12). Commensal bacteria can synthesize different neurologically active compounds, including neurotransmitters and their precursors. Among these, Lactobacillus species, members of the Firmicutes phylum, are particularly notable for their synthesis of γ-aminobutyric acid (GABA), a major neurotransmitter involved in modulating anxiety and mood. Studies show that Lactobacillus rhamnosus can attenuate anxiety-like behaviors in experimental models via its GABA-producing activity. Moreover, administration of L. rhamnosus has been associated with favorable regulation of brain-derived neurotrophic factor (BDNF) expression. It also showed influence on the gene expression involved in serotonin metabolism and signaling, particularly in zebrafish models (3,13). Another prominent species, Lactobacillus helveticus , is associated with regulation of mood and cognitive health due to its production of various neuroactive compounds. L. helveticus is capable of synthesizing neurotransmitters like serotonin, dopamine, norepinephrine, and GABA, that collectively affects motivation, mood, concentration, and other cognitive functions. Additionally, L. helveticus produces neuroactive peptides through its proteolytic activity during fermentation processes. Of particular significance is its capability to generate angiotensin converting enzyme (ACE)-inhibitory peptides, like,Ile-Pro-Pro and Val-Pro-Pro, which are sourced from milk proteins, including casein, and contribute to its neuromodulatory effects (14). These tripeptides exert inhibitory effects on angiotensin-converting enzyme (ACE), potentially enhancing cerebral blood flow and reducing cognitive decline associated with hypertension (15,16). Additionally, studies have shown that Lactobacillus helveticus strains, such as WHH1889, modulate serotonin (5-HT) metabolism in aged mice by increasing 5-hydroxytryptophan (5-HTP) level, a critical serotonin precursor. Although the specific peptides mediating this effect have not been definitively identified, bioactive fragments generated through the bacterium’s proteolytic activity likely influence neurotransmitter pathways. Collectively, ACE inhibition and serotonin modulation are thought to contribute to the observed enhancements in cognitive performance and mood regulation (15,17). Bacterial spp. like Fecalibacterium prausnitzii , Roseburia species., and Clostridium species. are major producers of SCFAs, which plays essential role in sustaining blood-brain barrier integrity and exerting neuroprotective effects. Among these, Roseburia intestinalis and Roseburia hominis are prominent species that commonly produce SCFAs in a healthy gut microbiota. SCFAs have a key role in regulating the function and maturation of microglia, thereby modulating neuroinflammatory processes (18). Specifically, butyrate has been shown to enhance neuroprotection as they upregulate the expression of BDNF. Additionally, Bifidobacterium species, belonging to the Actinobacteria phylum, contribute to neural health by supporting gut barrier integrity and producing SCFAs that promote neurogenesis and overall brain function (19). Additionally, some Clostridium species, particularly Clostridium butyricum , produce butyrate, which is essential for preserving the integrity of blood-brain barrier and exerting neuroprotective effects (20). The gut virome, primarily consisting of bacteriophages, hold impact in neural health by regulating bacterial populations and their associated metabolic functions. Bacteriophages such as Bacteroides phage B124-14, Pseudomonas phages, Escherichia virus JES2013, PAJU2 and Pf1, and Enterococcus phages EFRM31 and EFAP1 have been shown to affect both gut and neural function through interactions with key bacterial genera, including Bacteroides , Roseburia , Prevotella , and Fecalibacterium . By selectively infecting specific bacterial strains, these phages can influence the microbial composition, thereby enhancing stability and diversity of the ecosystem. A robust and balanced phage population is crucial for maintaining a healthy gut microbiota, which, in turn, supports immune homeostasis and metabolic pathways essential for brain health. Evolving studies depict the critical function of microbial diversity in maintaining optimal neural function, with specific viral-bacterial interactions emerging as potential biomarkers for cognitive health. For example, bacteriophages such as St. phage P7132 , Sc. phage 1717 , and Lc. phage ul36 has shown moderate predictive value in distinguishing individuals with mild cognitive impairment (MCI) from controls that are cognitively healthy. The gut virome contributes to this diversity through dynamic predator-prey interactions that regulate bacterial populations. Understanding these complex virome-bacteriota interactions has important implications for developing therapeutic strategies targeting neurological disorders. Moreover, bacterial species such as Ruthenibacterium lactaris , Roseburia hominis and Bacteroides xylanisolvens are identified as possible biomarkers for distinguishing the MCI from healthy cognitive states. These evidences emphasize the essentiality of healthy gut microbiome, including both bacterial and viral components, to support neural health throughout the lifespan (21). Gut bacteriome and virome in diseased neurological conditions: Emerging evidence links gut dysbiosis to various neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Schizophrenia (SCZ) through the complex GBA. In individuals with SCZ, both treated and untreated, microbial diversity is significantly diminished compared to healthy controls, with increased abundances of Veillonellaceae , Prevotellaceae , Bacteroidaceae , and Coriobacteriaceae , and decreased abundances of Lachnospiraceae , Ruminococcaceae , and Norank . Notably, changes in the populations of Streptococcus and Bacteroides , which are key regulators of glutamate and GABA metabolism, have been implicated in the pathophysiology of SCZ. Germ-free mice colonized with microbiota associated with SCZ exhibited neurotransmitter imbalances in the hippocampus and SCZ-like behaviors, particularly related to glutamatergic dysfunction. In AD, significant changes in gut microbial composition is observed, characterized by decreased Tyzzerella and Erysipelatoclostridium , along with increased abundances of Lachnospiraceae , Ruminococcaceae , and Clostridiales . These alterations are associated with a reduction in neuroactive metabolites, such as N-docosahexaenoyl GABA. Furthermore, Blautia species, known for their role in GABA synthesis, have shown an inverse correlation with AD risk, suggesting that Blautia -dependent GABA production in the cerebrospinal fluid (CSF) may offer neuroprotective benefits. In PD, distinct alteration in the GM is observed, including decreased levels of Lactobacillus and increased levels of Akkermansia , with notable differences in GABA concentrations between tremor-dominant and postural instability gait disorder subtypes. Importantly, supplementation with Pediococcus pentosaceus has been shown to improve dysbiosis of gut and elevate levels of GABA in PD models, underscoring the potential of microbiota-targeted therapeutic strategies (22). Microglia, constituting approximately 10% of all cells in the CNS, act as the housekeeping cells for immunity crucial for maintenance of homeostasis. In addition to their traditional role as immune surveillance cells, microglia actively regulate neurogenesis, angiogenesis, blood-brain barrier (BBB) integrity, synaptic remodeling, myelin maintenance, and the phagocytic clearance of apoptotic cells and protein aggregates. Continuously monitoring their environment, microglia rapidly respond to disruptions by orchestrating cellular adaptations to restore homeostatic equilibrium. Dysfunction of microglia is increasingly considered as a central parameter for pathogenesis in neurodegenerative diseases. In AD, microglia are directly implicated, as evidenced by their accumulation around amyloid-beta (Aβ) plaques and the expression of several genes associated with AD (23). Emerging research highlights a critical interaction between microglia and T cells in the context of dementia. Specifically, microglia expressing the APOE4 variant promote T-cell activation, which exacerbates tau pathology and neuronal loss. While modulating microglial-T-cell signaling shows reduced neurodegeneration, T-cell infiltration exacerbates disease progression in amyotrophic lateral sclerosis (ALS) and PD. These studies indicate that microglia not only regulate but also contribute to the propagation of neurodegenerative disorders, positioning them as promising therapeutic targets (24). The pathological markers of AD are buildup of amyloid-β plaques, neurofibrillary tau tangles, and associated neuroinflammation, which ultimately leads to synaptic dysfunction. Recent evidence implicates that gut dysbiosis may a key contributor to the AD pathogenesis. The GM influences progression of disease via varied mechanisms, like immune modulation, regulation of neurotransmitters, and alterations in amyloid-β plaque dynamics. Although targeting the microbiome holds significant therapeutic promise, a comprehensive understanding of the intricate GBA in AD is essential for the development of effective interventions (25). Gut dysbiosis significantly alters microbial metabolite profiles, which are key to the progression of AD. In individuals with AD, a decrease in SCFAs, mostly butyrate (C4), is linked to increased amyloid deposition and neuroinflammation. SCFAs exert neuroprotective effects by inhibiting amyloid-β polymerization and enhancing synaptic plasticity. Furthermore, tryptophan (Trp) metabolites exhibit neuroprotective properties, whereas elevated levels of bile acid metabolites are associated to the pathogenesis of AD. Interventions targeting microbiota, as in probiotic supplementation and modifications in diet, show promise for restoring metabolite balance and potentially slowing disease progression (26). 16S rRNA sequencing analyses have revealed substantial changes in bacterial composition, with a markedly reduced microbial diversity and richness in AD patients. Specifically, there was an observed enrichment of Bacteroidetes, particularly the genus Bacteroides , while Firmicutes, including essential families such as Ruminococcaceae and Clostridiaceae (Table 1), were notably depleted. Additionally, a decrease in Actinobacteria, particularly the beneficial genus Bifidobacterium , was observed, suggesting an increase in inflammation and gut permeability (27). Predictive functional analyses demonstrated a decline in bacterial motility and signal transduction capabilities, coupled with metabolic shifts characterized by enhanced oxidative phosphorylation and glucose metabolism. The increased Bacteroides population was correlated positively with biomarkers in cerebrospinal-fluid of AD pathology, linking gut dysbiosis to neurodegenerative processes. Interestingly, these microbial alterations resemble those observed in Parkinson’s disease and diabetes, conditions that are also associated with neurodegeneration and systemic inflammation (27). A recent study examined the differences in gut virome composition between amyloid-β-positive (Aβ⁺) AD patients and healthy population controls (HCs). Patients of AD with Aβ⁺ displayed a significantly reduced alpha diversity, reflecting a decrease in bacteriophage richness. The dominant phylum, Uroviricota , showed a 9% reduction, accompanied by a significantly decreased Siphoviridae and an increased population of Poxviridae by 11%. Notably, Caudoviricetes , particularly Siphoviridae , demonstrated a strong positive correlation with cognitive performance, with higher levels being associated with improved executive function (27). Several Lactococcus phages, including bIL285, bIL286, bIL309, BK5T, BM13, P335 sensu lato, phiLC3, r1t, Tuc2009, ul36, and bIL67, were significantly depleted in Aβ⁺ AD patients. Given their role in regulating Lactococcus bacterial diversity and metabolic activity, the loss of these phages may disrupt lactic acid homeostasis. Lactococcus species are involved in the production of both l-lactic and d-lactic acids. L-lactic acid is critical for memory formation, synaptic plasticity, and neuronal metabolism, whereas d-lactic acid accumulation can impair neuronal energy uptake and exacerbate neurodegeneration in AD. Thus, changes in the gut virome, particularly the depletion of beneficial Lactococcus phages, may contribute to dysfunction of GBA and cognitive deterioration in AD (28). 4.2) Microbiome, Virome and Parkinsons disease: PD is characterized by the aggregation of α-synuclein in dopaminergic neurons of the substantia nigra. A key pathway in the progression of the disease involves the VN, which facilitates the α-synuclein’s transmission to the brain from the gut. Age is a prominent risk factor for PD, with the condition primarily affecting elderly individuals. Intestinal dysbiosis, marked by a reduced Prevotellaceae (Table 1) and increased Enterobacteriaceae , has been linked to disease pathogenesis and is associated with gastrointestinal dysfunction. Additionally, neuroinflammatory processes are exacerbated by altered SCFA levels. Fecal transplants from PD patients have been shown to worsen motor deficits in experimental models. Interestingly, antibiotic treatment has been found to alleviate behavioral symptoms, highlighting the important role of the microbiome of gut in influencing PD Pathological processes and suggesting its potential as a target in therapeutics. These studies underscore the substantial effect of gut microbial imbalances on PD progression and point to new possibilities for microbiota-based therapeutic strategies (2). Gut dysbiosis in PD is linked with considerable alterations in microbial metabolite profiles. Individuals with PD exhibit increased amounts of secondary bile acids, like lithocholic acid (LCA), and deoxycholic acid (DCA) alongside reduced concentrations of SCFAs. These microbial alterations are linked with impaired motor function and gastrointestinal disturbances, which are commonly seen in PD. Among SCFAs, butyrate plays a complex involvement in regulating inflammation by modulating Th1 and Th17 cell activity. Notably, specific secondary bile acids, including tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA), have shown neuroprotective effects, suggesting their potential therapeutic value in alleviating PD pathology. However, more research is important to entirely understand the function of these microbial metabolites in the disease progression of Parkinson’s (26). Recent metagenomic investigations have unveiled the complex interplay between gut virome dysbiosis and Parkinson’s disease (PD), revealing previously underexplored viral contributions to neurodegeneration. Analysis of 158 samples from two independent cohorts demonstrated that PD patients exhibited significantly elevated viral richness and diversity compared to healthy subjects, with notable enrichment of viral families including Myoviridae, Siphoviridae, Podoviridae, p-crAss-like phages, Circoviridae, Salasmaviridae, and Herelleviridae, while showing depletion of Quimbyviridae . These PD-associated viral operational taxonomic units (vOTUs) predominantly targeted bacterial genera such as Alistipes , Fecalibacterium , Oscillibacter , and Ruthenibacterium , contrasting with healthy subjects where vOTUs were primarily associated with Prevotella and Bacteroides . The functional implications of this virome dysbiosis extend beyond microbial ecology, as viral-mediated depletion of beneficial bacteria, particularly Fecalibacterium , a major SCFA producer, may impair gut barrier integrity and increase ENS susceptibility to inflammation and α-synuclein aggregation. Functional analyses revealed distinct PD-associated viral signatures, including ATP-dependent Clp protease involved in mitochondrial maintenance, integrase facilitating viral genome integration, and thymidylate synthase regulating one-carbon metabolism pathways implicated in neurodegeneration. These findings suggest that gut virome alterations represent a novel molecular linkage between intestinal dysbiosis and neurodegenerative processes, highlighting the potential therapeutic relevance of targeting viral-bacterial interactions in the gut-brain axis for PD management (29). In PD, Siphoviridae and Myoviridae were the predominant phages infecting bacterial hosts such as Lawsonibacter , Alistipes , Fecalibacterium , Oscillibacter , Intestinimonas , Ruthenibacterium , Fournierella , and Flavonifractor , based on 640 differentially abundant vOTUs. In contrast, Bacteroides and Prevotella were the main bacterial hosts in HSs. Functional analyses further identified thymidylate synthase (K00560) and integrases (K14059) as key viral markers, highlighting their potential role in PD-associated gut dysbiosis (29). 4.3) Microbiome, Virome and Autism Spectrum Disorder: Neurodevelopmental conditions that are characterized by the presence of repetitive behaviors and impairments in social communication are termed as Autism spectrum disorders (ASDs). Patients of ASD commonly experience gastrointestinal (GI) issues, including constipation, diarrhoea, and bloating, which are most often linked with gut dysbiosis. Differences in GM composition can influence neuroimmune interactions and modulate neurotransmitter levels, such as serotonin, glutamate, and GABA. Studies have observed an increase in population of Fecalibacterium and Lactobacillus , accompanied by a reduced population of Bacteroides , Bifidobacterium , and Escherichia coli , in individuals with ASD (Table 1). These microbial imbalances are proposed to play roles in systemic inflammation, impaired nutrient metabolism, and vitamin deficiencies. While the precise mechanisms remain incompletely understood, accumulating proofs indicates that the GM and its metabolites have a significant involvement in the pathophysiology of ASD. This highlights the need for further research into treatment options targeting microbiome manipulation (30). A recent study explores the intricate relationship between bacteriophages and microbial communities in the view of ASD, uncovering a distinct connection between the gut virome and ASD pathophysiology. At the genus level, Skunavirus exhibited significant divergence from the dominant viral family, Siphoviridae (order Caudoviricetes ). Notably, an inverse relationship between Caudoviricetes and Petitvirales suggests that gut homeostasis may depend on a finely balanced ecological relationship. While overall viral diversity remained stable, children with ASD showed an increased abundance of Microviridae . Importantly, children with ASD presenting gastrointestinal symptoms exhibited a reduction in α-diversity, indicating potential virome dysregulation. This evidence confirmed the role and involvement of the gut virome in ASD and underscore the need for further investigation into its mechanistic contributions (31). The brain, as the central organ of the human nervous system, is essential for coordinating all bodily functions and maintains constant communication with other organs. For example, the simple act of thinking about food and experiencing hunger, or the suspension of digestive processes during the fight-or-flight response, illustrates the dynamic crosstalk between the gut and the brain, often called as the ”second brain.” The ENS within the GI tract is a key component of this interaction. The crosstalk between CNS and the GI tract is mediated through the GBA, a bidirectional pathway that involves various mechanisms, including neuronal, endocrine, immune, and microbial factors. Metabolic compounds such as neurotransmitters including γ-aminobutyric acid (GABA), glutamate, norepinephrine, dopamine, histamine, serotonin, and SCFAs, bile acids, play an integral role in this complex communication (32). The GM impacts the circulating tryptophan levels and its metabolite kynurenine, both of which can cross the BBB and affect the neurotransmitter metabolism (32). In the case of PD, the influence of the GM on neurotransmitter dynamics becomes evident. Levodopa (L-DOPA), a precursor of dopamine (DA), can cross the BBB and increase levels of DA in the brain. However, GM can metabolize L-DOPA, thus reducing its bioavailability. For example, Enterococcus fecalis , a common gut bacterium, decarboxylates L-DOPA to DA, while Eggerthella lenta further metabolizes DA by dehydroxylating it to form m-tyramine (33). Furthermore, dysregulated tryptophan metabolism is implicated in promoting inflammation in neurons and facilitating the accumulation of α-synuclein in the brain (34). Some studies suggest phage infections may increase oxidative stress in the gut epithelium, contributing to α-synuclein misfolding (34). Bile acids derived from cholesterol metabolism in the liver, undergo further modifications by the GM and play important functions in modulating various physiological processes and signaling pathways. A study comparing AD patients to cognitively healthy individuals found that AD patients exhibited lower serum levels of ‘cholic acid (CA), a primary bile acid, and higher levels of deoxycholic acid (DCA), a secondary bile acid. Gut bacteria produce secondary bile acids from the primary bile acids. The increased DCA: CA ratio observed in AD patients suggests enhanced microbial 7α-dehydroxylation activity, which is strongly correlated with cognitive decline (28). Additionally, gut dysbiosis is linked with neuroinflammation and amyloid-beta (Aβ) accumulation (35). Individuals with ASD show elevated concentrations of metabolites produced by bacteria, including indoles, LPS, and SCFAs in both blood and urine, indicating potential deterioration of the gut-blood barrier. ASD is also characterized by mitochondrial dysfunction, heightened oxidative stress, disruption of tight junctions, and structural abnormalities in key brain regions (36,37). Mitochondria are critical for maintaining neurological health due to the exceptionally high energy requirements of neurons, which exceeds those of other cell types. To meet these demands, neurons possess a high density of mitochondria. Consequently, mitochondrial functions and dysfunctions may mediate the gut-brain communication. Furthermore, microbial metabolites are capable of modulating mitochondrial activity, thereby they influence neurodevelopment and contribute to the pathogenesis of various neurodegenerative disorders (38). Several neurotropic viruses, including Rabies Virus (RABV), Herpes Simplex Virus (HSV), and Poliovirus (PV), have a profound impact on the central nervous system (CNS). Although these viruses act independently of the GM, immune modulation and microbial metabolites can influence their pathogenic mechanisms. HSV infiltrates the CNS via the olfactory pathway, inducing severe neuroinflammation. It also disrupts mitochondrial function by elevating intracellular calcium (Ca²⁺) levels, thereby impairing mitochondrial activity and promoting oxidative stress, a vital factor implicated. Similarly, PV induces apoptosis of motor neurons through mitochondrial dysfunction, mediated by calcium influx from the endoplasmic reticulum (ER). Viral proteins modify mitochondrial channels to enhance ATP production, facilitating viral replication while concurrently suppressing host cell apoptosis. RABV gains access to the CNS by evading immune surveillance, notably through suppression of type I interferon responses. Infected neurons display disturbances in release of cytochrome c, mitochondrial membrane potential, and intrinsic apoptotic pathway’s activation, ultimately causing damage and death of neurons (39). One study examining the impact of sleep deprivation on the gut microbiome in hypertensive patients reported an enrichment of Fusobacterium mortiferum and Roseburia inulinivorans among individuals with insufficient sleep (32). Fusobacterium mortiferum is recognized as an opportunistic pathogen, whereas Roseburia inulinivorans , a butyrate-producing bacterium, is generally considered a beneficial gut inhabitant. Nevertheless, as evidenced by investigations into glucose metabolism, the gut microbiome exhibits a complex interplay, and alterations in microbial populations involved in the production of beneficial metabolites may disrupt fermentation processes and promote low-grade inflammation (40). Moreover, Mendelian randomization studies identified that the population of Firmicutes and Betaproteobacteria positively associate with the risk of schizophrenia. Additionally, genera such as Akkermansia , Bacteroides , and Desulfovibrio have also been implicated in the disorder (41). Table 1: Comparative gut bacteriota-virome profile in neurological disorders: Disorder ↑ Virus ↓ Virus ↑ Bacteria ↓ Bacteria AD Poxviridae Uroviricota Lactococcus phages- bIL285, bIL286, bIL309, BK5T, BM13, P335 sensu lato, phiLC3, r1t, Tuc2009, ul36, and bIL67, Siphoviridae Bacteroides Ruminococcaceae Clostridiaceae Bifidobacterium PD Myoviridae, Siphoviridae, Podoviridae, p-crAss-like phages, Circoviridae, Salasmaviridae, and Herelleviridae Quimbyviridae increased Enterobacteriaceae reduced Prevotellaceae, Fecalibacterium ASD Microviridae Caudoviricetes , Petitvirales (↓ correlated) Fecalibacterium and Lactobacillus Bacteroides , Bifidobacterium , and Escherichia coli The significance of gut-associated eukaryotic viruses in maintaining brain health and advancing neurodegenerative diseases such as ASD, PD, and AD has been highlighted by recent studies. Compared to phages, eukaryotic viruses from the Anelloviridae , Picobirnaviridae , and Astroviridae families make up less than 10% of the gut virome and are less well-characterized. DNA viruses called Anelloviridae are primarily dormant, however illness conditions like IBD change how common they are. Astroviridae are more frequently linked to acute gastroenteritis than they are in healthy people (6,7). Anelloviruses exhibit immune system evasion in sick circumstances, notwithstanding the gray area in their functional role. Their capsid proteins are known to form a structure that conceals conserved viral domains while revealing highly variable areas that serve as immunological decoys. This could enable them avoid being neutralized by antibodies, which could increase their persistence and capacity to spread multi-strain infections (42,43). Phages, on the other hand, are more prevalent than eukaryotic viruses and are an essential part of the gut virome. They influence the GBA through increasing protein aggregation, changing the synthesis of microbial metabolites, and controlling immunological responses. Microbial metabolites, such as SCFAs, improve the intestinal barrier’s structural and functional integrity, boost mucosal immunity, and control systemic inflammatory responses, all of which have an impact on mood, cognition, and neuroprotection. Notably, an increased abundance of gut-resident viruses, particularly bacteriophages from families such as Podoviridae , Inoviridae , Myoviridae , and Siphoviridae , has been reported in older adults diagnosed with MCI. These studies suggest the crucial role of bacteriophages in shaping microbiome diversity, influencing bacterial community structure, and ultimately affecting cognitive outcomes through phage-bacteria interactions (21,44). AD, PD, ALS, and transmissible spongiform encephalopathies (TSEs), grouped under Neurodegenerative diseases (NDs) are characterized by pathological protein aggregation within the CNS. Viral infections are increasingly acknowledged as significant contributors to the progression of NDs, as they promote protein misfolding, aggregation, and neuroinflammatory responses. For instance, herpesviruses such as Herpes Simplex Virus type 1 (HSV-1) have been associated with AD, where viral reactivation enhances the aggregation of tau neurofibrillary tangles and amyloid-β plaques. Similarly, influenza A virus and hepatitis viruses have been shown to exacerbate pathological α-synuclein aggregation and dopaminergic neuron degeneration in PD. Endogenous retroviruses, notably HERV-K, have been implicated in the aggregation of TDP-43 and FUS proteins in ALS. These viruses disrupt cellular homeostasis by impairing autophagy and protein degradation pathways, leading to the build-up of aggregation-prone proteins and facilitating amyloid formation. Furthermore, viruses can promote the intercellular transmission of protein aggregates via extracellular vesicles or direct cell-to-cell contact, thereby amplifying the pathological processes underlying NDs (45). Pathogenic bacteria, such as Pseudomonas aeruginosa and Salmonella enterica serovar Typhimurium, contribute to the exacerbation of protein aggregation and neurodegeneration by disrupting proteostasis and initiating inflammatory responses. In contrast, beneficial microorganisms, including Bifidobacterium longum and Lactobacillus plantarum , have exhibited neuroprotective effects by restoring gut eubiosis, mitigating protein aggregation, and improving cognitive and motor functions in animal models. Additionally, butyrate-producing bacteria such as Clostridium butyricum support neural health by reducing inflammation, maintaining intestinal barrier integrity, and promoting proteostasis (46). In PD, alterations in the gut microbial and viral communities- characterized by an increased population of Lachnospiraceae and Lactobacillaceae and a reduction in Turicibacter , are linked with α-synuclein (α-Syn) aggregation. Recent evidence emphasizes the important role of the gut virome in the pathogenic mechanisms of neurodegenerative diseases. The gut virome, comprising bacteriophages (viruses that infect bacteria) and eukaryotic viruses, is fundamental to maintain microbial homeostasis and modulating immune functions. Disruptions within the gut viral community, particularly the overrepresentation of specific phages, are linked to elevated inflammatory responses and increased protein aggregation, thereby contributing to disorders like PD and Alzheimer’s disease (AD). In PD, viral dysbiosis could potentiate neuroinflammation via activation of Toll-like receptors (TLRs), which subsequently promote α-synuclein aggregation and degeneration of dopaminergic neurons. Similarly, in AD, alterations in the gut virome may enhance permeability of intestines and systemic inflammation, facilitating the translocation of tau aggregates and amyloid-beta from the gut to the brain (9). The virome also has an essential function in the psychiatric disorder’s pathophysiology related to stress, including depression and anxiety. Chronic stress shifts the constitution of both the gut bacteriome and virome, changes that correlate with behavioral impairments, immune dysregulation, and neurobiological abnormalities. Fecal virome transplantation (FVT) has demonstrated therapeutic potential in mitigating stress-induced behavioral deficits and restoring microbial homeostasis in animal models. Mechanistically, FVT modulates bacterial populations involved in neuroactive and metabolic pathways, including the enrichment of butyrate-producing bacteria, while simultaneously reversing stress-induced immune suppression and normalizing cytokine profiles. Transcriptomic analyses of stress-sensitive brain regions have revealed that FVT can reverse stress-associated alterations in gene expression, which highlights its promise as a potential treatment option for both neuropsychiatric and neurodegenerative disorders (47). Overall, the complex bidirectional crosstalk between the gut microbiota, virome, and microbial metabolites exerts a profound influence on neural health. While pathogenic microorganisms promote the establishment and progression of stress-related and neurodegenerative disorders, beneficial microbes and virome-targeted interventions offer promising avenues for preserving cognitive function and slowing disease progression. 6) Host-bacteriome-virome Interplay: Gut viruses modulate bacterial taxa that produce inflammatory and anti-inflammatory molecules. Viral effects on hosts, as mentioned before could be direct or indirect. Certain neurotropic viruses can produce viral proteins that are able to cross BBB displaying direct viral effects. For instance, HIV-1 proteins could disrupt tight junction proteins in BBB endothelial cells, potentially triggering neuroinflammation (48,49). While in IBD, the altered virome with increased lytic phages of order Caudoviricetes correlates with the dysbiosis in terms of reduced SCFA producers, thus contributing to gut inflammation. This is an example of indirect viral effects (50,51). Phage-mediated modulation of microbiome dynamics can indirectly influence the synthesis of neurotransmitters like dopamine, serotonin, and GABA, by altering bacterial populations involved in their biosynthesis. A comprehensive understanding of the interactions among the bacteriome, virome, phageome, and the human host is crucial for elucidating the complexity of the gut microbial ecosystem. The gut virome, which is predominantly composed of bacteriophages, prophages, eukaryotic viruses, and retroviruses, exhibits significant complexity, as demonstrated by fecal DNA sequencing analyses. Viruses within the gut are estimated to outnumber bacteria by a ratio of approximately 20:1. Prominent phage families inhabiting the human gut include Myoviridae , Podoviridae , Siphoviridae (dsDNA phages), and Microviridae (ssDNA phages) (52). The Microviridae family comprises phages that infect bacterial genera, including Bacteroides and Prevotella . A newly identified viral family targeting members of the Bacteroidetes phylum constitutes approximately 22% of total reads in the ‘Human Gut Metagenome Project, emphasizing its potential influence on gut microbial ecology. Furthermore, the clustering of Microviridae phages with prophages of Bacteroides and Prevotella suggests a stable, long-term association with the human gut microbiota (53). It is essential to recognize that most studies on microbiome alterations predominantly highlight associations rather than causal relationships. For instance, an increased abundance of Caudoviricetes phages are observed in patients with ulcerative colitis and Crohn’s disease, which is accompanied by a decline in bacterial diversity in contrast to healthy individuals. Similarly, eukaryotic viruses such as Anelloviruses, Picobirnaviruses, and Aichivirus are frequently detected in diseased gastrointestinal tracts; however, their roles as either causative agents or consequences of disease remain unresolved (54). Most models of the GBA have traditionally emphasized the function of bacteria, often overlooking the contributions of the virome. However, evolving evidence indicates that the abundance of gut bacteriophages correlates with cognitive function of host by modulation of bacterial metabolism and the production of downstream metabolites. For instance, supplementation of 936-type Siphoviridae phages in diet has been shown to enhance memory in Drosophila by upregulating genes associated with synaptic plasticity and neuronal development. Elevated levels of Siphoviridae were linked with improved cognitive performance, particularly in women, whereas elevated levels of Microviridae correlated with poorer cognitive outcomes. Caudoviricetes phages demonstrated positive associations with beneficial lactic acid bacteria and negative associations with Bacteroides , a pattern that was inversely observed for Microviridae (55). Functional genomic analyses revealed that Caudoviricetes phages were linked to suppression of folate-mediated one-carbon metabolism in bacteria, a pathway essential for DNA synthesis, methylation, and neurodevelopment. Key enzymes, including thymidylate synthase ( thyX ) and deoxyuridine 5’-triphosphate nucleotidohydrolase ( dut ), showed strong associations with these phages, suggesting that phage-driven modulation of bacterial metabolic pathways may play significant roles in maintaining host cognitive health (55). In PD, virome alterations are characterized by a reduced overall viral population and an increased prevalence of Lactococcus phages, leading to a higher phage-to-bacteria ratio, particularly among lactic acid bacteria. Concurrent microbiome analyses have demonstrated an increased population of Akkermansia muciniphila (Verrucomicrobiaceae) and unclassified Firmicutes , along with significant decreases in Prevotella copri (Prevotellaceae), Eubacterium biforme (Erysipelotrichaceae), and Lactococcus spp. This pattern of microbial dysbiosis may lead to the progression of neurological dysfunction in PD (56). In addition to their role in lysing bacterial host, virulent phages may indirectly influence non-host microbial communities. For example, phages targeting Enterococcus fecalis can activate the type VII secretion system in host, which further inhibits the neighbouring bacterial species. These phage-mediated alterations in the GM may further induce alterations in the metabolome in gut, including reductions in neurotransmitter levels and disruptions in bile acid metabolism, both essential for gut-brain and gut-organ communication. However, these observations have primarily been derived from studies utilizing limited in vivo bacterial consortia, necessitating further investigation to properly understand the effects of phage activity on the broader gut ecosystem and host physiology (57). Additionally, gut viruses are capable of disseminating through the lymphatic and circulatory systems, potentially reaching distant organs such as the brain. In Parkinson’s disease, elevated intestinal permeability enables the movement of microbial and viral components into the CNS, where they can elicit inflammatory responses. Alterations in the gut virome are linked with elevated pro-inflammatory cytokine levels and reduced neurogenesis. Moreover, enhanced permeability of gut and malfunction of the kynurenine pathway may promote the synthesis of neurotoxic metabolites, like quinolinic acid, contributing to brain inflammation and neuronal injury (57). Emerging studies indicate that gut microbial dysbiosis may have a function in the evolution of neurodegenerative disease (NDD)-related symptoms, involving senile plaque formation, oxidative stress, and inflammation observed in disorders such as multiple sclerosis (MS), PD, amyotrophic lateral sclerosis (ALS), AD, and Huntington’s disease (HD). Microbiota-derived acetate has been shown to regulate microglial-mediated removal of amyloid-beta (Aβ) in AD models. On the other hand, d-glutamate, a microbial metabolite, may enhance cognitive function via N-methyl-D-aspartate (NMDA) receptor activation. These findings reveal the possibility of the imporatnce of the gut microbiome in the pathogenic mechanism and progression of NDDs (9). Several gut microbial species are implicated in the biosynthesis of key neuroactive compounds. For instance, Lactobacillus reuteri produces vitamin B12, while Akkermansia muciniphila and Eubacterium hallii generate SCFAs like propionate, acetate, and butyrate, which exhibit neuroprotective properties. Additionally, genera such as Lactococcus and Pseudomonas influence the synthesis of neurotransmitters, including dopamine, serotonin, histamine, GABA, etc. Collectively, these findings emphasize the substantial effect of the GM on neurodevelopment and the pathophysiology of neurodegenerative diseases (58). Preclinical studies have highlighted important links between bacterial taxa, neurotransmitter dynamics, inflammation, and behaviour. For instance, when Bifidobacterium infantis colonizes germ-free mice, it normalized the stress responses through the hypothalamic-pituitary-adrenal (HPA)’ axis. In healthy individuals, the coevolution of bacteria and bacteriophages leads to a stable gut microbiome. Phages may influence host neurotransmitter synthesis by targeting microbiota capable of amino acid and precursor conversion. One study reported that IBD patients have less SCFA producing Fecalibacterium prausnitzii in their microbiota than healthy controls, while the higher population of some of its phages may indicate their activation during the diseased state. Their result suggest that prophage detection in sequenced microbiota strains can provide a useful complement to viral metagenomic studies. Another studyshowed reduced tryptamine levels when the tryptamine- producing bacterial species like Ruminococcus gnavus and Clostridium sporogens were targeted by phage treatment. Likewise lactic acid bacteria like Enterococcus fecalis , that convert tyrosine to tyramine, showed decreased tyramine synthesis after administration of a lytic phage- VD13 specific to E. fecalis (59–61). Beyond their involvement in modulating bacterial populations, phages can directly influence host immunity by releasing DNA upon phagocytosis, which activates toll-like receptors (TLRs), or by interacting with intestinal epithelial cells, thereby affecting mucosal defenses. In a model of depression, chronic restraint stress (CRS) mouse, analysis of the gut virome and fecal metabolites revealed an increased abundance of Siphoviridae phages, alongside phages infecting Gammaproteobacteria , Enterobacteriaceae, and Campylobacteraceae . Depression-like behaviour was found to correlate with alterations associated with 12 neurotransmitters, particularly within metabolism of tryptophan, where changes in the population of Podoviridae and Microviridae were linked with fluctuations in tryptamine and 5-methoxytryptamine hydrochloride levels (62). In people with Aβ + AD, gut virome profiles displayed a reduced alpha diversity and also a markedly decreased bacteriophage richness compared to healthy controls (HCs). Specifically, a significant reduction in the population of the Siphoviridae family, along with a decrease in multiple Lactococcus phages was observed (28). Alpha-synuclein, a neuronal protein essential for synaptic function, is implicated in the pathogenic mechanism of neurodegenerative diseases, such as PD, due to its abnormal aggregation into toxic aggregates. A study on the effect of α-synuclein on viral composition over five months demonstrated that injection of either monomeric or fibrillar α-synuclein into the ENS led to significant changes in the gut virome. The most substantial alterations were observed in rats receiving α-synuclein monomer combined with lipopolysaccharide (LPS), α-synuclein pre-formed fibrils (PFF), or α-synuclein PFF plus LPS. However, future studies are required to determine whether these α-synuclein-induced alterations in the virome mediate the progression of Parkinson’s disease or gastrointestinal disorders associated with the disease (63). Collectively, these studies indicates that the virome, particularly the phageome, has a crucial yet underexplored function in regulating gut microbial ecosystems, host metabolism, and, ultimately, neurodevelopment and the progression of neurodegenerative diseases. While accumulating evidence supports this concept, the underlying mechanisms remain inadequately understood. Future research employing advanced techniques such as Hi-C, CRISPR-spacer matching, and fecal virome transplantation (FVT) will be vital. A more comprehensive understanding of how specific viral populations interact with host genetics, gut permeability, and neuroimmune pathways is critical for the developing innovative strategies useful in therapeutics and medicines. 7) Impact of Diet: The gut virome is highly stable in healthy adults but is shaped early in life by diet. For example, breastfed infants exhibit a higher population of phages and a lower presence of eukaryotic viruses as compared to formula-fed infants. Diet continues to influence the virome throughout life, with common foods and medications promoting prophage activation and altering viral dynamics. Ethnic and geographic dietary patterns, particularly those associated with urbanization, affect virome diversity, with traditional lifestyles being associated with lower levels of crAssphage and greater enteric virus diversity in resource-limited settings. Additionally, viruses derived from foods, like plant viruses, are frequently found in the gut (62). 8) Future perspective: Current research primarily focuses on broad phage families, such as the Siphoviridae , while giving limited attention to genus-specific phages, including those targeting Streptococcus or Lactobacillus . This, coupled with the absence of advanced virome analysis tools and longitudinal datasets, hinders a more in-depth understanding of the potential role of phages in the progression of neurodegenerative diseases. To address this gap, clinical trials exploring phage-based interventions for cognitive impairment are urgently required (9). 9) Conclusion: The microbiota-gut-brain axis represents a fundamental regulatory system where gut microbial communities profoundly influence neurological health through diverse molecular mechanisms. This review demonstrates that maintaining optimal microbial diversity and metabolic function is crucial for preserving cognitive performance and preventing neurodegenerative diseases. The emerging significance of the gut virome, particularly bacteriophages, adds another layer of complexity to our understanding of microbial-neural interactions. Future research must prioritize longitudinal studies investigating specific phage-bacterial interactions, development of advanced virome analysis tools, and clinical trials evaluating microbiome-targeted therapeutics. The integration of high-throughput sequencing, metabolomics, and systems biology approaches will enhance our comprehension of these intricate relationships. Ultimately, targeting the MGB axis through precision microbiome interventions holds immense therapeutic potential for treating neurological disorders, offering hope for more effective, personalized treatment strategies that address the root microbial contributors to neurological pathology and cognitive decline. 10) Funding No funding has been received for writing this review article. 11) Acknowledgement The authors gratefully acknowledge the Publication Screening Committee (PSC) of ICMR-NIRTH, Jabalpur, for reviewing this manuscript (Unique ID: ICMR-NIRTH/PSC/16/2025) for plagiarism and research integrity. 12) References: 1. Rusch JA, Layden BT, Dugas LR. Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis. Front Endocrinol. 2023 Jun 19;14:1130689. 2. Tiwari P, Dwivedi R, Bansal M, Tripathi M, Dada R. Role of Gut Microbiota in Neurological Disorders and Its Therapeutic Significance. JCM. 2023 Feb 19;12(4):1650. 3. Appleton J. 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Keywords biostatistics & bioinformatics gastrointestinal analysis immune responses inflammation metabolic networks microbial cultures nervous system pathogenesis research and analysis methods Authors Affiliations Komal Shrivastav 0009-0004-9462-251X ICMR - National Institute of Research in Tribal Health View all articles by this author Muskan Pandey ICMR - National Institute of Translational Virology and AIDS Research View all articles by this author Hetarth Gor ICMR - National Institute of Translational Virology and AIDS Research View all articles by this author Vijay Nema 0000-0001-6420-9397 [email protected] ICMR - National Institute of Research in Tribal Health View all articles by this author Metrics & Citations Metrics Article Usage 564 views 239 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Komal Shrivastav, Muskan Pandey, Hetarth Gor, et al. Gut virome plays an extended role with bacteriome in Neurological Health and Disease. 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