The virome is an important component of the gut microbiota and consists of a large number and variety of eukaryotic and prokaryotic viruses, which are categorized by nucleic acid type into single- and double-stranded, and DNA and RNA viruses. Typically, members of the virome includes viruses infecting human and animal cells, phages with microorganisms as hosts (sometimes referred to as the phageome), and plant viruses coming from environmental and dietary sources (Liang and Bushman, 2021). Enteroviruses are challenging to detect and study because of various factors, including technological limitations and cost. As a result, they have been referred to as the “dark matter” of the intestinal microbiota (Clooney et al., 2019; Fitzgerald et al., 2021). For a long time, there was a lack of understanding of the viral community in the gut. Exploration of the gut virome was initiated on a small scale in the first decade of the 21th century and was mostly aimed at detecting pathogens and discovering viruses (Breitbart et al., 2008, 2003; Finkbeiner et al., 2008; Zhang et al., 2005). Since then, virus-like particles (VLPs) enrichment processes combined with the widespread use of metagenomic technologies (Franzosa et al., 2015; Ren et al., 2017; Roux et al., 2015a; Thurber et al., 2009), have enabled the rapid accumulation of knowledge about the gut virome (Junhua Li et al., 2022; Nayfach et al., 2021). The basic features of the human gut virome, which are highly diverse, individual-specific, and temporally stable, have gradually been elucidated (Minot et al., 2012; Shkoporov et al., 2019). In particular, over the past two decades, there has been growing evidence that the virome, similar to the bacteriome and the fungiome (Cho and Blaser, 2012), is broadly involved in the regulation of individual health states (Coughlan et al., 2021; Jiang et al., 2020; Khan Mirzaei et al., 2020; Lepage et al., 2008; Yang et al., 2021) .

The gut virome affects human physiology in a variety of ways, broadly categorized into direct and indirect effects. It is widely recognized that eukaryotic viruses infect human or animal cells and directly cause disease (Holtz et al., 2014; Neil and Cadwell, 2018). However, the mainstay of the virome that inhabits the gut of healthy individuals in the noninfected state on a long-term basis is bacteriophages. They consist of lytic phages that infect and lyse bacteria, as well as temperate phages that lysogenically integrate into the bacterial genome (Shkoporov and Hill, 2019). Although phages can sometimes directly interact with human cells and trigger immune responses (Eriksson et al., 2009; Sweere et al., 2019), most often they indirectly affect human physiological health by regulating bacterial community structure and function. Lytic phages exhibit strong predatory pressure on their bacterial hosts, which becomes an important driver of changes in bacterial community composition and function (Reyes et al., 2012). In human microbiome data, a predatory relationship between phages and bacteria can be inferred from quantitative correlations or indicators such as bacterial acquired immunity genetic elements (Roux et al., 2015b; Wang et al., 2016, 2013; Zhou et al., 2015). However, more obvious evidence for predation and colony regulation comes from phage therapy and phage manipulation experiments. In these experiments, the artificial removal of phages increases the chance of occurrence of originally rare bacterial species in the community, while the introduction of phages reduces the abundance of certain bacteria (Kortright et al., 2019; Weinbauer et al., 2007). Generally, lytic and temperate phages coexist in the gut and undergo mutual transformation in response to changes in the environment. This transformation process, if accompanied by frequent exchange of genes and rapid genome evolution (Minot et al., 2013), will probably endow phages with new capabilities. Together with phage-encoded auxiliary metabolic genes (AMGs) (Mangalea et al., 2021), it would be an important pathway to enrich the function of the gut microbiota, thus influencing human metabolism and function.

The human gut virome is influenced by factors such as geography (Camarillo-Guerrero et al., 2021; Monaghan et al., 2020; Van Espen et al., 2021), ethnicity (Junhui Li et al., 2022; Zuo et al., 2020), genetics (Maqsood et al., 2019; J. Wang et al., 2022), age (Gregory et al., 2020; Liang et al., 2020; Xiao et al., 2021), diet (Garmaeva et al., 2021; Nishijima et al., 2022; Pu et al., 2023; Zuo et al., 2020), and health status (Coughlan et al., 2021; Nakatsu et al., 2018; Norman et al., 2015; Wang et al., 2018). Of these factors, diet is a powerful driving force of the gut virome and the easiest factor to be modified and manipulated. In recent years, it has been found that dietary intake can alter the species diversity and community structure of the gut virome, and that there are certain preferences in terms of dietary categories. Moreover, the characteristics of the virome and phages are responsible for some of the unique features exhibited in response to diet. Herein, we focus on research progress on phage-host interactions and phage lifestyle changes in response to diet. We also extensively discuss the auxiliary metabolic functions of enteroviruses conferred by diet, with the aim of generating a more complete understanding of the basic rules of dietary regulation of the gut microbiota. This will further enrich our knowledge of the human microbiome, and lay a foundation for dietary interventions targeting the gut microbiota to promote health.

Under normal conditions, the gut virome shows a high degree of inter-individual dissimilarity but remains relatively stable within an individual over a long period of time. Studies have shown that the percentage of shared eukaryotic viruses and phages is low in adults regardless of their genetic relationship, suggesting that each individual’s gut virome is quite unique (Minot et al., 2011; Reyes et al., 2010). Two independent population-based follow-up surveys demonstrated that the virome of an individual is in a persistent steady state for at least one year without external disturbance, in terms of community similarity and the proportion of shared viruses, respectively (Reyes et al., 2010; Shkoporov et al., 2019). On this basis, dietary factors have been implicated in influencing the diversity of gut viral communities, as well as in perturbing virome homeostasis and decreasing inter-individual heterogeneity.

Dietary interventions cause changes in species diversity of the gut virome. This may be attributed to a cascade effect due to changes in the host bacteria of the phage caused by the intake of new nutrients, while the diet may also introduce new viruses into the gut. For example, in mice fed a polyphenol-free diet or a tea polyphenol diet, there was a tendency for the latter to have lower alpha diversity of their gut virome (Dong et al., 2022). In human experiments, the Shannon diversity index of the gut virome was significantly reduced if protein intake was increased on a daily basis (Cronin et al., 2018). Perhaps because the virome responds to diet with a dietary category preference, some studies have also noted that dietary category differences such as high or low fat content or gluten presence or absence did not significantly affect the alpha diversity of the gut virome (Garmaeva et al., 2021; Rasmussen et al., 2020). However, most of these studies refer to dietary interventions drastically altering the structure and community of the gut virome (Fig. 1).

Intake of the same diet can significantly increase the similarity of gut viral communities among individuals, meaning that the original viromes with high individual heterogeneity become more similar. Gut viral communities were generally more similar among individuals with a common dietary pattern than among individuals on a randomized diet with a diverse food composition. Bushman and colleagues investigated inter-individual differences in the gut virome and the response to diet by feeding human subjects a high-fat/low-fiber diet, a low-fat/high-fiber diet, or a randomized diet (Minot et al., 2011). After eight days of longitudinal observations, it was found that the gut virome was dramatically different between people in the randomized dietary state, and that dietary control shifted the viral community to a new state. In the new state, the ecological distance of viral communities decreased and the virome converged between individuals on the same diet. Similarly, for other dietary patterns or components, such as after gluten-free dietary intervention (Garmaeva et al., 2021) or after regular whey protein supplementation (Cronin et al., 2018), inter-individual viral community distances were significantly reduced compared with the pre-intervention state. The results suggest that the same dietary intake generally shapes the gut viromes of different individuals into more similar community patterns.

However, the intake of different diets resulted in greater heterogeneity in the gut virus community between individuals. In particular, the fat and carbohydrate content of the diet had a strong shaping effect on the gut virome. After the transition from a normal diet to a high-fat diet or a high-sugar diet, the shift in dietary pattern had a significant impact on the beta diversity of the viral community, although the shift in dietary pattern was not always accompanied by a large change in the species richness of gut viruses. Researchers from Kyung Hee University in South Korea significantly altered the gut virome of mice by alternating feeding with low-fat and high-fat with carbohydrate diets (Kim and Bae, 2018). Over a 12-week period, the researchers made three switches from low-fat to high-fat plus high-sugar diets or to low-fat plus high-phytoglycan diets. By reconstructing the gut metagenome and identifying active phages, they found significant differences in phage community composition in mice fed different diets. Further analysis revealed higher community similarity between the low-fat diet group and the high-fat plus high-phytopolysaccharide diet group compared with the low-fat plus high-phytopolysaccharide diet group. The study indicates that the high phytopolysaccharide diet drove the virome shift more strongly in the fat and carbohydrate dietary pattern, creating a unique community structure. Moreover, the effect of differential diets on mouse gut viral communities was stable and replicable. This is evident from experiments in which researchers fed mice from different supplier sources a low-fat or high-fat diet and compared gut virus composition using a virome approach. They showed that the gut viral components of mice from all supplier sources changed with diet, and the virome structure differed markedly between low-fat and high-fat dietary patterns (Rasmussen et al., 2019).

Through these studies, it is clearly evident that diet largely impacts on the diversity of gut viral communities. The modes of action include increasing or decreasing species richness, as well as converging viromes between individuals or decreasing the similarity of communities between groups after intake of the same or different diets, resulting in diet-dependent gut viromes. Furthermore, gut virome diversity is particularly affected in response to certain dietary categories.

As a result of the high mutability of viruses, the changes in the virome in response to diet are extremely variable. According to existing studies, it is not only the overall diversity of the viral community, but also the fact that some viral taxa respond preferentially to certain diets. For example, some viruses are more active and sensitive to dietary disturbances, responding to the induction and regulation of many different diets; whereas, some viruses are more conserved and restricted to specific dietary categories, such as dairy, and therefore display a simple correspondence with diet.

Gut viral components respond frequently and diversely to dietary categories. This was partially corroborated by a descriptive study of the gut virome that included nearly 1,000 healthy adult subjects from two regions and six ethnic groups in China (Zuo et al., 2020). Of 67 dietary components of typical Chinese food staples, side dishes, fruits, and beverages, 22 were significantly associated with intestinal DNA virome variants, compared with only 9 associated with gut bacterial variants. Multivariate linear regression model analysis also showed that the number of relationship pairs between viruses and dietary components was twice that of bacteria and dietary components. It was evident from their results, that fruits induced more variation in virus species. Fruits such as kiwifruit, passion fruit, and dates had the highest number of relationship pairs with viruses. These fruits were each significantly associated with more than 10 viral species, again reflecting the complexity of the relationship of the gut virome in response to diet.

A representative example of an active viruses responding to multiple dietary modulations is crAssphage. This phage taxon was first described in 2014 and is now recognized as the most abundant and widely spread virus present in the human body, accounting for around 90% of the total gut virome (Yutin et al., 2018). Dietary habits and diet can influence its distribution and abundance in the gut. The frequency and abundance of crAssphage is relatively higher in populations with a non-westernized diet compared with a westernized diet (Tomofuji et al., 2022). One descriptive study on crAssphage based on gut microbial data from over 1000 participants from more than one-third of the world’s countries, correlated its abundance with more than 200 exogenous and endogenous variables, including 78 dietary factors. The authors found that crAssphage was significantly correlated with a wide range of dietary components, including protein, carbohydrates, caloric intake, alcohol, and coffee (Edwards et al., 2019). This wide range of associations is thought to be largely determined by the preference of crAssphage host bacteria for dietary categories. Most crAssphage are hosted by members of the phylum Bacteroidetes (Dutilh et al., 2014), with different members often associated with different diets (Singh et al., 2017). For example, the genus Bacteroidetes is associated with long-term diets rich in animal proteins and sugars (De Filippo et al., 2010), whereas Prevotella and Paraprevotella are associated with low-protein and high-fiber diets (De Filippo et al., 2010; Kovatcheva-Datchary et al., 2015). Not only are the responding dietary categories variable, but the direction of crAssphage changes may also vary across dietary categories. The biomass of crAssphage was significantly increased (4-fold) in the gut of subjects following gluten-free dietary interventions (Garmaeva et al., 2021) and was down-regulated following green tea polyphenol treatment (Dong et al., 2022). These findings further reflect the sensitivity and complexity of the crAssphage response to the induction and modulation by different diets (Fig. 2).

By comparison, phages associated with host bacteria belonging to the order Lactobacillales are markedly diet-conservative, favoring abundant growth in the gut with dairy intake. Lactococcus phages have been found to be more prevalent and enriched in populations with a higher consumption of fermented dairy products such as cheese and yogurt (Waller et al., 2014). Lactococcus lactis, the host bacterium for these phages, is a bacterial strain that is essential for the fermentation of dairy products. The specific increase in L. lactis phages is often coincident with their host bacteria and may be a consequence of the increased number of host bacteria introduced by the intake of fermented dairy products. Other dairy products have a similar effect. For example, whey protein intake was found to significantly enrich Lactococcus phages in the gut in a prospective study (Cronin et al., 2018). In addition to dairy products, unprocessed natural milk also specifically enriches intestinal phages of Lactobacillales. Indirect evidence come from the observation that newborns and infants fed by breast milk have a significantly higher number of Lactobacillales phages in the gut. Multiple prospective cohorts of breastfed infants and young children from the USA, Europe, and Africa were constructed, encompassing subjects of different ethnicities and family economic status. The gut viromes of these participants were characterized by metagenome technology, consistently confirmed the higher abundance of Lactobacillales phage (Liang et al., 2020; Walters et al., 2023). Breast milk is rich in natural antibodies, oligosaccharides, lactoferrin, and other active ingredients (Turin and Ochoa, 2014) that inhibit rotaviruses, noroviruses, enteroviruses, influenza viruses, and SARS-CoV (Pou et al., 2019). Breastfeeding results in a lower accumulation of infectious Adenoviridae, Picornaviridae, and Caliciviridae, and other animal cell viruses, in the gut of infants and young children, and in a reduced risk of infections and illnesses (Lamberti et al., 2011). Taken together, these findings lighlight the advantageous composition of a more homogeneous, Lactobacillales phage-dominated virome.

The correlation between members of the gut virome and dietary components is complex, with some dietary components tending to alter the occurrence frequency and loads of several viruses. There are also active viral species that respond to a number of different dietary patterns or classes. In addition, some viral clades are highly conserved in response to diet and tend to either proliferate and be eliminated following exposure to specific dietary environments or components. In many cases, the direction of the diet-regulated virome is related to the host bacterial preference for diet.

Extensive viral and bacterial interactions occur in the gut, which can be clearly demonstrated in response to dietary disturbances (Fan et al., 2023; H. Wang et al., 2022). Although at times the gut virome and bacteriome respond independently to dietary intake in inconsistent or even opposing ways (Howe et al., 2016), more studies have reported highly consistent trends in the changes to the virome and bacteriome and strong correlations between phages and their bacterial hosts (Nishijima et al., 2022). This strong association may be determined by lytic phage-mediated predatory relationships.

Phage lifestyle shifts are an important form of phage-bacteria interaction in the gut microbiota, which are sometimes regulated by diet. Temperate phages integrated in bacterial genomes can be activated by diet to become lytic, leading to cell lysis and thus a reduction in bacterial populations. A study testing the response of three gut bacteria and an opportunistic pathogen to hundreds of common foods, additives, and plant extracts indicated that diet altered the abundance of gut bacteria via inducing phage lysis. Ingredients such as stevia and propolis extracts were observed to achieve specific inhibition of host bacterial growth via phages (Boling et al., 2020). Another study explored the potential of a series of sugar-induced phages to eliminate intestinal pathogens. The study validated in a mouse gut model that d-xylulose metabolism and propionic acid triggered a stress (SOS) response in Escherichia coli ATCC 25922, effectively inducing the release of dormant phages by E. coli, resulting in the death of the host bacterium (Hu et al., 2023). Similarly, fructose-enriched diets activate the acetate kinase pathway, producing acetic acid and thereby triggering the bacterial stress response. This subsequently led the activation and massive release of temperate phages from the Lactobacillus reuteri genome into the gut, affecting the survival and colonization of L. reuteri (Oh et al., 2019). These studies demonstrate a phage lifestyle in the gut that can be induced by diet or diet-influenced metabolites, providing a potential mechanism for dietary regulation of bacterial communities via gut phages (Fig. 3).

Dietary intake also increases the number of temperate phages and shifts the lifestyle of phages toward the lytic state. A series of reports indicates that a “Western” high-fat plus high-sugar diet tends to result in the formation of more temperate phages in the gut virome. Compared with mice fed a normal diet, the gut mucosa and lumen of mice fed a high-fat plus high-sugar diet were significantly enriched with temperate phages of the order Caudovirales (Kim and Bae, 2016). Most of these temperate phages are derived from bacterial hosts that respond to dietary changes, especially the temperate phages hosted by Bacteroides. They encode functions that facilitate the adaptation of the host bacteria to selection pressures from the ecological niche. The proportions of lytic and temperate phages in the mouse gut were compared after intervention with a high-fat plus high-sugar diet and a high-phytopolysaccharide diet. The results similarly demonstrated that the proportion of temperate phages remained high on the high-sugar plus high-fat diet and correspondingly low on the high-phytopolysaccharide diet (Kim and Bae, 2018). A higher proportion of temperate phages would induce pathogenicity in commensal gut bacteria by disrupting the function of bacterial genes (Brüssow et al., 2004). Recently proposed theoretical models of phage-mediated dysbiosis have similarly suggested that temperate phages drive pathogenicity in otherwise commensal bacterial hosts when exposed to the stresses associated with a “Western” diet (Lin and Lin, 2019). Phages encode genes that support bacterial survival mechanisms at the expense of the human or animal host. These models also propose that the pathogenic behavior of these resident bacteria promotes inflammation in the gut epithelium, thus perpetuating the dysbiotic state.

Horizontal gene transfer (HGT) events are frequent in microbial communities. Such events are usually realized through mobile genetic elements (MGEs), and phages are important MGEs. Phage-mediated HGT occurs during phage infection of bacteria and lifestyle shifts between temperate and lytic states, promoting the exchange of genetic elements among the intestinal microbiota (Borodovich et al., 2022). An experiment in the mouse gut showed that the HGT causing the evolution of E. coli was driven by two phages hosted by resident strains. This demonstrating that phage-driven HGT is a key driving force for gut colonization and the ecological evolution of the community (Frazão et al., 2019).

It is speculated that diet can influence the process of HGT in the gut. Successive studies by Hehemann and colleagues found that the Japanese gut metagenome contained porphyrins and agarases that were not present in the metagenomes of other geographic populations (Hehemann et al., 2010). They suggested that this may be due to the Japanese dietary tradition of consuming seaweed. Such dietary tradition results in the gut microbiota acquiring enzymes from the symbiotic bacteria of marine algae through HGT, introducing these enzymes into new ecosystems where they may aid the digestion of these dietary compounds (Hehemann et al., 2012). Other studies have demonstrated that a high-fat diet induces changes in MGEs in obese mice and may consequently enhance the transmission of antibiotic-resistant genes (Wang et al., 2021). There is evidence to support the possibility that dietary effects on HGT may be mediated partly by the gut virome, e.g., dietary intervention alters the abundance of key genes of MGEs in the virome, such as integrases, transposases, and reverse transcriptases (Howe et al., 2016; Kim and Bae, 2016; Pärnänen et al., 2018). Dietary components such as polysaccharides (El-Gendi et al., 2023), polyphenols (Yang et al., 2012), and flavonoids (Alaoui et al., 2019) have been found to inhibit reverse transcriptase activity on viruses. These studies suggest that diet widely influences HGT and that phages in the gut virome are common MGEs with the potential to play a role in diet-induced HGT (Fig. 4).

Phage-mediated HGT increases the exchange frequency of virulence factors and genes involved in metabolic functions among host bacteria (Hurwitz and U’Ren, 2016; Penadés et al., 2015). It also allows the phage itself access to AMGs from the host bacteria (Sullivan et al., 2006). Researchers assembled relatively complete phage genomes from metagenomes and identified abundant AMGs from several phage families (Gallego and Leonardo, 2023). Some of the AMGs were homologous to certain genes in Firmicutes and Bacteroidetes bacteria (Qin et al., 2023), suggesting that they may originate from phage-infected host bacteria, and be transmitted between different bacteria by infection, while conferring new functions on the phage.

Viromes do not only shape the microbiota by infecting and consuming host bacteria, but they also carry many AMGs that play a role in regulating the microbiota while reshaping the host bacterial metabolic network and enhancing host metabolic levels (Table 1) (Thompson et al., 2011). Lytic phages usually carry a higher diversity of AMGs and tend to mobilize the key metabolic pathways of the host to use the energy and substrates for self replication (Howard-Varona et al., 2020), whereas temperate phages likely to encode AMGs to enhance the survival of the host bacteria (Luo et al., 2022).

Diet is one of the factors that modulate the number and function of AMG stores in the gut virome (Fig. 4). Differences in urban and rural diets may result in different functions encoded by the gut virome, with genes participating in pathways of amino acid and carbohydrate transport and metabolism being more abundant in the gut virome of rural populations (Monaghan et al., 2020). In animal experiments with high-fat plus high-sugar diets and normal diet controls, the gut virome of mice fed a high-fat plus high-sugar diet was enriched for lipid metabolism, amino acid metabolism, carbohydrate metabolism, and a number of disease-related metabolic pathways. The enriched virome contigs were mainly annotated with genes for sulfur proteins, peroxisomal enzymes, and membrane transporter and chromosomal-allocating proteins (Kim and Bae, 2016). It was also reported that, after treatment with a high-fat diet, the genes related to lysine metabolism on the mouse gut viral genome were significantly different from those on a normal diet (Schulfer et al., 2020), further confirming that dietary intervention leads to changes in AMGs.

Virus-carried AMGs have the potential to enhance dietary metabolism. The top three gut virus AMGs in a cross-sectional study of participants in Inner Mongolia were amino acid metabolism, cofactor and vitamin metabolism, and carbohydrate metabolism, in addition to a relatively high abundance of polysaccharide-degrading genes (Jin et al., 2023). These genes may contribute to metabolism and dietary adaptation of the host bacterium during the intake of amino-acid-rich or different-energy-source diets. Although there is no additional information to support the direct involvement of AMGs of human gut viruses in the transformation of dietary components, studies of mammalian digestive tract viromes have provided some insights. The pig gut virome carries a large number of enzyme-encoding genes. Sequence comparisons and the analysis of structural domains predicted more than 10 AMGs from at least seven viruses that were related to carbohydrate metabolism, sulfur metabolism, and cofactor biosynthesis. Among them, the highest levels were for glycoside hydrolases (GH25), carbohydrate esterases (CE3), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which may contribute to the degradation of complex polysaccharides in the pig intestine. Two AMGs (CobS and CobT) encoding cobaltochelatases were involved in the biosynthesis of the cofactor cobalamin (vitamin B12) (Qin et al., 2023). In addition, the abundance of methenyltetrahydrofolate cyclohydrolase (folD) and glycine hydroxymethyltransferase (glyA) AMGs suggests the presence of carbon metabolism to folate metabolism reprogramming in the pig gut virome. These results were similar to those observed in the bovine rumen (Anderson et al., 2017) and together suggest that virus-encoded AMGs, such as glycoside hydrolases, could potentially enhance degradation of complex carbohydrates to enhance energy conversion and dietary adaptation.

Viruses of dietary origin, especially plant viruses, are frequently found in the gut virome. A large and diverse community of plant RNA viruses can be detected in human stools, and one such virus, pepper mild mottle virus (PMMV), was even more prevalent in two-thirds of the individuals tested from both the North American and Southeast Asian continents in a descriptive study (Zhang et al., 2005). Many pepper-based foods were positive for PMMV, and it was hypothesized that the PMMV in the gut may have originated from pepper intake. It is no coincidence that a large number of plant viruses have been found in the gut viromes of Malaysian, Chinese and Pakistani populations, and plant virus species have been associated with specific diets (Lee et al., 2022; Yan et al., 2021). In addition, the majority of eukaryotic viral sequences detected in the gut virome of some healthy subjects and patients with irritable bowel syndrome also belonged to plant viruses, with the diet-driven abundance of Squash vein yellowing virus being demonstrated (Mihindukulasuriya et al., 2021). In experiments in which subjects were given short-term diets consisting of entirely animal or plant products, spinach was a key component of the plant diets served. Spinach-infecting Rubus green spot virus appeared only in individuals on plant-based diets and not in those on animal diets (David et al., 2014), again suggesting that plant viruses may reach the human gut via plant-based diets. Moreover, viruses of dietary origin remain active in the gut and can continue to infect their host plant (Zhang et al., 2005). Transcripts from a variety of plant viruses have been detected in the human gut (David et al., 2014). When peppers were infected with PMMV-positive feces, all inoculated plant leaves showed symptoms of PMMV post-infection. The potential risk to human health from diet-derived viruses is therefore worthy of attention (Balique et al., 2015).

The gut virome is widely involved in physiological state transitions in human health and disease (Cao et al., 2022; Garmaeva et al., 2019; Nishijima et al., 2022). The virome has been reported to be associated with inflammatory bowel disease (Sinha et al., 2022), Clostridium difficile infection (Zuo et al., 2018), obesity and diabetes (Yang et al., 2021), malnutrition (Khan Mirzaei et al., 2020), liver disease (Jiang et al., 2020), colorectal cancer (Johnson et al., 2015), and many other disorders, which emphasizes changes in body state as a result of the direct or indirect effect of the virome on bacteria. The regulatory of the diet cannot be ignored. A poor diet can exacerbate the development of disease states including obesity or diabetes (Khazrai et al., 2014), while diets such as the Mediterranean diet (Castro-Barquero et al., 2020; Dernini et al., 2017) or nutrient interventions (Liu et al., 2020) can treat or alleviate such diseases related to the gut microbiota. It is worth noting that the development or outcome of disease states as a result of diet may also be partially mediated by the virome.

The virome is involved in disease states resulting from poor diet, including Crohn’s disease, a subtype of inflammatory bowel disease (Torres et al., 2017). Crohn’s disease is influenced by genetics, dietary factors, and the gut bacteriome, and the gut virome has also recently been found to play a role. In a research program of 208 participants from two independent cohorts in Guangzhou and Kunming, China, patients with Crohn’s disease were found to have both reduced temperate phage and lytic phage in the virome and a lack of interactions between Bifidobacterium phage and Lachnospiraceae phage with their host bacteria (Cao et al., 2024). Interestingly, Crohn’s disease shows the opposite association to coffee drinking with both these viral species and virome function, suggesting that the protective effect of coffee drinking on IBD (Lee et al., 2014) may be partially attributable to its effects on the intestinal mucosal virome at both the compositional and functional levels. Similarly, alcohol may have a deleterious effect on Bacteroides phage, promoting blooms of Bacteroides fragilis, which may be associated with mucosal inflammation in Crohn’s disease.

A poor diet can lead to malnutrition (Mehta et al., 2013), including nutrient shortage and obesity, and increasing evidence supports a bridging role for the virome within this malnourished state. Malnutrition is the leading cause of death in children under 5 years of age in middle- and low-income countries, and is associated with a poor diet lacking in protein, energy, and vitamins (Müller and Krawinkel, 2005). The gut virome has been found to play an important role in malnourished children. A positive correlation between bacterial richness and phage richness was found in the gut of a longitudinal prospective cohort of rural Malawian children with adequate/moderate growth, which was lacking in children with poor growth (Desai et al., 2020). This suggests that dysbiosis between bacteria and phage communities may be associated with poor growth due to dietary deficiencies. Significant changes occurred in the gut virome of multiple micronutrient-deficient mice compared with mice fed an isocaloric control diet, including enrichment of Herelleviridae, Marseilleviridae, and Microvirdae (Littlejohn et al., 2023). Obesity and diabetes possibly caused by overnutrition have also been reported to be associated with the virome. For example, 11 viruses enriched in obese individuals and 17 differential phages between controls and obese people with type 2 diabetes (ObT2), as well as reduced viral-bacterial cross-border interactions in ObT2 individuals, were found in a case-control cohort containing 229 individuals from Hong Kong and Kunming, China (Yang et al., 2021). In a study of the gut virome related to fat intake, transplantation of VLPs from mice on a low-fat diet to mice on a high-fat diet resulted in slower weight gain and lower oral glucose tolerance in high-fat mice (Rasmussen et al., 2020). Transplantation of VLPs also reduced the overgrowth of small intestinal bacteria induced by the high-fat diet in mice (Lin et al., 2019), suggesting that the virome plays some role in obesity and gut microecological imbalance induced by the high-fat diet and the effect can be reversed by transplanting the gut virome from lean individuals into obese individuals.

Dietary or nutrient interventions for the treatment of disease have been widely reported, and many also state observed changes in the virome or the implied role of the virome. Many veterans who fought in the 1990-1991 Gulf War developed chronic fatigue, somatic pain, diarrhea, and other symptoms, designated Gulf War illness (Saha et al., 2021). A study found that oral intake of an active ingredient of Andrographis paniculata restored the altered gut-brain axis-related pathology and bacteriome associated with Gulf War illness, and the virome families, Siphoviridae and Myoviridae, which are associated with gastrointestinal pathology, were significantly reduced. As another example, alcohol use disorder (AUD) is a poor drinking pattern frequently coexistent with psychiatric disorders such as depression (McHugh and Weiss, 2019). Individuals with this disorder often consume large amounts of alcohol regardless of the numerous adverse consequences of alcohol consumption and are predisposed to liver disease due to excessive alcohol intake (Ramkissoon and Shah, 2022). Alcohol control ameliorates steatosis represented by liver disease within 2-4 weeks, a process which involves gut phages. The decreased abundance of Propionibacterium, Lactobacillus, and Leuconostoc phages was observed in the gut virome of 62 AUD patients compared with controls during active drinking, whereas an increase in these phages was observed in the gut virome of AUD patients after 2 weeks of alcohol cessation (Hsu et al., 2022). To date, however, studies on the involvement of the gut virome in dietary regulation of human health have mostly focused on virome changes in response to dietary interventions, with the role and mechanistic function of the virome requiring further research.