A variety of conditions that occur simultaneously and increase the risk of heart disease, stroke, and T2D are referred to as metabolic syndrome. These conditions include increased blood pressure, hyperglycemia, excess body fat around the waist, and elevated cholesterol or triglyceride levels ^[1][47]. The main factor influencing the development of metabolic syndrome is diet, which has been reported to affect the GM, including the GV ^[2][15].

Since the GM is a relevant player in the development of metabolic syndrome, it is reasonable to think that phages infecting these bacteria may also play an important role in metabolic syndrome by regulating such bacterial populations ^[3][49]. A recent study has shown that metabolic syndrome is associated with decreases in GV richness and diversity in a manner correlated with bacterial population patterns ^[3][49]. Dietary changes that cause a reduction in bacterial diversity have a direct consequence on GV diversity because there are bacterial species that are depleted from the GM and are therefore less accessible for predation by viruses. A recent study found that phages infecting Ruminococcaceae, Clostridiaceae, Bacteroidaceae, and Streptococcaceae predominated in the GV of patients with metabolic syndrome, whereas Bifidobacteriaceae phages were less abundant in patients with metabolic syndrome than in control samples ^[3][49]. Such results could reflect unequal predation by phages among the corresponding bacterial families in the gut ^[3][49]. This fact is interesting because bacteria of the genus Bifidobacterium inhibit the colonization of harmful intestinal bacteria, regulate the immune system, and exhibit anti-obesity and anti-inflammatory activities, thus preventing the progression of metabolic syndrome ^[4][57]. The identification of Bifidobacteriaceae species and their phages as more abundant among healthy controls is in line with established studies showing the depletion of these families in metabolic syndrome ^[5][58] and disease states associated with metabolic syndrome ^[6][59].

Furthermore, viral phages were significantly more prevalent in the GV of controls than in metabolic syndrome patients ^[3][49]. This apparent depletion of viral phages in GVs from metabolic syndrome patients may indicate a decrease in their infectivity and could be considered a link between this prominent human gut phage order and a disease state ^[3][49]. In contrast to what was reported by ^[3][49], the richness and diversity of the GV of children with metabolic syndrome were higher than those of normal-weight children without metabolic syndrome, along with an increased abundance of Myoviridae ^[1] (Table 1)[47].

Obesity and diabetes are two forms of metabolic diseases that are highly prevalent worldwide [31]. In recent decades, there has been substantial evidence that abnormalities in GM composition can play a major role in the development of both diseases, although most evidence refers to gut bacterial composition and activities ^[34][66]. However, recent findings found significant differences in some viral families between obese and diabetic patients with respect to healthy patients in children ^[28][32][43,44] and mouse models ^[35][67].

A recent study found that both viral richness and diversity in the GV were lower than those found for lean subjects and in obese patients with T2D compared to lean controls [31]. Surprisingly, these results are contradictory to those previously reported by Ma et al. ^[23][45], who found a higher phage richness in T2D patients than in nondiabetic controls, as well as an increased relative abundance of the families Siphoviridae, Podoviridae, and Myoviridae and the unclassified order Caudovirales in T2D patients ^[23][45]. Previous Enterovirus infection was found to be a risk factor for T1D in children ^[28][43]. Afterward, another study showed a higher prevalence of the families Circoviridae and Picornaviridae in T1D pediatric patients than in healthy children ^[32][44]

High-fat-diet-induced obese mice showed a significant reduction in the family Siphoviriade and an increase in the virus families Microviridae, Phycodnaviridae, and Miniviridae in the fecal virome ^[29][65]. Rasmussen et al. ^[35][67] proposed GV modification as a potential therapeutic strategy against T1D and obesity. To verify this hypothesis, VLPs were transferred from slim mice to high-fat diet-induced obese mice, and as a result, weight gain and diabetes symptoms significantly decreased in obese mice ^[35][67].

Regarding viral species, 17 were found to have significantly different proportions in obese and diabetic subjects compared with lean subjects ^[29][65]. Among them, 4 viral species (Micromonas pusilla virus, Cellulophaga phage, Bacteroides phage, and Halovirus, unclassified DNA viruses) were higher in obese and T2D patients, whereas 13 viral species, including Hokovirus, Klosneuvirus, and Catovirus, were lower in obese-plus-T2D subjects with respect to lean controls ^[29][31][31,65].

Malnutrition is a global health problem that affects large numbers of individuals regardless of age, gender, race, social status, and geographic boundaries. It can be defined as an imbalance between energy and nutrient intake and the individual’s requirements, which can alter body measurements, compositions, and functions ^[36][68]. Children with malnutrition have been reported to have an immature gut GM composition compared to those without malnutrition. This lack of maturity in their GM is characterized by a lower α-diversity of the GM as well as a disproportionate expansion of the phylum Proteobacteria ^[37][69]. Similarly, disruption of the GV, including that of intestinal phages and eukaryotic virus members, could increase the risk of severe acute malnutrition ^[27][64]. A recent study found that phages of the order Caudovirales contributed differentially to stunted growth in malnutrition induced by environmental enteric dysfunction ^[12][37]. As the phylum Proteobacteria exists in a higher proportion in the GM with malnutrition relative to that of children without stunting and as Caudovirales phages (especially Siphoviridae) have Proteobacteria as one of the main bacterial hosts ^[38][70] and are also present in greater numbers in malnourished children than in healthy children, there might be a cooccurring phage-bacterial dynamic in the gut of stunted children ^[39][14], with both viruses/phages contributing to the severity of malnutrition.

The liver is a very important pivotal organ for host metabolism and maintains bidirectional communication with the gut via the gut–liver axis ^[20][61]. Thus, the liver plays a central role in the pathogenesis of several metabolic diseases. Recent works have investigated the potential changes in GV linked to liver diseases such as alcoholic hepatitis ^[18][51], NAFLD ^[20][61], and bile acid metabolism ^[9][50]. Additionally, although it is not a liver disease itself, the potential changes in the GV in response to the high intake of fructose are also important ^[26][63]. Beyond its lipogenic effect, fructose intake is also related to hepatic inflammation and cellular stress, such as oxidative and endoplasmic stress, which contributes to the progression of simple steatosis to nonalcoholic fatty liver disease ^[40][71].

In the case of NAFLD, patients with a more severe disease showed lower viral diversity than patients with a lower degree of disease or healthy controls ^[20][61]. At the same time, the proportion of phages among the total GV was also significantly lower in the case of severe NAFLD patients than in the less severe cases of the controls ^[20][61].

Regarding fructose intake, fructose increases the growth of Lactobacillus reuteri, a key important bacterial species considered an important lysogen, which are bacterial prophages inserted within their genomes that promote phage production ^[26][63]. Due to its higher sweetening power, fructose is one of the most abundant sugars consumed in a Western-style diet and results in more pronounced fructose-mediated phage production by L. reuteri than the intake of other sugars ^[26][63].

In the case of alcoholic liver disease, disease-specific alterations in the GV were reported, and gut viruses were identified as potent drivers of alcohol-specific liver disease ^[18][51]. In contrast to NAFLD, in alcoholic liver disease, increased viral diversity was found in patients with alcoholic liver disease, especially in those with a higher degree of alcoholic hepatitis ^[18][51]. Regarding viral proportions, the authors found an increase in eukaryotic viruses such as Parvoviridae and Herpesviridae, along with increases in intestinal phages such as Enterobacteriaceae phages, Escherichia phages, and Enterococcus phages in patients with alcoholic liver disease compared to controls ^[18][51]. Both Parvoviridae and Herpesviridae may be found in higher proportions in NAFLD subjects because they may have a depressed immune system or because the medication administered to them indirectly causes increased replication of the viruses in host cells ^[18][51]. The latter aspect regarding the relation of GV and hepatic disease is the relation of the activity of the Bacteroides phage BV01, a temperate phage integrated into Bacteroides vulgatus, a species that can repress the microbial modification of the bile acid pool in the host, which could be linked to beneficial changes in human host metabolism ^[9][50].

Although the relationship between the GV and some types of cancer, such as metastatic melanoma ^[41][56] or adenoma ^[15][60], has been investigated, most works on the relationship between the human GV and cancer have focused on colorectal cancer (CRC) ^{[15][16][22][25][42]}[52,53,54,55,60], which is logical since it is the type of cancer that has the most direct contact with the intestinal virome. According to Wong and Yu ^[43][72], CRC is related to modifications in the GM, in which some bacterial genera, such as Roseburia, are potentially protective taxa, whereas other genera, such as Bacteroides, Escherichia, Fusobacterium, and Porphyromona, are considered procarcinogenic agents.

Metagenomic analysis of stool samples from CRC patients revealed an increase in the richness and diversity of the intestinal GV with respect to control patients ^[15][22][25][53,54,60]. In another case, it was found that the differences between CRC patients and controls were insufficient for identifying specific virome communities between healthy and cancerous states ^[16][52]. The fact that phage richness is higher in CRC patients was hypothesized to be due to an increase in intestinal permeability, known as a “leaky gut”, caused by this phage, which facilitates the infiltration of pathogens and triggers chronic inflammation ^[44][73]. Another study found that phages, especially those from the families Siphoviridae and Myoviridae, are vital driving factors during the transformation from a healthy intestine to intestinal adenocarcinoma and to CRC ^[3][49].

In another work, the families Inovirus and Tunalikerirus were related to the development of CRC due to their capacity to insert random oligonucleotides into the bacterial genome, stimulating the production of bacterial biofilms and thus contributing to the carcinogenesis of the colon ^[45][74]. Both families are known to infect gram-negative bacterial hosts, including enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and genotoxic Escherichia coli, bacterial species often implicated in CRC development ^[25][53].

Another recent study of the GV in bulk from CRC patients reported significant reductions in Enterobacteria phages and CrAssphages compared to healthy controls ^[15][60]. Some viral species were reported to have the potential to act as discriminant markers of CRC; Orthobunyavirus, Tunalikevirus, Phikzlikevirus, Betabaculovirus, and Sp6likevirus were the viral genera with significantly higher abundances in CRC patients than in control patients ^[25][53].

Upon investigating primary tumor tissues of CRC, phages were found to be the most preponderant viral species, and the main families were Myoviridae, Siphoviridae, and Podoviridae ^[22][46][54,75]. The most frequently detected eukaryotic viruses include human endogenous Retrovirus K113, human Herpesviruses 7 and 6B, Megavirus chilensis, Cytomegalovirus, and Epstein-Barr virus ^[22][54]. A higher relative presence of human papillomavirus was also found in CRC versus non-CRC tissues ^[47][76]. Additionally, it was also shown that Epstein-Barr virus infection could contribute to CRC development by inducing mutagenesis in intestinal cells ^[22][54].