Although alterations of the microbiota are known to be crucial for the development of such pathologies, previous studies focused on the roles of bacteria, fungi, and eukaryotic viruses, while bacteriophages were not considered to play a role in human health [20,21,22,23,24,25].

Human body sites are not as sterile as previously thought and data from phage diversity studies showed that this diversity tends to be very different between ecological niches. The amount of uncharacterized, unknown, and abundant phage populations described in the late years in metagenomics studies highlighted the emergent need to characterize bacteriophages and disclose their role in human health and disease (Hyman and Abedon, 2012). Phages were previously expected to be found everywhere their bacterial host is present, but recent studies [give] strength to the possibility of phage translocation through the human body (Górski et al., 2006; Brown-Jaque et al., 2016; Tetz and Tetz, 2018).

1. Bacteriophages as Human Viral Pathogens
Causes of bacteriophage infections encompass bacterial viruses that are present in humans and are harmless under normal conditions, but can become pathogenic under certain circumstances. This can be due to an increased translocation (for example due to impaired intestinal permeability caused by any underlining condition) of phages to biological fluids, leading to profound direct phage interactions that normally do not occur. Another cause is an increase in the numbers of prophages or free lytic phages as a result of a shift in the microbiota [88,96]. Furthermore, certain mutations in prophage genes that arise within the human microbiota can lead to the formation of viruses able to overcome bacterial defense systems, for example, the so-called Abi-escape phage mutants [73]. Finally, we suggest that an individual can be more or less susceptible to bacteriophage infection under certain circumstances. Notably, the alterations in susceptibility are realized on the levels of macroorganism or microbiota sensitivity to phages, which can be altered by a variety of different factors.
In another way of indirect interaction, phages can affect human hosts through the induction of increased intestinal permeability. We were the first to show that bacteriophages could induce leaky gut and an impaired intestinal barrier with an elevated lactulose/mannitol ratio, due to a cascade of microbiota alterations finally resulting reduced Lactobacillus spp. and Feacalibacterium spp., which are important regulators of the intestinal barrier [19,20]. The phage-induced intestinal permeability was accompanied with an increase in plasma endotoxin concentrations and elevation of inflammation-related cytokines, reflecting chronic inflammation. The fact that phages have been previously overlooked as a cause of increased intestinal permeability is notable as leaky gut is a well-known trigger of various poly-etiological diseases associated with chronic inflammation and underlies the development of various multifaceted diseases, such as AD, PD, amyotrophic lateral sclerosis, chronic fatigue syndrome, diabetes, autism, and certain cancers [74,75]. Moreover, phage-induced altered gut barrier results in phagemia and the circulation of phages in the CSF contribute to phage interplay with human cells and proteins that normally are not exposed to phages.


2. Natural Occurrence of Escherichia coli-Infecting Bacteriophages in Clinical Samples
A total of 111 samples were screened for the presence of lytic bacteriophages infecting E. coli DSM 12242 (Table 1). Coliphages were detected in 16 samples, representing a prevalence of 14.4% in the body fluids analyzed. Phages were more commonly found in blood (23.8%), followed by urine (20.5%) and tracheal aspirates (6.1%). No coliphages were found in other samples analyzed (abdominal, lung, pleural, shoulder and knee fluid, nasal swabs, IV catheters). From 88 samples, 16 were positive for the presence of E. coli, with bacterial counts ranging between 1,65 × 107 and 3,45 × 1012 CFU/ml. From these 16 samples, in 5 of them lytic phages were concomitantly isolated. In fact, a statistically significant association between the absence/presence of E. coli and the presence/absence of coliphages in the sample was determined (p = 0.016).
No bacterial antimicrobial resistance gene, toxin or virulence determinant were found in the phage genomes.