Bacteriophages and inflammation: Very interesting read

Mediators of Inflammation
Volume 2019, Article ID 3730519, 14 pages
https://doi.org/10.1155/2019/3730519

3.2. Phage-Mediated Alterations in the Intestinal Bacterial Communities: Implications for Immune Disorders

Despite the prevalence of lysogeny in the gut, there is growing evidence that phage predation can shape microbial communities in this environment [75–79]. Reyes et al. staged a “phage attack” of isolated virus-like particles (VLPs) from the feces of 5 unrelated volunteers to germ-free mice colonized with a collection of 15 bacterial isolates. Following phage administration, changes in the relative abundance of members of the bacterial community could be detected, suggesting that gut-derived phages were still infectious [75]. Using a similar approach, Hsu et al. colonized germ-free mice with a mock community of 10 known bacterial isolates before administering phages specific to a subset of these bacteria. They concluded that phage predation had cascading effects on the microbiota due to knockdown of susceptible species and subsequent disturbances to networks of interbacterial interactions. Further, these phage-induced changes of the microbiota were sufficient to alter the concentrations of a number of bacterial-derived metabolites, including neurotransmitters, amino acids, and bile salts [77].

These phage-mediated changes of gut bacterial communities could have downstream effects on immune signaling by allowing for the proliferation of proinflammatory or pathogenic microorganisms or altering the production of immunomodulatory bacterial-derived products (Figure 2(a)). The detection of bacterial DNA systemically following oral phage administration supports the idea that phage-mediated cell lysis could be responsible for the release of immunostimulatory pathogen-associated molecular patterns (PAMPs) [80]. With increased gut permeability, these PAMPs could translocate the epithelial layer and cause immune activation (Figure 2(a)) [80].

Both phage and bacterial communities have been shown to be altered in the context of intestinal inflammation [10, 50, 51, 81, 82]. Norman et al. concluded that the increase in Caudovirales and the expansion of overall phage richness observed in IBD patients were not driven by increases in bacterial richness [50]. The authors also found significant associations between the expansion of Caudovirales and specific members of the bacterial community [50]. These findings suggest that changes in the bacterial community associated with IBD could be driven by an imbalance of phages infecting these bacteria. In line with this hypothesis, Cournault et al. found that phages which infect the bacterium Faecalibacterium prausnitzii were elevated in the feces of IBD patients [83]. Since levels of F. prausnitzii, a producer of the SCFA butyrate, are depleted in the gut of IBD patients, the expansion of phages infecting these bacterial taxa could contribute to its loss and increased inflammation during the course of disease [84]. Similar associations have been made in Parkinson’s disease (PD), where the gut microbiota has been implicated in disease progression through the regulation of inflammatory responses and subsequent interactions with the enteric nervous system [85–88]. In PD patients, there is an increase in lytic Lactococcus phages and a corresponding decrease in Lactococcus bacteria, which have been shown to be potent inducers of anti-inflammatory responses and involved in the production of neurotransmitters [52]. Most recently, Tetz et al. found that children who presented seroconversion or developed Type 1 diabetes (T1D) had a high abundance of lysogenic E. coli phages compared to their bacterial hosts [54]. Interestingly, these data could suggest that prophage induction could cause release of DNA-amyloid complexes and trigger autoimmune cascades leading to T1D development [54].

The findings mentioned above show clear associations between altered phage and bacterial communities, and inflammatory diseases. Additional studies will need to identify factors that influence the changes in phage communities during disease. Different diets and specific dietary components have now been shown to shape the intestinal phage communities and the phageome [33, 89, 90]. Xenobiotics have also been shown to increase the expression of prophage induction genes, which could have widespread effects on bacterial and phage community composition [91]. Given that KtW or predator-prey interactions between phages and their hosts are most prevalent in early childhood, the infant phageome may be key in driving the appropriate maturation of the gut microbiota. Understanding the factors that shape the initial phage community during early childhood will provide insight into how microbial imbalances and their associated inflammatory diseases develop.

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