O-antigen component of the LPS of Gram-negative bacteria (Van Belleghem et al.
2018).
The critical role of phages in modulating the composition of the microbiota is
suggested by several observations. First, there is evidence that phages bind to
intestinal mucus via Ig-like domains, and contribute a layer of phage-mediated
immunity. Moreover, the rate of replication of different organisms in the gut is
enormously varied (Korem et al. 2015), and it seems likely that phages are at least
partly responsible. Differing replication rates can potentially lead to misinterpretations of the relative importance of bacterial species. An organism that is present in
low numbers because rapid proliferation is counteracted by rapid phage-mediated
lysis might be providing more signals to the physiology of the human host than an
organism present in greater numbers, with a low replication rate and low turnover.
More evidence of the crucial role of phages is provided by the observation that
Clostridioides difficile infection can be treated using sterile faecal filtrates (Ott et al.
2017). This study did not identify the components of the sterile filtrate responsible
for the cure, but phages must be strong candidates. Alcoholic liver disease provides
another example. This condition is partly mediated by a cytolysin released by certain
strains of Enterococcus faecalis. In a mouse model bacteriophages that specifically
targeted cytolytic E. faecalis abolished alcohol-induced liver disease (Duan et al.
2019). Finally, compared to matched healthy controls, children who developed
autoantibodies characteristic of T1D (type 1 diabetes), or who developed clinical
disease, had less diverse bacteriophages in their guts and less species richness (Zhao
et al. 2017).
So could the natural environment influence our gut bacteriophages, and if so,
how? We know that there are about 10
9 phages/g of soil (Batinovic et al. 2019), and
they are also found in drinking water where their presence is used as a test for water
purity and for contamination with human-derived waste. Phages are found on all
body surfaces including the skin, airways, urinary tract, and gut, and they can
penetrate epithelial surfaces via rapid transcytosis and enter eukaryotic cells. They
also enter the circulation. It is suggested that every day ~30 billion bacteriophage
particles cross the gut epithelium and enter human tissues (Van Belleghem et al.
2018), and many phages can be identified in human blood. Therefore, phage intake
from the natural environment must be massive, and likely to include phages of
human gut-adapted bacteria and archaea. These phages could directly modify the
composition of the gut microbiota (Fig. 18.2).
However, there is a second potential mechanism. Phages induce an immune
response, and phage-neutralising antibodies are commonly found in the blood of
humans and other animals (Fig. 18.2). Specific IgA in the gut, but also IgG and IgM
can all inactivate phages and decrease the titre of active phages in the faeces (Van
Belleghem et al. 2018). It is therefore possible that antibody-mediated disturbances
of gut phage populations might be one way in which dysbiosis can occur. Could
contact with the vast variety of phages in the natural environment affect control of
gut phages by the immune system? It is at least possible that intake of phages,
especially during early life, might modify the immune response to phages, and
18 Darwinian Medicine: We Evolved to Require Continuing Contact with the. . .
351
2018).
The critical role of phages in modulating the composition of the microbiota is
suggested by several observations. First, there is evidence that phages bind to
intestinal mucus via Ig-like domains, and contribute a layer of phage-mediated
immunity. Moreover, the rate of replication of different organisms in the gut is
enormously varied (Korem et al. 2015), and it seems likely that phages are at least
partly responsible. Differing replication rates can potentially lead to misinterpretations of the relative importance of bacterial species. An organism that is present in
low numbers because rapid proliferation is counteracted by rapid phage-mediated
lysis might be providing more signals to the physiology of the human host than an
organism present in greater numbers, with a low replication rate and low turnover.
More evidence of the crucial role of phages is provided by the observation that
Clostridioides difficile infection can be treated using sterile faecal filtrates (Ott et al.
2017). This study did not identify the components of the sterile filtrate responsible
for the cure, but phages must be strong candidates. Alcoholic liver disease provides
another example. This condition is partly mediated by a cytolysin released by certain
strains of Enterococcus faecalis. In a mouse model bacteriophages that specifically
targeted cytolytic E. faecalis abolished alcohol-induced liver disease (Duan et al.
2019). Finally, compared to matched healthy controls, children who developed
autoantibodies characteristic of T1D (type 1 diabetes), or who developed clinical
disease, had less diverse bacteriophages in their guts and less species richness (Zhao
et al. 2017).
So could the natural environment influence our gut bacteriophages, and if so,
how? We know that there are about 10
9 phages/g of soil (Batinovic et al. 2019), and
they are also found in drinking water where their presence is used as a test for water
purity and for contamination with human-derived waste. Phages are found on all
body surfaces including the skin, airways, urinary tract, and gut, and they can
penetrate epithelial surfaces via rapid transcytosis and enter eukaryotic cells. They
also enter the circulation. It is suggested that every day ~30 billion bacteriophage
particles cross the gut epithelium and enter human tissues (Van Belleghem et al.
2018), and many phages can be identified in human blood. Therefore, phage intake
from the natural environment must be massive, and likely to include phages of
human gut-adapted bacteria and archaea. These phages could directly modify the
composition of the gut microbiota (Fig. 18.2).
However, there is a second potential mechanism. Phages induce an immune
response, and phage-neutralising antibodies are commonly found in the blood of
humans and other animals (Fig. 18.2). Specific IgA in the gut, but also IgG and IgM
can all inactivate phages and decrease the titre of active phages in the faeces (Van
Belleghem et al. 2018). It is therefore possible that antibody-mediated disturbances
of gut phage populations might be one way in which dysbiosis can occur. Could
contact with the vast variety of phages in the natural environment affect control of
gut phages by the immune system? It is at least possible that intake of phages,
especially during early life, might modify the immune response to phages, and
18 Darwinian Medicine: We Evolved to Require Continuing Contact with the. . .
351