Commensal virus to the rescue

We all heard about gut microbiome and how an important job they do to keep us healthy. Still, there is the situations when the antibiotic therapy is necessary. 

Since many beneficial microbes in our gut are sensitive to broad spectrum antibiotics used in today's medicine, such treatment could lead to dysbacteriosis and gut inflammation. Now, beneficial microbiome therapy (fecal transplantation) is an obvious option, but such therapy could be inefficient due to the fact that such flora itself is sensitive to antibiotics. So what is the solution?

It appears that some friendly viruses in the gut could provide such beneficial, cover effect. Such study, led by Ken Cadwell from New York University School of Medicine, was recently published in journal Nature.

The authors studied the murine norovirus (MNV). This virus is endemic in laboratory mice colonies but does not produce an overt gut inflammation in a immune-competent host. 

Reconstitution of germ-free mice with MNV produced changes in the gut morphology and immune cells resembling conventional mice gut. 

More relevant, MNV could reverse antibiotic-induced negative effects on gut immune system.

Mechanistically, such beneficial effect of MNV on gut immune system was type I IFN dependent.

Finally, MNV could prevent antibiotic-induced gut sensitivity to chemical damage (DSS).

In summary, the authors showed that viral therapy could be an viable alternative (since virus would not be sensitive to antibiotic itself) to treat or prevent antibiotic-induced gut immune malfunctions.

Of course, application of this study to human population would require additional research. 

First, human Norovirus is clearly not a benign virus (cruise ship virus). So we need to find the virus that does not induce an overt gut inflammation in healthy humans. 

Second, this study examined immune-competent mice. However, analyses of immune-deficient mice responses to NMV would be more informative since in humans, antibiotic therapies are frequently used to compensate for immune deficiencies.

Third, if gut commensal, beneficial viruses exist, they should naturally (automatically) take over the beneficial microbes functions during antibiotic treatment. Do they do it?

Fourth, recent studies indicated that viruses, including MNV, require the presence of bacteria for their infectivity. How this knowledge affects the results of this study is to be determined.

David Usharauli

microbiota greenlights brain inflammation

For the past few years published literature in immunology became enriched in studies related to commensial microbiota found mainly in mammalian gut. There is one simple explanation for this renewed interest in commensial microbiota: discovery and characterization of Toll-like receptors (TLRs) in late 90's (recognized by Nobel prize in Physiology or Medicine 2011). TLRs opened the door to study microbiota-host interaction at molecular level and made it easy to explain experimental observations mechanistically. In general, commensial microbiota could influence immune system in two ways: first, it could provide the antigenic material for adaptive immune system activation (T or B cells activation) and second, it could provide TLR ligands for innate immune system activation.

If you are interested to know more about commensial microbiota-host interaction, I will recommend to read the following article recently published in Nature. This study by Kerstin Berer et al. (1), examined the effect of commensial microbiota on the development of brain autoimmune disease in SJL/J TCR transgenic mice. In this mouse, if housed in a regular laboratory mouse facility, brain inflammation occurs spontaneously and is mediated by combined effect of MOG-specific T cells and B cells. However, according to this study, this type of brain inflammation does not occur in this mouse made germ-free (in sterile, microbiota free state). The disease development in this mouse require the presence of MOG protein because in its absence there is no brain inflammation irrespective of presence of absence of commensial microbiota. This results suggest that microbiota provide antigen-independent effect leading to stimulation of MOG-specifc T and B cells. However, how microbiota does it is not clear. The authors showed that there is reduction of IL-17 producing T cells in the gut of germ-free mouse. However, the authors provide no direct evidence whether IL-17-producing T cells play any role in disease development.

David Usharauli