Further evidence that the microbiome can improve melanoma cancer therapy

T stages of melanoma

Yesterday we discussed a paper that discussed how the microbiome impacted a melanoma cancer therapy.  In the same issue of Science another article was published where researchers from Chicago independently made a similar discovery - that the microbiome itself can impart an anti-tumor effect on melanoma.

The scientists were using a  common mouse model for melanoma between two different laboratories (Taconic Labs and Jackson Labs) when they noted that the cancer progressed much differently between the labs.  The Taconic mice had more aggressive cancer than the Jackson mice.  They hypothesized that one possible difference between the mice in the two labs were their microbiomes.  In fact, when the Taconic mice were given the Jackson mice's microbiomes, the Taconic mice's cancer grew more slowly.  The scientists then attempted to identify which bacteria were having the effect.  They compared the mice's microbiomes and discovered that Bifidobacteria were much more abundant in the Jackson mice.  Upon treating the Taconic mice with strains of Bifidobacterium longum and Bifidobacterium breve the Taconic mice's cancer grew more slowly.  Interestingly, the scientists discovered that the bacteria were likely increasing the activation of T-cells, because mice that had mutated T-cells did not have the microbiome-mediated anti-cancer effect.

This study points to an exciting role of the microbiome in mediating and activating the immune system to attack and destroy some cancers.  The researchers note that there are likely other microbiome bacteria that have this effect, but that they have only identified the Bifidobacteria.  Hopefully the scientists will be able to measure the effect in humans, and observe an association between patient outcome and the presence and absence of certain gut bacteria.

Melanoma cancer therapy’s efficacy may depend on the existence of specific gut bacteria

Ipilimumab is a monoclonal antibody (mAb) that binds to, and activates T-cells. (Technically, the drug binds to the CTLA-4 receptor on T-cells, which decreases T-cell suppression)  It is currently an approved therapy for the treatment of metastatic melanoma.  Unfortunately, activation of the immune system can damage the microbiome, and taking iplimumab often results in adverse side effects in the gut, such as diarrhea.  Scientists from France were studying the effect of the drug on the microbiome when they discovered that its efficacy was actually dependent on the presence of certain gut bacteria.  They published their results in the journal Science.

First, the scientists administered the ipilimumab to three groups of mice that had been given cancer through an established model.  One group of mice had a normal microbiome, the second group was germ-free, and the final group had a normal microbiome, but then were given antibiotics.  Surprisingly, the mAb activated much fewer T-cells and was much less effective in destroying the cancer in the mice that were germ free and had been given antibiotics compared to the normal mice.  In addition, the scientists noted that intestinal inflammation occurred in the normal mice, but less so in the others.  Next, the scientists measured the microbiome changes as a result of administration of the mAb, and observed a rapid decrease in Bacteroidales, Burkholderiales, and an increase in Clostridiales.  The scientists then inoculated cancerous mice with specific bacterial species prior to administration of the drug, and then measured the drug’s efficacy.  Remarkably, specific species, such as Bacteroides thetaiotaomicron were able to reestablish the drug’s therapeutic potential and decrease inflammation.

The microbiome’s complex dynamic with the immune system once again presents itself, this time by modulating the efficacy of ipilimumab.  The scientists did do some work on humans, and they noted that not all human patients suffering from melanoma and taking ipilimumab have those beneficial bacteria in their stool.  The scientists did not discuss whether their existence was associated with the cancer’s progression in humans, although it would be interesting to see.  Ipilimumab is just one of many drugs that use the immune system to attack cancer.  Continued research is needed on the microbiome’s impact on these drugs.

Our gut microbiome may be contributing to some forms of blindness

Our eyes are considered ‘immune privileged’, which means that they are generally protected from our own immune system.  The major mechanism for eye immune privilege comes from a tight physical barrier that separates our lymphocytes, such as T cells, from the actual eye.  T cells do have the ability to cross this barrier, but they first must come in contact with, and be activated by eye antigens.  These antigens are sequestered on the opposite side of the barrier, in the eye, so that they are not exposed to the T cells.  There are diseases in which these retinal T cells do mysteriously become activated though, and they cause an inflammatory disease known as uveitis.  Uveitis is responsible for causing blindness and other eye issues in many people, but again the cause for the T cell activation is largely unknown.  Researchers at the NIH recently created a mouse model for uveitis, and were able to test a variety of factors that may be activating the T cells.  To their surprise, the gut microbiota seemed to be activating the T cells.  They published the results of their study last week in the journal Immunity.

The researchers first created a mouse model of uveitis where the retinal T cells spontaneously become activated.  They then noticed that the highest concentration of these T cells were near the gut, suggesting the gut bacteria were playing a role.  The scientists then treated the mice with antibiotics to decrease the gut bacterial concentration.  Although the mice still developed some symptoms of uveitis, the disease was ameliorated greatly in these mice.  As previously discussed, the normal T cell activator antigen is in the and physically separated.  In order to ensure that this antigen wasn’t somehow leaking out of the eye to activate the T cells in their model they created mice that lacked these antigens in their eye.  Still though, the mice presented symptoms of uveitis, meaning that the antigen that is activating the T cells is not from the eye, but rather is being produced somewhere else, such as the gut.  In order to firmly prove the gut bacteria’s role, the scientists showed that T cells could be activated by specific proteins from gut bacteria.  In fact, germ free mice, which otherwise would not have an ocular inflammatory response in their model, showed strong uveitis when they were given just the protein extract from other wild type mice. 

This research is the first to connect the gut microbiome with ocular autoimmune inflammation.  It presents many questions as to how to therapeutically combat this disease, perhaps through monitoring the gut microbiota for presentation of antigens that could activate these retinal T cells.  It also begs to be connected with other sites immune privilege breakdown in the body.  The fetus and placenta in pregnant women, for example, is an immune privileged space.  Immune activation of this site can sometimes lead to miscarriage.  Are gut or vaginal bacteria involved with this response, as we have discussed a few times in this blog?  In time, scientists will know enough to accurately answer this question.

Scientist culture critical gut bacteria

Example of a segmented filamentous bacteria.

Scientists from France recently announced in Nature that they had successfully cultured segmented filamentous bacteria (SFBs) for the first time.  These bugs likely exist in the intestines of all mammals, including humans, and research has shown they may be amongst the most important commensal bacteria we have.  Previous research has shown that the existence and abundance of SFBs is directly linked to the induction and recruitment of immunity cells, like T cells.  The SFBs exist right on the mucosal boundary of the gut and appear to intimately interact with it.  This close interaction allows the bacteria to use the gut to survive, but also to send molecular signals to the body.

The scientists were able to culture the bacteria by first culturing epithelial cells (i.e. the cells that line the gut) and then culturing the SFBs in close proximity.  During their experimentation they discovered that the bacteria grew best when they were physically touching the epithelial cells, but that they could survive so long as they were close by.  The scientists also discovered many of the important requirements for successful colonization and growth of SFBs, and we invite anyone interested in learning more to read the article.

While the results of this study may not sound very exciting to the lay-man, they are in fact significant.  If these SFBs turn out to indeed be a critical component to mediating the immune system, being able to culture and perform experiments on them in the lab will be essential.  Future studies could possibly identify the key molecules that are critical in signaling host immunity by the microbiome, and important compounds could be made into therapeutics.

Our beneficial relationship with our virome

X-ray crystallographic structure of a Norovirus capsid.

We have been championing the virome since the inception of the AMI.  We believe that with time, viruses will prove equally as important as bacteria within the microbiome.  To this end, a paper published last week in Nature shows evidence that a specific virus can promote a healthy gut in mice the same way that bacteria do.  The virus, murine norovirus (MNV), was able to successfully restore function to mice with compromised guts.

The authors started with two groups of mice, a control group and a germ-free group.  The control group had normal guts and immune function as measured by gut morphology, and the amount of T-cells.  The germ free mice had thin, leaky guts, and low levels of T-cells.  The scientists infected these germ free mice with MNV and allowed it to proliferate.  Upon investigation of these mice, their gut integrity and immune function resembled the control group.  A second experiment was performed on mice that had been given a course of antibiotics that wiped out the normal microbiome and resulted in an abnormal immune system and compromised gut.  When these mice were infected with MNV they too saw an improvement in health.  In a final experiment mice were given pathogenic bacteria that damaged the gut, but when infected with the virus the negative effects from the pathogens were diminished.

Viruses have a bad reputation, but that’s because we generally only care about the ones that make us sick.  There are countless viruses that exist in our guts though, many that we do not interact with at all, and many symbiotic ones which have yet to be discovered.  It is time that we appreciate the entirety of our microbiome, not just the bacteria but the eukaryotes, archaea, fungi, and viruses as well.