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.

Helminths suppress the immune system by modulating the gut microbiota

The nematode Heligmosomoides polygyrus, which was used in this study, seen into an optical microscope. Taken from the digestive tractus of a rodent.

Helminths, or gut worms, are known to be powerful suppressants of the immune system.  In fact, this is the basis for using helminth therapy for various autoimmune conditions, such as IBD.  Still though, the mechanisms for helminth immunosuppression is unknown.  There have been some studies that suggest the worms are secreting molecules that have this anti-inflammatory effect, but this may not tell the whole story.  Researchers from Switzerland hypothesized that because helminths and our gut bacteria evolved together, it was likely that the helminths were modulating the bacterial gut microbiome, and that this modulation was anti-inflammatory.  They tested and published results that support this idea in the latest issue of Cell Immunity.

The scientists started by showing the efficacy of a mouse helminth, Heligmosomoides polygyrus bakeri (Hpb), in reducing inflammation in mouse models of asthma.  The scientists infected mice with the parasite and exposed those mice, along with non-infected control mice, to dust mites in order to elicit and immune response.  The scientists observed that the Hpb mice had much lower circulating levels of specific cytokines and immune cells after exposure to dust mites than the controls.  Next, the scientist gave the Hpb infected mice antibiotics, which eliminated the gut bacteria but left the helminths intact.  They then exposed these mice and control mice to dust mites to elicit the immune response.  Interestingly, while the helminths alone did decrease the levels of some inflammatory molecules and cells, inflammation still occurred, similar to what was observed in controls.  This meant that the gut bacteria play a role in modulating the helminthic immune suppression.  In order to validate these findings, the scientists then performed fecal microbiota transplants from control mice or helminth infected mice into germ free mice (with no worms).  After, the challenged these mice with house dust mites and discovered that the gut bacteria alone created an immune suppression in the mice, even in the absence of the worms.

The researchers attempted to identify which bacteria may be causing this immune suppression, and measured the microbiomes of the mice.  They noted that higher levels of Clostridiales occurred in the Hpb mice.  They then measured the levels of short chain fatty acids (SCFAs) in the mice’s guts, because Clostridiales are known to produce SCFAs.  They noticed that higher levels of SCFAs, which have previously been linked to immune suppression, did occur in higher levels in mice with Hpb compared to controls.  The scientists then studied this connection between worm infection and increase in SCFAs in pigs and humans.  Remarkably, the increase in SCFAs in helminth-infected subjects compared to controls was observed across species, suggesting the immune suppressing helminth phenomenon is extensible to many mammals.  The researchers even investigated possible mechanisms for why SCFAs were able to suppress the immune system.  They discovered the SCFAs were binding specific receptors that modulate T-cells, and more depth on this issue can be found by reading the paper. 

This study is quite important as it shows that helminths in combination with the bacterial microbiome are important to immune suppression.  This suggests that future therapeutics that may take advantage of helminth-derived molecules may not be as effective.  It does, however, support helminth therapy as an immune suppressant.  However, helminths are also very dangerous and can lead to various diseases.   So, while clinical trials that use helminths are underway, there are still no approved uses for worms.