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.  

Can hookworms fight against celiac disease?

Helminths, or gut worms, are native inhabitants of our microbiome that are known to have substantial immunosuppressive effects.  Some scientists believe they are a keystone species in the microbiome and that their absence in people following a Western lifestyle may be contributing to the rise in autoimmune diseases, such as celiac disease.  In fact, scientists have recently shown that hookworm infection leads to higher gluten tolerance in individuals with celiac disease.  The cause of hookworm’s broad immunosuppression is unknown, but those same scientists investigated the possibility that it may be caused by the worms’ ability to modulate the bacteria in the gut.  The researchers recently tested this hypothesis and published their results in Nature Scientific Reports.

First, the researchers measured the fecal microbiota of eight human subjects with celiac disease, all of whom had followed a gluten free diet for at least five years prior to the trial.  Compared to a control group that hadn’t followed a gluten free diet, the trial subjects had a greater abundance of Bacteroidetes, while the control group showed greater abundance of Firmicutes.  Next, the subjects were successfully infected with hookworm and gluten was slowly reintroduced into their diets over a period of 44 weeks. The scientists measured the subjects gut microbiota at different time points and discovered that the hookworms, in conjunction with the gluten introduction, restored levels of Firmicutes in the celiac disease patients.  By the end of the study all of the remaining participants had rich abundances of both Bacteroidetes and Firmicutes.

It should be noted, and the authors admit, that the study is limited by its small sample size.  Still though, the results lead one to believe that helminths are modulating the microbiome, and that this may contribute to the overall immunosuppressive effects of these worms.  People have been known to practice helminth therapy to achieve immunosuppression in the gut, however this is dangerous for a number of reasons.  Instead researchers, such as the ones that performed this study, are in search of the mechanism for this immunosuppression.  There is certainly some very interesting biology that occurs during a helminth infection, and hopefully sometime soon scientists can turn these helminths into therapies.

Microbiome composition of children infected with helminths

Schistosoma parasite worm, otherwise known as a blood fluke.

While much has been explored regarding the microbiome’s role in nutrition and immunology, more research is needed in uncovering interactions between the host microbiome and infection as this represents a high unmet medical need.  A few weeks ago we talked about a study that describes an interesting relationship between helminth infection and sensitivity to insulin in Indonesia.  Helminth infections are also prevalent in sub-Saharan Africa, where many children become exposed to Schistosoma haematobium, causing schistosomes and dramatically affecting childhood health and development.  Researchers from Africa sought to investigate whether there were significant differences in microbiome composition between children who were infected with S. haematobium and those who were not.  Furthermore, investigators explored whether praziquantel (PZQ) – an effective agent that kills schistosome worms – has any influence on the human microbiome composition of infected patients. 

Stool samples were collected from 139 pediatric patients from six months to 13 years old, and groups were segregated following proper diagnosis of S. haematobium infection.  DNA was extracted from the samples and microbiota were characterized using 16S rRNA sequencing.  Overall microbiota compositions were similar across sex and all age groups, and Bacteroidetes phyla were found to be most abundant.  However, there was a significant difference in operational taxonomic unit (OUT) microbiota clusters (a measurement that categorizes bacteria colonies) between infected and non-infected groups.

In the next experiment, researchers investigated the microbiomes in the 62 patients who took the PZQ therapy, comparing microbiota after 12 weeks of treatment to their baseline compositions (i.e., prior to PZQ administration).  Interestingly, there was no statistical difference in microbiota composition in patients between pre and post administration time points. 

Though this study did not necessarily present breakthrough findings, the researchers presented more data that will assist doctors and clinicians to better understand helminth infection with respect to the microbiome.  Learning more about the exact differences in microbiota composition between infected and non-infected children will advance our understanding of interactions that could potentially lead to a novel and much-needed therapy.