The microbiome can modulate helminth-mediated allergic inflammation

We’ve talked about how helminths can impact health, highlighting many studies that describe relationships between helminth infections, disease, and industrialization versus underdevelopment.  Asthma is a condition prevalent particularly in industrialized/westernized societies, and helminths have been shown to directly regulate immune responses and are linked with a reduction in asthma prevalence.  Correspondingly, there is less incidence of asthma in underdeveloped societies.  Additionally, helminth infections are typically associated with compositional shifts in intestinal microbiota.  A large research team sought to investigate the potential role of intestinal microbiota in modulating helminth-induced allergic inflammation, postulating that there is indeed significant cross-talk between the microbiome and helminths as opposed to intrinsic inflammatory responses to helminths. 

The researchers first determined that helminth infection can reduce the severity of allergic airway inflammation in mice.  Mice were infected with Heligmosomoides polygyrus bakeri (Hpb) murine-specific helminths and then exposed to house dust mite to induce allergic inflammation.  The mice exposed to the Hpb helminth demonstrated a reduction in severity of inflammation.  Next, the researchers were able to demonstrate that intestinal bacteria play a role in helminth’s modulatory role of allergic airway inflammation.  Antibiotics were administered to Hpb-infected mice to eliminate intestinal microbiota populations.  Helminths infection reduced inflammation, but did not attenuate inflammation in anti-biotic treated mice, even though total worm-count was similar between both groups (antibiotic group and non-antibiotic group). 

Helminth exposure and subsequent shifts in microbiota composition and biochemical activity was then examined.  16S sequencing revealed that Hpb-infected mice induced an outgrowth of Clostridiales bacteria.  Increases in small-chain fatty-acid (SCFAs) were also observed in Hpb-infected mice, a likely outcome of a shift in bacterial community structure.  Interestingly, the microbiota of a Hpb-infected mice were transferred to naïve mice, and this was sufficient in protecting against allergic inflammation, further confirming the microbiome’s modulatory roles.  Previous reports have pointed to regulatory T cells (Tregs) as responsible for regulating immune/inflammatory responses, and in this study the researchers demonstrated Treg involvement.  Furthermore, helminth-induced Treg suppression and anti-inflammatory activity was observed, mediated by a G-protein receptor entitled GPR-41. 

Together these findings further elucidate the role of helminths in disease, while uniquely pointing to the gut microbiome as a critical mediator of this interaction.  Learning more about these relationships can help us better understand broad epidemiology trends associated with helminth infection and human health.  

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Helminths may influence fecundity rates in women

We’ve often discussed helminths and their impact on human health, and researchers have recently provided more insight as to how these infective parasites can influence female reproductive health.  The immune system plays an important role in fecundity in women.  Shifts in immune responses in regulation are dynamic and these changes can have influence on pregnancy.  Helminths are known to induce marked immunological changes and they infect 500 to 800 million people worldwide.  In addition to modulating systemic immune responses, helminths are also known to directly infect reproductive organs or even the fetus.  While studied extensively in animal models, there is little known as to how helminths influence reproductive processes in humans.  A conglomerate group of scientists sought investigate how helminth infection could affect fecundity rates in women, hypothesizing that helminth infection during pregnancy may increase fecundity because the helminth-mediated immunologic responses may in fact modulate those that impair fertility. 

The researchers collected 9 years-worth of health data from 986 Bolivian women who were forager-horticulturists residing in the Amazonian lowlands of the country.  Western medicine and contraceptives are not used in this region, and it is estimated that different types of helminths infect up to 70% of the population.  Cox proportional hazards model first determined that there was an association between helminth infection and birth spacing.  Next, it was shown that women infected with hookworm were associated with a delayed age of first pregnancy.  Interestingly, and in contrast to hookworm, roundworm infection was associated with early first births (in comparison to hookworm) and shortened interbirth intervals.  The researchers postulated that these differences in associations could be explained by each respective helminth species unique effect on the immune system modulation.  Specifically, roundworm infection is associated with regulatory T cell (Treg) Type 2 immune activation, while hookworm infections are associated with mixed Treg immune activation (e.g. both Type 1 and Type 2 activation).  The association with the specific immune response could also explain why roundworm association was shown to be more favorable to conception, as Treg Type 2 activation more closely resembles pregnancy immune system activity while a Type1/Type2 mix more closely resembles an inflammatory response. 

From a broad viewpoint, these findings are interesting as they point to a species-host interaction that may have an underlying - and underappreciated - influence on demographic/population distribution.  The study of helminths is deserving of more attention, as we continue to acquire a wealth of information from their interactions with humans and implications on human health.  

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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.

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.  

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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.

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Helminths may provide therapeutic benefit to treat brain disorder

We’ve recently talked about a few articles that have studied helminth infection with respect to the microbiome, and how these infections could possibly confer some therapeutic benefits.  Another recent study conducted by researchers at Duke University reinforces these findings.  Autoimmune and inflammatory disorders appear to be more common in developed societies, and many have suggested that the microbiome is a major driver of these changes to our immunity.  These investigators wanted to assess whether or not helminths – which have a lot of influence on the immune system – had any effect in modulating the brain immune system in the context of living conditions and early-life infection, as this has been shown to result in neurodevelopment disorders. 

In this study, male and female rats were infected with a H. diminuta cystercircoid rat tapeworm a few weeks prior to breeding.  The rats were segregated by living conditions, housed in either dirty colonies (or “farm-like” environments), where no water or air filtration was provided) or standard clean pathogen-free laboratory conditions.  The offspring in both environments were delivered helminths, and the males were infected with E. coli early in life. 

Later in adulthood, the immune systems of the progeny animals were challenged by lipopolysaccharide (LPS) inductions in learning tests, and brains were collected shortly after to examine changes in molecular immune responses.  Exaggerated immune responses were observed in rats that were infected with E.coli early in life in the standard clean lab conditions.  Alternatively, the cohort that lived in the farm-like conditions did not experience an increase.  Both groups were infected with helminths.

To narrow down further, the researchers examined the impact of helminths alone in rats housed under clean pathogen-free laboratory conditions.  Indeed, cytokine responses in rats infected with E.coli were reduced in the animals whose mothers were infected with helminths before giving birth.  In addition to immunologic modulation, helminth infections in adult rats where shown to reduce memory deficits that are common following E. coli infection, suggesting helminth infection played a role in modulating developmental disorders due to bacterial infection. 

The helminths also had an effect on the microbiomes of the rodents.  16s rRNA sequencing revealed an average 25% shift in microbiome composition of animals infected with helminths (with a predominant shift of Bacilli to Clostridia).  Rats that were infected with E. coli early in life experienced a microbiome composition shift in adulthood, as more harmful Bacteroidetes species were found in adults.  Interestingly, this observation was not found in those who were E.coli infected but also infected with helminths, suggesting helminths prevented this composition shift. 

Overall, these findings suggest that helminths could provide therapeutic benefit, especially after infection early in life.  It will be interesting to see how this research can translate to human models, especially by narrowing down bacterial infections that could harm or benefit development.  Understanding what drives these developmental complications could have immense health benefits for the public. 

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Microbiome composition of children infected with helminths

Schistosoma  parasite worm, otherwise known as a blood fluke.

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.  

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