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.  

The microbiome plays a role in antipsychotic-mediated weight gain

Weight-gain is a common side effect associated with taking anti-psychotic therapies, and unfortunately the mechanism of action by which this specifically occurs is poorly understood.  Risperidone is a commonly-prescribed second generation antipsychotic that is known to induce significant weight gain in patients taking the drug, and addressing this side effect represents a high unmet medical need.  Up to this point it has been thought that there is a myriad of underlying causes to risperidone-induced weight gain.  Recent evidence has suggested that alterations in the gut microbiome composition of patients who are taking SGAs could be implicated in loss of healthy metabolism leading to weight gain.  Researchers from the University of Iowa sought to expand upon this theory by examining whether or not shifts in the microbiome brought on by risperidone treatment in mice are linked to metabolic dysfunction and subsequent weight gain. 

The researchers treated wild-type C57 mice with risperidone and the animals displayed significant weight gain after 6 weeks as compared to controls.  The gut microbiomes of these animals were then sequenced by analyzing fecal matter and microbiota composition was significantly different in risperidone mice as compared to the control group (e.g. increases in relative abundances of Firmicutes and decreases of relative abundances of Bacteriodetes).  Next, a technique known as bomb calorimetry determined that the weight gains in risperidone-treated mice were due to suppressed energy expenditure.  The researchers conducted a final unique experiment to further associate the microbiome’s role in risperidone-induced weight gain.  Risperidone-naïve mice received fecal transplants from overweight mice that had received risperidone.  The naïve mice who had received the transplant form risperidone mice demonstrated reductions in non-aerobic resting metabolic rate and energy expenditure as well as weight gain.  The researchers also conducted fecal phage transplants, as the bacteriophageome could also play a role in energy expenditure.  After having received transplant from risperidone-treated mice, naïve mice demonstrated a marked reduction in energy expenditure coupled with weight gain. 

Together, the results from this study support risperidone’s role in altering composition of the gut microbiome which can be mechanistically linked to reductions in energy expenditure.  The implications from this study are significant as second generation anti-psychotics represent some patients’ only viable treatment option for schizophrenia or psychosis.  Targeting cognitive maladies such as psychosis is challenging as drug interactions must be specific while avoiding non-specific targets.  Addressing this common weight-gain side effect by focusing on the microbiome could encourage the development of ancillary therapies to maximize treatment benefit for patients through reduction of undesired side-effects.  

Leading scientists propose a Unified Microbiome Initiative

This week, a group of leading microbiome scientists proposed a Unified Microbiome Initiative (UMI) “to discover and advance tools to understand and harness the capabilities of Earth’s microbial ecosystems.” Microorganisms inhabit almost every habitat on Earth and a better understanding of the dynamics of these habitats could lead to new innovations in all of these sectors.

The scientists argue that while there have been significant advances in understanding the diversity of microbial communities, they lack the tools and technologies to enable predictive and actionable understanding of global microbiome processes. They state that cross-disciplinary collaborations are needed between diverse constituents to develop these tools.

You can read about the details of the various tools and technologies that are proposed here, however they all involve developing technology platforms leading to more applied applications of microbiome science. Much of what they propose is an extension of existing technologies that would lead to better understanding of how microbial communities function.

As we wrote about last month, the White House is already paying close attention to the microbiome and considering what the best plan would be for such an initiative. Many of the authors on this proposal were in attendance at that White House meeting and are working in collaboration with Jo Handelsman and her team.

It is important that there be unified efforts as major technological advances would lead to broad advances among all of Earth’s habitats. While we talk mostly about the human microbiome on this blog, the microbiome of the ocean, soil, and countless other environments are vitally important to maintaining the world’s well being. We highly recommend that people take a look at the pieces in Science and Nature. We are excited about these proposals and look forward to seeing what type of initiatives come out of this. 

Short chain fatty acid composition in the gut is associated with Hirschsprung associated enterocolitis

Ball and stick representation of an acetate molecule, CH3COO-

Hirschsprung disease is a disorder in which a baby is born without nerves in part or all of the large intestines, rendering them functionless. Hirschsprung-associated enterocolitis (HAEC) is a complication of Hirschsprung disease (HD), in which the intestines become inflamed due to infection. HAEC is a common cause of death in children with Hirschsprung disease, but the real cause of infection in not very well understood yet. Poor immunity, poor intestinal wall function, and an altered gut microbiome are thought to contribute to the issue. An important role of the gut microbiome is to produce short chain fatty acids (SCFAs) from complex and indigestible fiber. The short chain fatty acids contribute to bacterial homeostasis of the gut, and so they may be associated with intestinal issues observed in HAEC. Scientists from California, Michigan, and Sweden set out to test this possible connection by measuring the SCFA, and SCFA-producing bacterial composition in HD children who have HAEC.  The study was published by the Journal of Pediatric Surgery. 

The study population consisted of 18 children with HD, with ages ranging from 3 months to 8 years, and a median age of 2.7 years. Nine participants had a history of HAEC, while nine did not. Fecal samples were collected from the children and analyzed for SCFAs and bacterial composition. Among the children involved in the study, there were no significant differences in early feeding type, probiotic use, complications unrelated to HAEC, and length of HD diagnosis. One patient in the HD group and two in the HAEC group had trisomy 21, better known as Down Syndrome.

Total fecal SCFA composition in children with a history of HAEC was four-fold lower than that of HD patients who did not have a history of HAEC.  When broken into individual SCFAs, the children with HAEC had substantially less acetate in their stools, but actually slightly higher butyrate levels compared to non-HAEC.  Interestingly, the HAEC patients actually had higher levels of butyrate and acetate producing bacteria, despite the dramatically lower acetate levels.  The authors suggest that perhaps the butyrate producing bacteria are actually converting acetate to butyrate, resulting in higher levels of both butyrate and butyrate producing bacteria, along with lower levels of acetate.

While we still don’t know a cause for Hirschsprung-associated enterocolitis, this study does provide an association between HAEC episodes and alteration of short chain fatty acid composition of the large intestines. This study is limited by its small sample size and other factors that are difficult to account for, but the results still do help scientists identify possible causes of the disease.

The microbiome’s response to the flu and its treatment

In 2013 there was an avian flu (H7N9) outbreak in China that affected 140 people, killing 46 of them.  During the outbreak doctors from one of the major hospitals in China treated 40 of these patients by giving them antivirals and antibiotics, amongst other first line treatments.  In addition, they gave probiotics along with the antibiotics to restore the gut microbiome.  All the while, they measured the patients’ microbiomes to track how they changed throughout the course of treatment.  The results of this study were published last week in the journal Nature Scientific Reports.

Twenty six patients were enrolled in the study, and each of them was given antibiotics within 6 hours of admission to the hospital.  In addition, each one was given Clostridia probiotic capsules along with the antibiotics.  Thirty one healthy control stool samples that represented the demographics of those undergoing flu treatment were also measured as a part of the study.  Before the antibiotics were taken, the patients with the flu already had altered microbiomes that were low in diversity and had lower abundances of Bacteroidetes and higher levels of Proteobacteria.  After antibiotics were given there was a dramatic shift in the microbiomes, that was characterized by a relative increase in the abundance of Escherichia coli.  In addition, the scientists noted that the probiotics were in fact increasing the amounts of Clostridia in the guts of patients who took them, and that the probiotics may have led to better clinical outcomes.  In their hospital only 20% of patients died of the flu, whereas 40% died in the rest of China.

The major takeaway from this study is the changes that the flu has on the microbiome, decreasing diversity and altering the levels of certain phyla.  The fact that the probiotics did appear to take hold and improve clinical outcomes is interesting, but the study was extremely small and limited in its scope to reach any statistically significant conclusions.  Overall though, this study suggests that if you come down with a flu that it may be wise to feed and nourish your microbiome because it is ‘getting sick’ right alongside you.

Does the use of antibiotics for bacterial vaginosis during pregnancy reduce the risk of preterm birth?

Bacterial vaginosis (BV) is an inflammatory disease that is defined as a vaginal microbiome that is not dominated by Lactobacilli.  This abnormal vaginal flora is associated with preterm birth and miscarriage.  A recent study showed that women’s vaginal microbiomes shift frequently during pregnancy, but that the amount of time spent with a flora not dominated by Lactobacillus was associated with the length of the pregnancy, i.e. the less time spent with Lactobacillus the shorter the pregnancy.  Considering these studies, doctors may want to begin screening the vaginal microbiome during pregnancy, and treating BV (which is currently done through antibiotics).  Strategies such as that one have not yet been rigorously studied, so their efficacy is still unknown.  Last week a study out of Japan performed a study that showed little improvement in preterm birth risk by monitoring and treating BV during pregnancy.  The results were published in Nature Scientific Reports.

The researchers measured the microbiomes of 1,735 pregnant women and split them into two groups.  Women in the intervention group that had BV were given antibiotics, whereas women in the control group, whether they had BV or not, proceeded as normal through their pregnancy.  Women in both groups had their vaginal microbiomes sampled at various time points throughout the pregnancy. The first group would have their BV status verified, and placed on antibiotics. In both groups, approximately 10% of the women had preterm birth at around 30 weeks gestational age.  There was no significant difference in these rates between the two groups, meaning that administration of antibiotics did not appear to prevent preterm birth.  Even though the antibiotics did not prevent preterm birth, the researchers noted that regardless of group, women who entered preterm birth did have abnormal vaginal flora compared to women who went full term, supporting the notion that BV is highly correlated with preterm birth.  They noted that many of the women who entered preterm labor did not have BV at the initial time of screening, but acquired BV at some point during pregnancy. 

This paper supports the idea that BV may cause preterm birth, however it cannot recommend universal screening for BV in pregnant women for two reasons.  First, the antibiotics did not appear to affect the rates of preterm birth, and second many of the women who had preterm birth only had abnormal flora after initial screening.  Perhaps a better strategy would be to constantly monitor BV status throughout pregnancy.  In addition, there will soon be healthier and more effective methods to treat BV than antibiotics, which are only shown to have a transient effect on BV and disrupt the rest of the microbiome.