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.  

Sometimes-pathogenic Neisseria are constantly invoking immune response in humans

Fluorescent antibody stain of Neisseria gonorrhoeae.

Bacteria from the genus Neisseria exist as normal commensals in greater than 95% of adults.  That being said, two strains, Neisseria meningitides (a cause of bacterial meningitis) and Neisseria gonorrhoeae (the cause of gonorrhea),are known pathogens, although these too can often asymptomatic.  A new study published last week in Science suggests that although asymptomatic, Neisseria may always be inducing an autoimmune response, via a metabolite they are constantly producing and releasing into the environment. 

Using genetic approaches, scientists from the University of Toronto identified the inflammation-inducing metabolite as heptose-1,7-bisphosphate (HBP), which prior to the study had not been implicated as causing an immune response.  To prove its effect, the researchers injected the metabolite into mice and showed that these mice displayed inflammation almost immediately.  The scientists recognized that this metabolite is actually produced by many bacteria, and wondered if these others were causing harm as well.  Using mouse studies though, they demonstrated that other bacteria do not release it from their cells into the environment, so these bacteria only induce a response when they are lysed.  Thus far only Neisseria have been shown to produce and release this metabolite, which is important because it means as long as they are growing they are constantly producing an immune response. 

The scientists also discovered the immune pathway by which HMP triggers a response: the TRAF-interacting protein with forkhead-associated domain (TIFA).  Interestingly, it has been known for many years that infection with N. meningitidis or N. gonorrhoeae increases HIV shedding and transmission, but the reason was still a mystery.  The scientists figured out this connection when they recognized that HIV actually use the TIFA pathway to reproduce.  They observed that these bacteria invoke the TIFA response via HBP, which gives the HIV the proper cells it needs to replicate.

Given what we know about the effects of chronic inflammation and its effects on many diseases these findings could be very important.  Perhaps there is no such thing as a nonpathogenic Neisseria, and its existence in ‘healthy’ guts may not be so healthy after all.

Immune cells are educated in the gut to not attack beneficial bacteria

The gastrointestinal tract is made up of trillions of bacteria that are largely ignored by the body’s immune system.  Why is it that the body’s immune system knows to ignore these beneficial bacteria that are so important for our ability to live a healthy life? The answer to this question could play an important role in understanding how to maintain a healthy gut and how to treat diseases. Scientists led by Gregory Sonnenberg at Weill Cornell Medical College may have answered this question in a study published last week in Science.

The researchers studied T cells, cells that are made in the thymus and are trained there to kill-off foreign microbes and other intruders that make their way into the human body. But why don’t these T cells attack helpful bacteria in the GI tract? They found that the T cells are again educated in the gut to not attack beneficial bacteria but when this education is disrupted, it can lead to disease.  For example, inflammatory bowel diseases like Crohn’s disease and ulcerative colitis occur when the immune system attacks the GI tract and bacteria in the GI tract.

In the thymus, T cells that could attack the body are destroyed before they are released into circulation. In the gut, a type of cell called innate lymphoid cells (ILCs) educate the T cells to not attack beneficial bacteria. These ILCs had previously been found to make a physical barrier between the bacteria in the gut and the immune system.

In mice, they found that ILCs attacked T cells that were destroying beneficial bacteria and when they prevented this attack by ILCs on the T cells, severe intestinal inflammation resulted. They also looked at intestinal biopsies of young patients with Crohn’s disease. In the biopsies they found that the ILCs lacked specific molecules that are important for educating the T cells not to attack the bacteria in the gut. They found that a decrease in this molecule correlated with an increase in pro-inflammatory cells in children with Crohn’s disease.

The authors state that it may be possible to get rid of these T cells that are causing the inflammation and by doing so you may be able to help treat the disease.  By restoring this molecule (Major Histocompatibility Complex class II) that is preventing the education of the T cells, pro-inflammatory T cells may be reduced resulting in reduced intestinal inflammation.

Bacteria on the skin help shape immune response

The skin is the largest organ of the human body and the first line of defense against harmful microorganisms in the environment. However, it is also home to trillions of microbes that are beneficial to the host individual. In a study published in Nature, scientists found that specific bacteria on mammalian skin influence the host immune response.

To better understand this relationship, researchers chose Staphylococcus epidermidis, a bacterium commonly found on human skin, to see how the bacterium shaped the immune response. Using mice, the researchers found that the presence of S. epidermidis on mice skin caused an increase in CD8 β+ T cells, cells that are involved in immune response.  The application of other common skin bacteria to mice resulted in the increase of different T cell populations. The scientists next investigated how the skin cells detected the presence of S. epidermidis. The results suggested that a specific type of dendritic cell – located not on the exterior epidermal layer of skin cell, but within the dermal, second layer of the skin – is the cause of the unique CD8 β+ T cell response.

While mechanisms are still unclear, it is possible that S. epidermidis produce specific proteins that can trigger an immune response within the human skin when exposed to skin pathogens. What is clear from this study is that different bacteria living on the skin can elicit different immune responses. This suggests a commensal or possibly mutualistic relationship between skin cells and certain bacteria. Further investigation and knowledge of this relationship could lead to better understanding of the immune system and how the human microbiome participates in immunity as well as how this can be translated into therapy.            

How our body's normal bacteria avoid destruction by the immune system

The human gut is exposed to toxins, pathogens, dietary changes, antibiotics, and other disturbances that can cause alterations to our microbiome. So how is it that the gut of healthy individuals remains largely stable despite these perturbations? When we get sick, why is it that our body’s “good” bacteria remain in the gut while the bacteria causing the infection are killed off by our immune system?  A study out of Yale, published last week in Science, identified a single gene in bacteria that allows for these bacteria to resist inflammation-associated antimicrobial peptides that are released by the body to kill off harmful bacteria.

The scientists found that this gene, lpxF, encodes for an enzyme in the cell membrane of bacteria to be slightly altered from bacteria lacking this specific gene.  To figure this out, they exposed 17 commensal (or normal) bacteria to antimicrobial peptides (AMPs) and found that they were more resistant than pathogens that were also exposed to the same AMPs. They then mutated the genes of five species of Bacteroidetes at various points and checked to see which ones became less resistant to AMPs.  They found one gene that was common across all five species, lpxF.

They also did experiments in which they genetically manipulated bacteria to knock out the lpxF gene and put these bacteria into germ free mice along with the same bacteria with the functional lpxF gene. In the absence of a pathogen, the bacteria lacking the lpxF gene performed just as well as the bacteria with the gene.  When a pathogen was introduced into the mouse, inducing an immune response, the bacteria lacking the lpxF gene was greatly reduced in comparison to the other bacteria with functional lpxF.  This showed that the gene was protecting the bacteria from the AMPs. 

Lastly, they took fecal samples from twelve individuals and exposed bacteria from them to AMPs. They found that in comparison to pathogens that did not survive very well after exposure, the commensal bacteria performed very well.  This is a very important study as it opens up a new understanding of how bacteria in the body are saved from an immune response after exposure of a pathogen in the body.  There are most likely many more genes that play similar roles to lpxF and this work opens up new avenues to better understand how commensal microbes interact with the human body as well as pathogens in the body.   

The microbiome modulates the function of specific cells of the immune system

Regulatory B cells are specific white blood cells that are involved in protecting the body and have the ability to differentiate (or turn into) other types of immune cells in response to inflammation in the body. Their role is to regulate and restrain immune responses by producing the anti-inflammatory interleukin-10 but it is unclear what specific signals cause regulatory B cells to differentiate. In an article published in Nature Medicine, a team of scientists explored the effects of changes to the gut microbiome in mice on the differentiation abilities of regulatory B cells.

The authors studied a control group of conventionally housed mice with groups of mice treated with various antibiotics, including vancomycin, neomycin, and metronidazole. Mice treated with antibiotics had the majority of their gut microbiome eliminated and as a result developed milder arthritis, showing that the microbiome is responsible for the induction of arthritis. It was also found that the mice that were treated with antibiotics had reduced numbers of undifferentiated precursor B cells.

The authors later recolonized the gut microbiome of antibiotic-treated mice using fecal samples of the control mice. Examination of the regulatory B cells of the newly recolonized mice showed suppressive activity of arthritis inflammation. To examine if changes in housing had an effect on regulatory B cells, the researchers also studied conventionally raised mice compared to mice housed in a specific pathogen-free environment and this group showed reduced regulatory B cell activity.

In this study, the authors showed a strong correlation between the gut microbiome of mice and immune system inflammatory response to pathogens. This study also suggests that an overuse of antibiotics will not only deplete our gut microbiome as we have seen in several previous studies, but also reduce the function and differentiation of our regulatory B cells that play a critical role in our immune system function.