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.  

Emidermolysis bullosa, a severe skin disorder, may be influenced by skin microbiome

Epidermolysis bullosa (EB) is a terrible hereditary disease that results in blistering skin and can become so severe that the skin falls off the body (I highly recommend that you do not search for images of the disease, really). Severity levels vary but this disease can be lethal and the age of death is often very young. While recently many stem cell research advancements have been made bringing new treatments to young patients, treatments for the disease are lacking and a full understanding of the disease is not complete.

EB is a disease that is characterized by antibodies that target type VII collagen (COL7), an important part of the skin. In previous experiments, when mice are immunized for COL7, skin blisters result in 80% of the mice however 20% of mice remain healthy. To look at why this happened, scientists in Germany looked at the innate and adaptive immune response of mice that were healthy and compared this to the mice that became sick after immunization and published the results in the Journal of Autoimmunity.

They studied the skin microbiome of the mice by taking a biopsy prior to immunization because the skin microbiome has been shown to influence cutaneous inflammation. One of the major findings was that in the mice that did not develop the clinical symptoms of EB, there was greater richness and diversity of the skin microbiome before immunization. This showed that the results of the experiment could have been predicted prior to experimentation and therefore is an important factor in future studies looking at the transition from autoimmunity to the onset of autoimmune disease.

These results also lead us to the conclusion that it may be possible to prevent or reduce clinical inflammation in autoimmune disease by influencing the skin microbiome. 

Our gut microbiome may be contributing to some forms of blindness

Our eyes are considered ‘immune privileged’, which means that they are generally protected from our own immune system.  The major mechanism for eye immune privilege comes from a tight physical barrier that separates our lymphocytes, such as T cells, from the actual eye.  T cells do have the ability to cross this barrier, but they first must come in contact with, and be activated by eye antigens.  These antigens are sequestered on the opposite side of the barrier, in the eye, so that they are not exposed to the T cells.  There are diseases in which these retinal T cells do mysteriously become activated though, and they cause an inflammatory disease known as uveitis.  Uveitis is responsible for causing blindness and other eye issues in many people, but again the cause for the T cell activation is largely unknown.  Researchers at the NIH recently created a mouse model for uveitis, and were able to test a variety of factors that may be activating the T cells.  To their surprise, the gut microbiota seemed to be activating the T cells.  They published the results of their study last week in the journal Immunity.

The researchers first created a mouse model of uveitis where the retinal T cells spontaneously become activated.  They then noticed that the highest concentration of these T cells were near the gut, suggesting the gut bacteria were playing a role.  The scientists then treated the mice with antibiotics to decrease the gut bacterial concentration.  Although the mice still developed some symptoms of uveitis, the disease was ameliorated greatly in these mice.  As previously discussed, the normal T cell activator antigen is in the and physically separated.  In order to ensure that this antigen wasn’t somehow leaking out of the eye to activate the T cells in their model they created mice that lacked these antigens in their eye.  Still though, the mice presented symptoms of uveitis, meaning that the antigen that is activating the T cells is not from the eye, but rather is being produced somewhere else, such as the gut.  In order to firmly prove the gut bacteria’s role, the scientists showed that T cells could be activated by specific proteins from gut bacteria.  In fact, germ free mice, which otherwise would not have an ocular inflammatory response in their model, showed strong uveitis when they were given just the protein extract from other wild type mice. 

This research is the first to connect the gut microbiome with ocular autoimmune inflammation.  It presents many questions as to how to therapeutically combat this disease, perhaps through monitoring the gut microbiota for presentation of antigens that could activate these retinal T cells.  It also begs to be connected with other sites immune privilege breakdown in the body.  The fetus and placenta in pregnant women, for example, is an immune privileged space.  Immune activation of this site can sometimes lead to miscarriage.  Are gut or vaginal bacteria involved with this response, as we have discussed a few times in this blog?  In time, scientists will know enough to accurately answer this question.

Common yeast may trigger celiac disease onset

Candida albicans growing in petri dish

Celiac disease is a serious autoimmune disorder in which gluten, found in wheat, rye, and barley, triggers an immune response that damages the absorption capabilities of the intestines. The AMI has covered this topic in a few previous blogs (click celiac disease tag below) in relation to autoimmune disorders and possible bacterial triggers. One contributing factor to the celiac disease response is due to the protein gliadin, which is found in gluten. Gliadin, along with transglutaminase (which is a human protein that binds to, and deaminates gliadin), trigger a T Cell response that leads to the inflammation and tissue damage.

The yeast Candida albicans is a common gut commensal that is linked to inflammatory bowel diseases and vaginal infections.  This yeast also binds with transglutaminase, using a protein called Hwp1, in an identical fashion as gliadin.  This results in the bacteria’s strong binding to the intestinal wall, where it triggers an autoimmune response to destroy the yeast.  

Researchers in France hypothesized that the similarity between gliadin's and C. albicans' binding to transglutaminase may result in a similarity in the body's response to these two things.  In essence, they suggested that gluten ‘tricks’ the body into an immune response because it 'looks' similar to C. albicans.  

In the study, recently published by Plos One, blood cultures from 87 adult patients with celiac disease and 41 patients with C. albicans infection were collected.  The scientists then isolated the body's natural antibody for Hwp1 and measured its response to both gliadin and Hwp1.  They discovered that gliadin also binds to Hwp1's antibody, meaning that it should elicit the same immune response as Hwp1.  Therefore, the body should mount an immune response for gluten that is characteristic of C. albicans infection, and this response could manifest itself as celiac disease.

The significance of this study is that it comes closer to finding a cause and prevention of celiac disease. The T cell immune response that results from transglutaminase binding to gliadin could initially be triggered by a C. albicans yeast infection. This may explain why some people only become gluten sensitive later in life - perhaps it only occurs after they have a C. albicans infection and the body builds up antibodies for this yeast. This is another example of how microbes found in healthy individuals can be harmful when homeostasis is not controlled. 

Hand washing dishes may decrease risk of allergies

A study published on Monday by the journal Pediatrics has gotten a lot of press this week because it shows a connection between allergies in children and the method by which parents wash their dishes. Parents, especially new parents, often consider good hygiene as one of the most important factors in raising their new child, but according to the hygiene hypothesis it may be true that too much cleanliness actually negatively affects a young child.  Asthma, eczema, and other autoimmune diseases are becoming more common conditions in children, and each has been linked to the hygiene hypothesis.  Researchers in Sweden reinforced this link when they discovered a possible connection between allergies in children and whether dishes were washed by hand (less clean) or by machine (more clean) in their homes.

 The researchers sent a questionnaire to parents of children aged 7-8 which was filled out by 717 families in Molndal, Sweden and 312 families in Kiruna, Sweden. The questionnaire asked many questions pertaining to the children, including previous symptoms of asthma or eczema, method of washing dishes, and if their food was farm grown or fermented.  When examining the results it is important to remember that all forms of bias cannot be eliminated when doing surveys, because, among other reasons, it is difficult to get a perfectly random sample.

Results of the study showed that there were lower instances of allergies in children whose families washed their dishes mainly by hand rather than by machine. In addition, this effect was amplified if the children ate food that was either fermented or purchased from a farm (both of which should introduce diverse bacteria to the children).  Of course, there were other variables that were not inquired in the questionnaire that are also known to decrease rates of allergies in children, and which may be related to washing dishes by hand, for example a lower socioeconomic status.  Then again, the authors suggest that hand washing dishes may reasonably be responsible for these lower rates of allergies in children of lower socioeconomic status.

So, you may be wondering how exactly this pertains to the microbiome. Hand washing dishes cleans less thoroughly than highly efficient machines, which sounds gross, but the exposure to more microbes when you are young may help develop the microbiome and immune system.  While this study is not perfect, it still shows us that exposure to bacteria is potentially a good thing for the new and developing microbiome. 

Treating celiac disease with bacteria?

Celiac disease is a condition that results in an individual's immune system attacking it’s own small intestine as a result of gluten consumption. Researchers at the University of Nebraska and the University of Alberta published a study in the Journal of Applied Microbiology that aimed to identify gastrointestinal bacteria that are able to break down gluten proteins, possibly opening the door for therapeutic interventions. To do this, they studied the gastrointestinal tract of pigs, as they are physiologically similar to humans.

The scientists found four strains from the Lactobacillus species that had the greatest ability to degrade gluten, L. amylovorus, L. johnsonii, L.ruminis, and L. salivarius. Pigs were fed a diet supplemented with 20% gluten for at least 16 weeks and samples of their gastrointestinal bacteria were collected. They found that the four bacterial strains were enriched, and these strains were capable of degrading specific molecules that have been linked to the immune response in celiac disease.

This study identified specific bacteria that could potentially be used to treat celiac disease. Other studies have also identified L. ruminis and L. amylovorous as bacteria that are primary degraders of gluten, making them prime candidates for therapeutic use. Currently, the only way for an individual with celiac disease to remain healthy is to avoid any product containing gluten. In the future, it may be possible for bacterial strains, possibly those identified in this study, to be introduced into the gut of a celiac disease patient through a probiotic or other method to allow for the digestion of gluten.