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 effect of various treatments for juvenile Crohn’s disease on the microbiome

CT scan showing Crohn's disease in the fundus of the stomach

Crohn’s disease is a type of inflammatory bowel disease that is characterized by an autoimmune response in the colon.  It is generally thought that the bacteria in the gut elicit this immune response and cause the disease.  In otherwords, Crohn’s is caused by a shift in the microbiome from a healthy state, to a dysbiotic one, although the ultimate cause of the disease is still unknown.  The standard of care for Crohn’s in adults is combinations of immunosuppressive drugs, although in children this is not normally recommended.  Instead, children take either a prescribed diet, normally something like Soylent that involves only essential nutrients, or antibiotics.  Scientists from UPenn recently monitored the microbiomes of children with Crohn’s that were put on various courses of treatment, as well as the progression of the disease.  They discovered the changes that occurred in the microbiome that yielded a therapeutic response, and many new associations between the microbiome and Crohn’s disease.  They published their results in Cell Host and Microbe.

The scientists measured the microbiomes and inflammatory markers of 90 children before and after entering therapy for Crohn’s: 52 taking anti-TNF (an immunosuppressant), 22 taking the enteral nutrition exclusively (i.e. something like soylent), and 16 taking the enteral nutrition along with any other food they wanted.  The scientists also took samples from 26 healthy children.  They discovered that of the 45 most abundant bacteria in each child, 14 were different between the Crohn’s children and the healthy children.  These included bacteria such as Prevotella and Odoribacter that were largely absent from the Crohn’s group, and Streptococcus, Klebsiella, and Lactobacillus that were in higher abundances in the diseased group.  Overall diversity was also higher in healthy patients compared to those with Crohn’s.  The researchers also discovered that high levels of fungi, such as Saccharomyces cerevisiae, in the stool were high associated with Crohn’s.  When the researchers monitored the response of Crohn’s patients to treatment they saw that in many patients the microbiome shifted rapidly to a healthier state, with less inflammation, within a week of treatment for all three therapies involved.

This study helped further define the dysbiosis that is associated with Crohn’s disease, as well as demonstrate how this dysbiosis is altered using treatment.  It was especially useful that treatment naïve children were used in the study, as many adult studies are unable to remove confounding variables of various previous courses of treatments.  IBD is a difficult disease to study because of its complexity, but this study supports the hypothesis that a dysbiosis is at the root of the problem.

Fish oil may be important to altering the microbiome, reducing anxiety

Last week we published a blog on the gut-brain axis, and the various associations between brain health and the gut microbiome.  One of the ailments we discussed was depression, which is often studied in mice by inducing early life stress on the mice.  One way to do this is by separating mice from their mothers for hours at a time at a young age.  The Maternal Separation model, as it is known, causes stress and anxiety in these mice, but more importantly, research has shown that it creates a dysbiosis of their gut microbiomes as well.  Many scientists believe the dysbiosis may be implicated in causing some of the stress phenotypes, and so reversing this dysbiosis could have therapeutic value.  Researchers from the University College Cork, in Cork Ireland, experimented with N-3 polyunsaturated fatty acids (PUFAs), like those found in fish oil, in these maternally separated mice, and found they may be important to preventing the dysbiosis.  They published their findings in the journal PLoS ONE.

In the study, the researchers separated mice into two groups, one underwent maternal separation, and the other had a normal upbringing.  Within each group the mice were separated into two more groups, one that received fish oil supplements and the other that didn’t.  Over the course of 17 weeks each groups’ feces were sampled for their microbiomes.  The Maternal separation tended to decrease the bacteroidetes to firmicutes ratio of the mice’s microbiome, which has previously been linked to depression in humans.  Interestingly, supplementation with the fish oil increased this ratio in those maternally separated mice.  In addition, the fish oil also increased the concentration of bacteria that were higher in non-separated mice, such as populations of Rikenella.  Finally, the fish oil increased the amount of butyrate producing bacteria, and as we have seen many times before, butyrate and other short chained fatty acids (SCFAs) are often associated with health.

Overall this study showed that fish oil shifted stressed mice’s microbiome to a more natural state, presumably helping them in the process.  While the scientists did not directly measure stress levels in these mice to support the microbiome connection, hopefully that will be part of a follow up study.  The scientists noted that fish oil is clinically shown to reduce inflammation, and made it a point to connect the stress in the mice to systemic inflammation.  Systemic inflammation is also mediated by the microbiome.  Indeed, people that have inflammation from IBD, for example, do tend to have more stress and anxiety.  In the end, fish oil could make for an interesting prebiotic to shift the microbiome, counteract inflammation, and improve mental health. 

New study suggests gut microbiome directly influences BMI, triglyceride, and HDL levels

Molecular structure of cholesterol

The microbiome has long been associated with cardiovascular disease, especially after studies showing differences between the gut microbiomes of obese and slim individuals.  The mechanisms by which the microbiome may be influencing heart disease are still unknown, but there are a few mechanisms that have been identified.  For example, as has been previously discussed on this blog, trimethylamine N-oxide (TMAO) in the blood is an independent risk factor for atherosclerosis, and is produced by gut bacteria from choline and carnitine.  In addition, systemic, chronic inflammation is associated with heart disease, and our avid readers will know that the microbiome can cause chronic inflammation in the vagina, gut, and mouth.  Overall though, a direct relationship between specific bacteria and heart disease has not been shown.  A recent epidemiological study though, did just that.  The researchers, mostly from the Netherlands, were able to identify specific species that were associated with higher BMIs, as well as those that were directly correlated with HDL cholesterol levels.  They published their results in the journal Circulation Research.

The scientists measured the genomes, microbiomes, BMI, and blood lipids of 1500 adults.  Their results showed that higher overall diversity and richness of the gut microbiome was associated with a lower a lower BMI (healthier state), lower triglycerides (healthier state), and higher level of HDL cholesterol (healthier state).  The diversity was not, however, associated with total cholesterol nor LDL levels.  The researchers then identified specific bacteria associated with these health indicators.  There are too many to list in this blog, so we encourage interested readers to take a look at the article.  Some examples though: Akkermansia, Christensenellaceae, and Tenericutes were each associated with low BMI, low triglycerides, and high HDL (all healthy states), while Eggerthella was associated with high BMI and high triglycerides, and Butyricimonas was associated with high BMI, high triglycerides, and low HDL (all unhealthy states).  Finally, the researchers sought to determine just how important the microbiome was to overall BMI, triglyceride levels, and HDL levels by incorporating the host genetics, age, and gender into their calculations.  They showed the 4.5% of the variance in BMI, 6% of the variance in triglycerides, and 4% of the variance in HDL is directly attributable to the microbiome.

These study results reaffirm the importance of the microbiome to our overall health, and even quantitatively show its influence on specific health indicators.  The authors do not attempt to explain why specific bacteria would cause variation in these metrics, although as previously mentioned some mechanisms have already been demonstrated.  To check to see which other diseases these bacteria have been associated with, use the search tool, or click the tags below to see all the blog articles that mention them.

Different types of dietary fat affect obesity through changes to the microbiome

A triglyceride molecule, the main constituent of lard.

Dietary fat comes in many in many different forms, such as saturated fats that come from foods like lard, and polyunsaturated fats that come from foods like fish oil.  It is generally believed that saturated fats lead to inflammation and obesity, but that polyunsaturated fats are healthier, and can counteract inflammation and promote healthy metabolism.  The role of the microbiome in mediating these effects is still unknown, but is beginning to be elucidated.  A team of researchers from Sweden, Belgium and Denmark showed that the lipids themselves alter the microbiome, which induces the characteristic inflammation associated with ingesting saturated fats.  Their results were published in the journal Cell Metabolism.

The scientists fed groups of mice identical diets that only differed in the type of fat that was consumed: lard composed of saturated fats, and fish oil composed of polyunsaturated fat.  As expected, the group that ate the saturated fat gained weight and had higher fasting glucose than those eating unsaturated fat.  When they measured the gut microbiomes of these mice, they discovered that the overall diversity of bacteria were much lower in the mice eating the saturated fat diet.  Next, the scientists measured the contents of the blood of the mice and discovered that there were higher levels of bacterial metabolites and bacterial components in the blood of mice eating the saturated fat diet.  Using complicated techniques that are beyond the scope of this blog, the researchers were able to trace the inflammation to an increase in specific receptors in the gut that are activated by bacteria from the saturated fat diet, including some specific toll like receptors (TLRs).  The scientists conducted a final experiment to show the importance of the microbiota, rather than the diet, in inducing these effects.  They transplanted the feces of both groups of mice into new, healthy mice.  The mice given the feces of the saturated fat group gained weight, whereas the ones given the microbiomes of the polyunsaturated fat group tended to lose weight.

The scientists believe that diets high in saturated fats upregulate specific immune system receptors that are activated by factors derived from the gut microbiome.  Moreover, these factors find their way into the blood much more easily after consuming saturated fat, as opposed to unsaturated fat, so they can easily activate these receptors.  After activation the factors lead to inflammation and obesity.  Overall, this research explains one of the reasons why polyunsaturated fats are healthier than saturated ones.  We know It’s not often anyone is faced with the choice between fish and lard, but after reading this study we recommend our readers go with the fish.

Sialic acid may be key carbohydrate responsible for inflammation and dysbiosis in the gut

A surface mucous cell bordering on the stomach lumen secretes mucus (pink stain).

Our diet is full of various carbohydrates, composed of different monosaccharides and polysaccharides.  Many of these survive our own digestion and make it all the way to the colon where they modulate our microbiome.  Another source of saccharides for our gut bacteria is the mucous that we produce, which can be a rich source of fucose or sialic acid.  Sialic acid has been implicated in many inflammatory diseases, such as bacterial vaginosis.  Last week, researchers from Switzerland showed that sialic acid may play a critical role in colitis, at least in one colitis model commonly used in mice.  They published their results in Nature Communications.

One way to induce intestinal inflammation in mice is to feed them dextran sodium sulfate (DSS).  The reason this molecule causes colitis in this mice is unknown, but it is used in many models of the disease.  In order to understand the possible role of sialic acid in the colitis, scientists created mice that could not produce mucous with sialic acid.  They quickly realized that these mice were not as susceptible to the DSS-induced colitis as their normal counterparts.  After, they tested how various antibiotics affected colitis in the DSS—colitis mice and discovered that Escherichia coli abundance was directly associated with the severity of the disease. Putting these ideas together, they tested and discovered that E. coli used sialic acid as their main carbohydrate source in vitro.

Interestingly, the E. coli cannot actually access the sialic acid from mucins, but instead need other bacteria, such as Bacteroides vulgatus to cleave and release the sialic acid from the mucins in order to access it.  If sialic acid is indeed important to the human form of the disease there may be multiple approaches to combatting the disease.  First, by eliminating E. coli, and second by eliminating the free sialic acid.