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.  

Red wine and coffee modulate the microbiome

Prebiotics are foods that alter the microbiome.  They are important to many potential microbiome therapeutics because they could be used to shift the microbiome from a dysbiotic, or unhealthy state, to a normal healthy state.  Most scientists that study prebiotics investigate indigestible fiber, because these are known to survive digestion are broken down by specific microbes, thus predictably selecting for specific organisms’ growth.  Recently though, other prebiotics are being studied.  A major class of these are polyphenolic compounds, which provide the antioxidant characteristics of plant material.  Last week researchers from Spain studied the shift in the microbiome that may be induced by red wine and coffee in particular.  They published their results in the journal Food & Function.

The researchers studied 23 patients that had allergic rhinosinusitis or asthma as well as 22 age-matched controls.  They chose individuals with autoimmune diseases because of the promise of prebiotics affecting their diseases.  They asked all of the individuals to fill out a food survey of what they had eaten in the past year, and how often they ate it.  After, the scientists took samples of their feces and measured the bacteria within it.  The scientists found that the abundance of Clostridium, Lactococcus and Lactobacillus was directly associated with polyphenol intake from coffee, and that Bacteroides was positively associated with red wine consumption.  Unfortunately, they noted that these did not differ between allergic people and healthy ones.

This study was certainly lacking in its scope and rigor.  It did not attempt any interventional studies to controllably reproduce these effects, and it did not identifiy specific polyphenols that are responsible.  Nonetheless, it does begin to define how alternative prebiotics may affect our microbiome.  Polyphenols in particular are linked to all sorts of health benefits, normally attributed to their anti-oxidation, however perhaps they positively impact the microbiome as well. 

Gut bacteria may help prevent asthma in children

The world has seen an explosive rise in asthma over the past three decades. Such a rise in prevalence cannot be only a result of genetic variation and leads us to believe that environmental factors play an important role in this change. There are several possible explanations for this including what we call the “hygiene hypothesis”, or the idea that we now live in an environment that is too clean and we are no longer exposed to the bacteria and germs that earlier generations were exposed to. Another possible explanation is as the world changes and becomes more modern, these environmental changes are affecting our microbiome and the “normal” microbiome is shifting to a new normal.

To better understand why some children are at high risk for becoming asthmatic, scientists in Canada studied the microbiome of 319 children in the Canadian Healthy Infant Longitudinal Development (CHILD) Study. They sequenced fecal samples from the children and found that 4 groups of bacteria that were decreased in prevalence compared to the children without asthma. Bacteria from the genus Lachnospira, Veillonella, Faecalibacterium, and Rothia (FLVR) were at lower levels after 3 months for the children at high risk for asthma however over time, this leveled out and was similar to the children not at risk for asthma.

The study did not identify what exactly caused these differences as there could be several reasons for these differences including antibiotic use, the method in which the child was delivered either vaginally or by C-section, and if the child was breastfed or not. It is also possible and maybe even likely that some of the mother’s behaviors during the pregnancy such as diet could play an important role in the early development of the child’s microbiome.

The next obvious question is what can we do about this? Does this mean that we can now treat children that are deficient of these bacteria and they won’t get asthma? While it sounds simple, we don’t yet know too much about these bacteria and it will be important to better understand the impact his would have on the rest of development. Promising results from this study did show that when mice with low levels of FLVR were treated with probiotic samples of the bacteria, it protected them from getting asthma.

This is a very exciting study that may lead to new diagnostics for asthma and with more research and understanding, allow us to prevent the disease from developing. 

Elective vs. acute c-section deliveries: does it make a difference?

Caesarean sections are often needed when there are complications during a pregnancy or a woman often will elect to undergo a c-section due to a variety of reasons. In some nations, c-section delivery rates are incredibly high and there are attempts to lower these numbers. In Brazil for example, 85% of births in private hospitals are c-section deliveries. Babies born via C-section have been shown to have an increased risk of disease related to immune function. Previous studies had not discriminated against elective or acute c-sections and scientists in Denmark set out to do just that.

Conducting a population based study of 750,569 children born between January 1997 and December 2012, they analyzed children born via elective c-section, acute c-section, and those born vaginally as the reference. They found that the children born by either elective or acute c-section had a higher risk of asthma, laryngitis, and gastroenteritis though electively born c-section babies had a more pronounced risk than acute c-section babies. Those born via elective c-section had an increased risk of lower respiratory tract infection and juvenile idiopathic arthritis. Babies born by acute c-section had an increased risk of ulcerative colitis and celiac disease.

There were other factors not taken into account such as if the children were breastfed or if the mothers had asthma. While not everything was able to be taken into account, with such a large sample size, it is likely that the results from this study would not have been significantly affected by other factors. Most of the effects were seen in diseases that involved the mucosal immune system. The authors believe that the reason for the differences is a result of disturbed immune function as a result of differing microbial colonization in c-section babies.  

Asthma could be brought on by maternal diet and lack of bacterial metabolites

Asthma has become increasingly prevalent in Western societies, and while many theories have been explored as to the reason for this rise in prevalence, many are beginning to explore connections between dietary intake and associations with the microbiome as a manifestation for this malady.  High fat, low fiber diets – which are common in the West – are associated with high rates of asthma.  Investigators in Australia sought to explore this relationship further by understanding the cellular underpinnings of these associations.  Specifically, they explored whether or not high fiber diets in mice could suppress the onset of Allergenic airway disease (ADD -i.e. asthma).  Furthermore, maternal fiber intake was also examined to see what affects would result for the progeny when challenged with asthma inducing conditions.  They published the results in Nature Communications.

Using 16S sequencing the researchers first confirmed that the high fiber diet shaped gut microbiome composition in mice.  Specifically, a significant difference was observed between control diet and no fiber diet.  Bacteroidetes were highly abundant in mice that were fed the high fiber diet, including high acetate producing Bacteroides acidifaciens strain, while Proteobacteria were found abundant in the no fiber diet.  High fiber diet mice also displayed higher levels of short-chain fatty acids, metabolic products of the gut microbiota that provide overall positive health benefits. 

Turning next to the pathology, experimenters were first able to validate that HDM did indeed induce AAD, as confirmed by inflammatory cells and signal markers found in the bronchoalveolar fluid of mice.  Indeed, mice that were on the high fiber diet did not develop AAD symptoms.  Interestingly, this was also shown in control animals who were administered HDM but were provided acetate (a short-chain fatty acid) in their drinking water. 

Mice were then bred and split into three dietary groups based on diet, a control group, high fiber group, and no fiber group.  Allergenic airway disease (AAD) was induced using a house-dust mite (HDM) model which replicates certain aspects of human asthma.  Diets were provided three weeks prior to sensitizing the animals to HDM, and AAD was evaluated after 16 days following 15-day HDM exposure.

Pregnant mice were also subjected to the three different diet regiments in the previous experiment.  The offspring were born and given a control diet, but after 6 weeks they were administered AAD.  The mice that were born from mothers on the high fiber diet did not develop AAD into adulthood, demonstrating that maternal diet can suppress AAD in adult offspring.  Interestingly, these findings were correlated with human data that demonstrated that high fiber diets in mothers’ in late-stage pregnancy was correlated to high acetate in serum samples.  Maternal acetate levels above median levels of samples taken was associated with significantly less visits to the general practitioner for wheezing complaints and/or asthmatic incidences in their children.    

Increasing numbers of studies are showing similar patterns that behaviors of the mother can affect microbiome transfer to progeny, consequently affecting the health and development of the offspring.  One of these important factors as we have seen is the diet of the mother.  As further evidence is uncovered as to the importance of high fat diets and specifically the diet of the mother, it will be important to have conversations on the best way to educate the public about this evidence as well as implement recommendations for dietary habits during pregnancy. 

The nasal microbiome of infants may impact risk of developing asthma

Many lower respiratory illnesses have been shown to associate with specific lung, throat and nasal bacteria, but the role of the microbiome is still unclear, and mechanisms for the connection have yet to be proven.  Of particular interest is asthma, which affects around 7% of people in the US, and increases a person’s risk for many other conditions.  While it is normally diagnosed in toddlers, scientists believe that the groundwork for the disease is actually laid during infancy.  With that in mind, researchers in Australia performed the first longitudinal study of infants’ nasopharyngeal (nose and throat) during the first year of their lives, and tracked episodes of respiratory illness during that time.  They discovered a strong connection between the microbiome and respiratory illness, including asthma, and last month published their results in Cell Host and Microbe.

The researchers collected nasopharyngeal microbiome samples from 234 infants at different time points during their first year of life.  Most infants’ microbiomes were dominated by the following species: Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Alloiococcus otitidis.  Interestingly, this was true for infants regardless of birth delivery mode (i.e. cesarean or vaginal) as well as length of breast feeding.  In contrast, having a furry animal in the house tended to increase the abundance of Streptococcus, but having older siblings tended to decrease it.  In addition, there were strong seasonal effects on the microbiome, with Haemophilus being associated with the summer, and Moraxella the winter.  In children with respiratory illness, Haemophilus, Moraxella, and Streptococcus were most frequently measured, and Staphylococcus, Alloiococcus, and Corynebacterium least frequently measured.

When the scientists compared their results with the asthma outcomes of the children at 5 years old they noticed one significant trend.  Colonization by Streptococcus at around 2 months old, which was asymptomatic at the time and occurred in 14% of infants tested, was strongly connected to chronic wheezing (itself an indication of asthma) at 5 years old.  They suggest that the developing airways in infants may be especially vulnerable to Streptococcus.

This long term study does a really nice job of defining how the microbiome grows and develops in the airways of infants – something which previously hadn’t been performed at such a large scale.  While this study alone does not figure out exactly what the microbiome’s role is in childhood respiratory illnesses, it does provide a baseline for future studies to work off of.