Helminths may increase sensitivity to insulin

Different helminth eggs

Countries that are becoming more exposed to Westernization have experienced many positive health impacts, such as decreases in infectious disease rates.  At the same time, however, there have been some negative consequences, such as increases in type 2 diabetes (T2DM) patients in these developing countries.  T2DM is linked to disruptions in energy balance and increases in systemic inflammation.  Interestingly, helminth infections – i.e., the parasitic worms that can reside in the intestines – have been previously shown to enhance glucose tolerance in animal models as well as induce anti-inflammatory immune responses.  Researchers sought to explore this relationship in humans, hypothesizing that insulin resistance is lower in subjects with soil-transmitted helminth infection. 

A homeostatic model assessment for insulin resistance (HOMAIR) test was used to examine insulin resistance in 646 adult study participants on Flores Island in Indonesia.  Soil-transmitted helminth (STH) infection is common on this island.  The HOMAIR model measures insulin in blood samples in a well-validated insulin-resistance assay.  Stool samples were also collected from the subjects, and microscopy and PCR were used to detect various helminth species. 

Of the 646 participants, 424 were STH-infected while 222 were not.  In the STH-infected cohort, participants were further categorized by how many different species were found.  Body mass index and waist to hip ratio were significantly lower in the STH-infected group, suggesting STH-infection may be beneficial toward glucose metabolism.  Furthermore, there was an association between the number of distinct STH species present and HOMAIR.  For every additional species found in a subject, there was an incremental decrease in homeostatic insulin resistance. 

These experiments display an interesting causal relationship between STH species and insulin resistance, however there were certainly limitations.  No association was found between subjects in systemic inflammation in infected versus non-infected groups, failing to elucidate modulations of inflammatory pathways that could be correlated with the observed trends.  Additionally, the changes in insulin resistance may be related to a change in body-mass index rather than helminth infection.  Specifically, participants located in more rural areas may have more active, healthier lifestyles, and would be subsequently leaner and thus more sensitive to insulin.  On top of this, patients with helminths tend to exhibit lower weight in general as these parasites significantly affect metabolism. 

Despite these limitations, this study points to an interesting relationship that is deserving of more examination.  This epidemiology research will impact global health policy and can offer good perspective as more nations around the world are on the path toward development.  

A population based study of S. aureus colonization in infants for atopic eczema

Atopic eczema (AE) is a skin condition that is often measured by transepidermal water loss (TEWL), a mark of dry skin. The ailment is often associated with the colonization of Staphylococcus aureus and dysfunction of the skin barrier (a few months ago we had a long blog post about atopic eczema and S. aureus so if you're interested in this topic, take a look at that post as well).  A group of scientists in Oslo set out to find if whether S. aureus colonization in the nasal cavity or the back of the mouth, the fauces, led to increased TEWL in healthy infants and those with eczema. They also set out to identify if TEWL on the upper arm and forearm provide similar associations between TEWL and atopic excema.

In the study published in PLoS One, 240 infants were enrolled and 167 of them met the requirements.  Three study groups were included, those with no eczema, those with possible eczema, and those with eczema. Three samples were taken from the upper arm as well as three samples from the lower forearm.

They found that TEWL measurements from the upper arm and lower forearm were equally appropriate which is important because measurements are generally taken from the lower forearm. Taking measurements is often difficult in these young infants so the ability to take measurements from the upper arm would be seen as an advance as it is more readily accessible.  

The scientists also found that while 53% of the infants in the study had S. aureus colonization in the back of the nose and back of the mouth, this was not associated with higher levels of TEWL or atopic eczema. This lack of association differs from previous studies (such as the one I linked earlier) that have shown correlations between S. aureus colonization and atopic eczema. Other human studies have also shown associations with S. aureus on the forehead and cheek and increased TEWL.

The reason for these discrepancies may arise from several different factors including age and sampling site.  Adults generally have lower TEWL than infants and this study sampled the bacteria in the nose and mouth while other studies sampled on the eczematous or normal skin directly. While this study does not show a correlation between S. aureus colonization in the mouth and nose with atopic eczema, more work is needed to better understand differences between these studies and what the role of this bacteria is on the condition.

Identifying probiotics using healthy individuals for preventing oral disease

The oral microbiome consists of many hundreds of species of bacteria, some harmful and some beneficial. The importance of a healthy microbiome should be stressed not only because having clean, white teeth looks good but because diseases like periodontitis increase risk of other issues such as respiratory infections and inflammatory diseases. Having unhealthy teeth can cause more systematic problems than you would think. Probiotics, different from antibiotics, are one way that microbiome science is combating the colonization of harmful bacteria in the body. Many researchers have investigated using probiotics to maintain a normal healthy oral microbiome, and in a new study published last week, scientists researched probiotics that may reduce the smell of “bad breath” that is caused by volatile sulfur compounds, and prevent cavities and periodontitis.

The study, performed by researchers at the Yakult Central Institute for Microbiological Research in Tokyo, Japan (a division of Yakult, the makers of yogurts and probiotics),  was aimed toward finding new potential probiotic candidates. Thirty-two volunteers were recruited and selected based on factors such as non-smoking habits, no large cavities or bleeding on probing, and no bad breath. Oral bacteria samples were taken from multiple specific locations in the mouth of the volunteers. The bacteria were cultured in a lab and tested for the characteristics that follow: lack of production of volatile sulfur compounds (causes bad breath) and water insoluble glucan (causes cavities), antibacterial activity against bacteria that cause periodontitis, ability to healthily adhere to teeth and cells in the mouth, and caused no infections in an artificial mouth system or in a rat model.

After culturing in a lab and testing the criteria on 896 oral samples from the 32 participants, the study found that Lactobacillus crispatus YIT 12319, L. fermentum  YIT 12320, L. gasseri YIT 12321, and Streptococcus mitis YIT 12322 are good candidates for probiotics.  The next step is to now test for these probiotics’ effects in the mouths of many people, and likely develop a product.  Interestingly, L. crispatus and L. gasseri are two of the major bacterial strains found in a healthy vaginal microbiome, and perhaps this suggests a route of access for these bacteria to access the vagina. In any case, the promise of new ways to help maintain a healthy oral microbiome is exciting, and it is encouraging to read papers from major companies that have the ability to actually manufacture products in this space.

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.

Episode 9 of The Microbiome Podcast: The skin microbiome and AOBiome with Dr. Larry Weiss

On the ninth episode of The Microbiome Podcast, we talked with Dr. Larry Weiss, Chief Medical Officer of AOBiome.  AOBiome is a leading company based in Cambridge, MA that is developing treatments for inflammatory skin conditions. They also have a cosmetic product on the market that consists of Ammonia Oxidizing Bacteria that the user applies to the skin twice a day. We discuss both the cosmetic product as well as AOBiome’s approach to treating skin conditions with Dr. Weiss. 

AOBiome is offering listeners of The Microbiome Podcast a 25% discount if you order their product before June 29th. The discount code is ami25. Click here to learn more about the product.

Also, as we discussed on last week’s podcast, the AMI is sponsoring a citizen science project where individuals can sequence their vaginal or penile microbiome. To be entered to win a free sampling, enter your information here. 

Remember to call in to ask any questions about the microbiome that you would like answered on future podcasts. The number is 518-945-8583. 

Listen to the podcast on our website, on iTunes, or on Stitcher. 

For more detailed shownotes, read below:

On this week’s podcast we discussed:

• (2:00) Ritter Pharmaceuticals, a microbiome pharmaceutical company that is working on an oral therapy for reducing lactose intolerance symptoms, filed for a $17 million IPO and is becoming a public company. Read more. 
• (2:30) Seres Health, a microbiome company working on a therapeutic for treating Clostridium difficile infection, also filed for an IPO for $100 million and received Breakthrough status from the FDA. Read more.
• (4:55) A study out of NYU found that wearing contact lenses altered the eye microbiome compared to non-contact wearers. Read the abstract. 
• (9:31) We talked a bit about AOBiome. Learn more about AOBiome. www.aobiome.com
• (11:17) Dr. Larry Weiss gave an overview of the skin microbiome and ammonia oxidizing bacteria.
• (13:22) An article out of NYU (led the same scientist who led the contact lens study) that studied a group of aboriginal Amerindians and found that they had perfect skin and still contained ammonia oxidizing bacteria on the skin. Read our blog post about the study. 
• (16:34) Dr. Weiss discussed the goals of AOBiome and how they are approaching the skin microbiome.
• (18:55) AOBiome’s cosmetic product that applies ammonia oxidizing bacteria to the skin. Learn more about the product. There is a discount code for our listeners for 25% off - ami25. 
• (26:00) Larry mentioned a Ted Talk about combatting smelly armpits. Watch the TED Talk. 
• (29:18) AOBiome’s therapeutic research areas and specifically acne.
• (32:25) Eczema and how the microbiome could be used to treat the condition.
• (39:15) Bacterial vaginosis and AOBiome’s approach to this infection.
• (42:51) Larry’s career going from a company called CleanWell, an antimicrobial company, to AOBiome, a company that administers bacteria to the body.
• (45:25) Hang hygiene and hand washing and Larry mentioned a study from the US Navy that found washing hands lowered the risk for getting a respiratory illness. Read the study.
• (50:16) On the aftershow, we discussed hand washing, whether we wear glasses or contacts, and Lebron James and the NBA finals.

The microbiome’s role in the immune system of the brain

A large body of evidence continues to support the microbiome’s role in interacting with the gut-brain axis.  Researchers in Germany recently investigated this relationship further by studying how host-microbiota can specifically influence the brain immune system of mice.  The researchers studied microglial cells, which are essentially the macrophages of the brain.  They patrol for pathogens, help maintain synaptic function, and play an important role in brain development.  Unlike macrophages that operate in our peripheral immune system, microglia cells operate behind the blood brain barrier and are thus subject to a different standard of biological rules.  Understanding how the microbiome interacts with this unique immune complex will shed light on this unique aspect to our body’s immunity. 

Twenty-four mice were divided into two groups; germ free (GF) mice and mice colonized with specific pathogen free (SPF) bacteria populations.  The researchers first measured microglial gene signatures and surface molecules between both groups.  The GF mice showed a marked contrast to SPF mice in expression of genes linked to microglial cell activation.  Molecular analysis also showed differences in surface protein expression between both groups, namely revealing that the GF mice had phenotypically immature microglial cells.  After these findings, researchers gave antibiotics to SPF mice to wipe out their microbial populations.  After a 4-week antibiotic regiment, the microglial cells were shown to be phenotypical similar to those of the GF mice, demonstrating crucial involvement of host-microbiota.   

Bacterial isolates were also characterized to search for trends in microbiota population versus immune response.  Overall examination concluded that limited complexity in species diversity was correlated with microglial immaturity.  Researchers also demonstrated that recolonizing microbiota populations in mice was able to restore microglial integrity.  Another unique experiment reinforced this finding.  Short-chain fatty acids, metabolic products of bacteria, were mixed in the drinking water of GF mice.  These additives were also shown to rescue the malformed microglia. 

The microbiome is an emerging field, but the immune system of the brain is an evolving topic as well.  The brain and CNS in general used to be considered as immune privileged, meaning antigen introductions do not trigger immune responses.  Although this definition is now considered incorrect, the brain is a unique tissue site with many interesting features, including the blood-brain barrier (mentioned above).  This experiment demonstrates that the microbiome interacts with this distinct physiological immune complex, and elucidating more mechanisms could lead to exciting new discoveries in the future.