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. 

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.

Using microbiome bacteria for cosmetics

Topical cosmetics are widely used for skin care, maintenance, and beauty.  There are entire industries dedicated to providing skin care products to a wide range of consumers, because for the most part, everyone desires healthy skin.  Scientifically speaking, skin is considered healthy if it effectively retains moisture, has a low surface acidity, and has good texture.  Many topical cosmetics act to augment or support these features.  Interestingly, researchers in Japan demonstrated that a microbiome bacterium can also provide these benefits to the skin, introducing the possibility of developing novel skin care therapy.

Staphylococcus epidermis has recently gained attention as a beneficial topical agent due its demonstrated skin care benefits.  Specifically, its metabolic products have been shown to enhance moisture retention and reduce surface acid levels.  Researchers investigated this by creating their own S. epidermidis topic gel and testing it on human subjects in a double-blind randomized study.  Skin was collected from the foreheads of 21 patients enrolled in this clinical trial.  Genetic analysis confirmed that S. epidermidis was removed from the skin.  Once isolated from other cells and bacteria, the S. epidermidis bacteria were cultured and lyophilized – or freeze dried – to preserve bacterial integrity.  The lyophilized S. epidermidis was then mixed in with a gel and continuously applied to patients’ faces in a double blind randomized clinical trial study that included a control population just receiving the gel, no bacteria. 

Patients who received the S. epidermidis had 1.4 times the amount of water in their skin after the trial was completed compared to before they started.  Additionally, a suppression of water evaporation on the skin surface was shown, concomitant to an increase in lipid content.  The increased lipid content was hypothesized to be a direct result of S. epidermidis metabolism, as the lipid metabolites provided an ample surface coat to keep moisture trapped on the skin surface.  Moreover, the S. epidermidis regiment also maintained a low acidic environment on the skin surface.

This study demonstrates S. epidermidis’s efficacy to support healthy skin.  Using certain microbiota as a topical agent is already being seen in practice, as Cambridge-based AOBiome are developing skin therapies using bacteria.  This unique approach has a lot of potential, and it will be interesting to see how bacteria can be used in this health arena.

New study suggests S. aureus and skin dysbioses cause eczema

Atopic dermatitis, also known as eczema, is a skin inflammation and rash that has an enigmatic cause.  There are many genetic and environmental risk factors involved, but to date the exact triggers and mechanisms that cause this autoimmune response are unknown.  Importantly, a growing percentage of infants and toddlers are developing this disease, which itself is a known risk factor for other autoimmune diseases like asthma and allergies.  Discovering the cause of atopic dermatitis is an important endeavor, because it may lead to a cure for a number of other diseases.

Staphylococcus aureus has long been associated with atopic dermatitis.  It appears to occur at relatively high abundances in the areas of skin that are affected.  Then again, S. aureus is a one of the most common skin microbiome bacteria (it is ubiquitous around the world), and it has yet to be definitively connected to the disease.  In addition, mouse models for many skin diseases, including this one, do not exist or are insufficient, so controllably studying the atopic dermatitis is difficult.  Recently though, a team of scientists from Japan and the NIH developed a mouse model for atopic dermatitis, and made a new discovery that showed S. aureus can indeed drive skin inflammation.  They published their results in Cell immunity.

The scientists were studying how a specific genetic mutation in mice affected bones and hair follicles when they serendipitously realized that it was causing eczema in the mice after around three weeks.  When they investigated the skin microbiomes of these mice, as well as normal mice, they realized that right around the time that the eczema was appearing in the mice, these mice’s skin microbiomes drastically shifted.  First, a bacterium called Corynebacterium mastitidis emerged, followed by S. aureus a few weeks later, which was coincident with the presentation of the worst symptoms.  Of note, species of Corynebacteria are associated with eczema in humans, much like S. aureus.

Next, the researchers then performed a series of experiments by providing mice with antibiotics in an effort to combat the dysbiosis.  When newborn mice with the genetic modification were treated with antibiotics they never developed eczema at all.  Moreover, genetically modified mice that were in the midst of the rash that were treated with antibiotics had their eczema subside soon after.  In addition, genetically modified mice that were taken off of antibiotics had eczema emerge shortly thereafter.  Strikingly, in all of the above situations changes in the skin microbiome corresponded with the disease state: a lack of S. aureus and high diversity were associated with healthy skin, and the emergence of S. aureus and a lack of diversity were associated with the disease.  Finally, when S. aureus was inoculated onto the skin of genetically modified mice, they developed eczema rapidly.

The researchers performed a number of other experiments to try and tease out the mechanism by which S. aureus causes atopic dermatitis.  Their results show that it appears a combination of genetic and environmental factors that affect the skin may be important in defining an individual’s risk for the disease.  Regardless, it appears that S. aureus is a major culprit in causing eczema, so future therapies that eradicate the bacteria, or at least decrease its abundance should be considered.

High salt diet mediates the skin immune response

Salt in our diet has been linked with all sorts of nasty side effects such as hypertension and autoimmune disease.  Researchers from Germany, though, wondered how Na+ in our diet may be affecting the skin microbiome, especially during infection.   Our skin is an important physiological barrier between our body and our microbiome, and because it is partially covered in organisms whenever we get a cut we are at risk for infection.  Fortunately our skin is actually loaded with immune cells that help destroy any of these organisms that may cause harm, and they mitigate the risk for infection.  The German researchers recently discovered that Na+ in our skin may actually be critical for our body to properly fight these infections.  The results were published in Cell Metabolism.

The scientists first infected the skin of both humans and mice with a eukaryotic organism called Leishmania major, which is a common skin pathogen primarily found in Northern Africa and the Middle East.  When they observed the infections using MRI they discovered that the local Na+ concentration around the infection increased in concentration.  They then showed that after treatment of the infection with antibiotics the local Na+ decreased.  

The scientists speculated that the Na+ was perhaps helping to fight the infections, so they designed an experiment to test this hypothesis.  They fed two groups of mice a high salt diet or a no salt diet.  Then they infected the mice with L. major.  They showed that after infection the mice that had not eaten salt struggled to clear the infection, while those that had eaten the high salt diet cleared the infection quickly.  The researchers performed a series of experiments on these mice to learn the actual mechanisms by which salt mediated the immune response, and learned that the Na+ activates and promotes certain immune cells in the skin.

This study shows an unexpected benefit to salt in the diet.  Interestingly, the salt content of our skin increases with age.  While this process has been linked to hypertension, perhaps it also helps fight bed sore infections and other types of skin infections that primarily afflict the elderly.     

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.